Skip to main content
Top
Published in:

28-01-2025 | Buprenorphine | Review Article

Buprenorphine Pharmacodynamics: A Bridge to Understanding Buprenorphine Clinical Benefits

Author: Mellar Davis

Published in: Drugs | Issue 2/2025

Login to get access

Abstract

Buprenorphine is an agonist at the mu opioid receptor (MOR) and antagonist at the kappa (KOR) and delta (DOR) receptors and a nociceptin receptor (NOR) ligand. Buprenorphine has a relatively low intrinsic efficacy for G-proteins and a long brain and MOR dwell time. Buprenorphine ceiling on respiratory depression has theoretically been related multiple factors such as low intrinsic efficacy at MOR, binding to six-transmembrane MOR and interactions in MOR/NOR heterodimers. Buprenorphine reduces analgesic tolerance by acting as a delta opioid receptor (DOR) antagonist. As a kappa opioid receptor (KOR) antagonist, buprenorphine reduces craving associated with addiction. Buprenorphine is a model opioid for the ordinal bifunctional analogs BU10038, BU08028 which have been shown to be potent analgesics in non-human primates without reinforcing effects and little to no respiratory depression.
Literature
2.
go back to reference Cowan A, Lewis JW, Macfarlane IR. Agonist and antagonist properties of buprenorphine, a new antinociceptive agent. Br J Pharmacol. 1977;60(4):537–45.PubMedPubMedCentralCrossRef Cowan A, Lewis JW, Macfarlane IR. Agonist and antagonist properties of buprenorphine, a new antinociceptive agent. Br J Pharmacol. 1977;60(4):537–45.PubMedPubMedCentralCrossRef
3.
go back to reference Samways DSK. Clarifying intrinsic efficacy, partial agonism, and full agonism: the case of buprenorphine. Br J Anaesth. 2024;132(2):431–2.PubMedCrossRef Samways DSK. Clarifying intrinsic efficacy, partial agonism, and full agonism: the case of buprenorphine. Br J Anaesth. 2024;132(2):431–2.PubMedCrossRef
4.
go back to reference Cowan A. Buprenorphine: new pharmacological aspects. Int J Clin Pract Suppl. 2003;133:3–8 (discussion 23-4). Cowan A. Buprenorphine: new pharmacological aspects. Int J Clin Pract Suppl. 2003;133:3–8 (discussion 23-4).
5.
go back to reference Davis MP, Davies A, McPherson ML, Reddy A, Paice JA, Roeland E, et al. Opioid analgesic dose and route conversion ratio studies: a scoping review to inform an eDelphi guideline. Support Care Cancer. 2024;32(8):542.PubMedCrossRef Davis MP, Davies A, McPherson ML, Reddy A, Paice JA, Roeland E, et al. Opioid analgesic dose and route conversion ratio studies: a scoping review to inform an eDelphi guideline. Support Care Cancer. 2024;32(8):542.PubMedCrossRef
6.
go back to reference Kogel B, Christoph T, Strassburger W, Friderichs E. Interaction of mu-opioid receptor agonists and antagonists with the analgesic effect of buprenorphine in mice. Eur J Pain. 2005;9(5):599–611.PubMedCrossRef Kogel B, Christoph T, Strassburger W, Friderichs E. Interaction of mu-opioid receptor agonists and antagonists with the analgesic effect of buprenorphine in mice. Eur J Pain. 2005;9(5):599–611.PubMedCrossRef
7.
go back to reference Leng X, Li Z, Lv H, Zheng Y, Liu Y, Dai K, et al. Effectiveness and safety of transdermal buprenorphine versus sustained-release tramadol in patients with moderate to severe musculoskeletal pain: an 8-week, randomized, double-blind, double-dummy, multicenter, active-controlled, noninferiority study. Clin J Pain. 2015;31(7):612–20.PubMedCrossRef Leng X, Li Z, Lv H, Zheng Y, Liu Y, Dai K, et al. Effectiveness and safety of transdermal buprenorphine versus sustained-release tramadol in patients with moderate to severe musculoskeletal pain: an 8-week, randomized, double-blind, double-dummy, multicenter, active-controlled, noninferiority study. Clin J Pain. 2015;31(7):612–20.PubMedCrossRef
8.
go back to reference Naing C, Aung K, Racloz V, Yeoh PN. Safety and efficacy of transdermal buprenorphine for the relief of cancer pain. J Cancer Res Clin Oncol. 2013;139(12):1963–70.PubMedCrossRef Naing C, Aung K, Racloz V, Yeoh PN. Safety and efficacy of transdermal buprenorphine for the relief of cancer pain. J Cancer Res Clin Oncol. 2013;139(12):1963–70.PubMedCrossRef
9.
go back to reference Wolff RF, Aune D, Truyers C, Hernandez AV, Misso K, Riemsma R, et al. Systematic review of efficacy and safety of buprenorphine versus fentanyl or morphine in patients with chronic moderate to severe pain. Curr Med Res Opin. 2012;28(5):833–45.PubMedCrossRef Wolff RF, Aune D, Truyers C, Hernandez AV, Misso K, Riemsma R, et al. Systematic review of efficacy and safety of buprenorphine versus fentanyl or morphine in patients with chronic moderate to severe pain. Curr Med Res Opin. 2012;28(5):833–45.PubMedCrossRef
10.
go back to reference Magnelli F, Biondi L, Calabria R, Fiore A, Peluso E, Vonella D, et al. Safety and efficacy of buprenorphine/naloxone in opioid-dependent patients: an Italian observational study. Clin Drug Investig. 2010;30(Suppl 1):21–6.PubMedCrossRef Magnelli F, Biondi L, Calabria R, Fiore A, Peluso E, Vonella D, et al. Safety and efficacy of buprenorphine/naloxone in opioid-dependent patients: an Italian observational study. Clin Drug Investig. 2010;30(Suppl 1):21–6.PubMedCrossRef
11.
go back to reference Poulain P, Denier W, Douma J, Hoerauf K, Samija M, Sopata M, et al. Efficacy and safety of transdermal buprenorphine: a randomized, placebo-controlled trial in 289 patients with severe cancer pain. J Pain Symptom Manag. 2008;36(2):117–25.CrossRef Poulain P, Denier W, Douma J, Hoerauf K, Samija M, Sopata M, et al. Efficacy and safety of transdermal buprenorphine: a randomized, placebo-controlled trial in 289 patients with severe cancer pain. J Pain Symptom Manag. 2008;36(2):117–25.CrossRef
12.
go back to reference Likar R. Transdermal buprenorphine in the management of persistent pain - safety aspects. Ther Clin Risk Manag. 2006;2(1):115–25.PubMedPubMedCentral Likar R. Transdermal buprenorphine in the management of persistent pain - safety aspects. Ther Clin Risk Manag. 2006;2(1):115–25.PubMedPubMedCentral
13.
go back to reference Varey NC. The safety of buprenorphine (Temgesic). N Z Med J. 1990;103(882):24.PubMed Varey NC. The safety of buprenorphine (Temgesic). N Z Med J. 1990;103(882):24.PubMed
14.
go back to reference Aguilar B, Penm J, Liu S, Patanwala AE. Efficacy and safety of transdermal buprenorphine for acute postoperative pain: a systematic review and meta-analysis. J Pain. 2023;24(11):1905–14.PubMedCrossRef Aguilar B, Penm J, Liu S, Patanwala AE. Efficacy and safety of transdermal buprenorphine for acute postoperative pain: a systematic review and meta-analysis. J Pain. 2023;24(11):1905–14.PubMedCrossRef
15.
go back to reference Barutell C, Camba A, Gonzalez-Escalada JR, Rodriguez M, Opioid Group of the Spanish Society for the Study of P. High dose transdermal buprenorphine for moderate to severe pain in spanish pain centres—a retrospective multicenter safety and efficacy study. Pain Pract. 2008;8(5):355–61.PubMedCrossRef Barutell C, Camba A, Gonzalez-Escalada JR, Rodriguez M, Opioid Group of the Spanish Society for the Study of P. High dose transdermal buprenorphine for moderate to severe pain in spanish pain centres—a retrospective multicenter safety and efficacy study. Pain Pract. 2008;8(5):355–61.PubMedCrossRef
16.
go back to reference Bridge TP, Fudala PJ, Herbert S, Leiderman DB. Safety and health policy considerations related to the use of buprenorphine/naloxone as an office-based treatment for opiate dependence. Drug Alcohol Depend. 2003;70(2 Suppl):S79-85.PubMedCrossRef Bridge TP, Fudala PJ, Herbert S, Leiderman DB. Safety and health policy considerations related to the use of buprenorphine/naloxone as an office-based treatment for opiate dependence. Drug Alcohol Depend. 2003;70(2 Suppl):S79-85.PubMedCrossRef
17.
go back to reference Canneti A, Luzi M, Di Marco P, Cannata F, Pasqualitto F, Spinoglio A, et al. Safety and efficacy of transdermal buprenorphine and transdermal fentanyl in the treatment of neuropathic pain in AIDS patients. Minerva Anestesiol. 2013;79(8):871–83.PubMed Canneti A, Luzi M, Di Marco P, Cannata F, Pasqualitto F, Spinoglio A, et al. Safety and efficacy of transdermal buprenorphine and transdermal fentanyl in the treatment of neuropathic pain in AIDS patients. Minerva Anestesiol. 2013;79(8):871–83.PubMed
18.
go back to reference Frost M, Bailey GL, Lintzeris N, Strang J, Dunlop A, Nunes EV, et al. Long-term safety of a weekly and monthly subcutaneous buprenorphine depot (CAM2038) in the treatment of adult out-patients with opioid use disorder. Addiction. 2019;114(8):1416–26.PubMedPubMedCentralCrossRef Frost M, Bailey GL, Lintzeris N, Strang J, Dunlop A, Nunes EV, et al. Long-term safety of a weekly and monthly subcutaneous buprenorphine depot (CAM2038) in the treatment of adult out-patients with opioid use disorder. Addiction. 2019;114(8):1416–26.PubMedPubMedCentralCrossRef
19.
go back to reference Hale M, Urdaneta V, Kirby MT, Xiang Q, Rauck R. Long-term safety and analgesic efficacy of buprenorphine buccal film in patients with moderate-to-severe chronic pain requiring around-the-clock opioids. J Pain Res. 2017;10:233–40.PubMedPubMedCentralCrossRef Hale M, Urdaneta V, Kirby MT, Xiang Q, Rauck R. Long-term safety and analgesic efficacy of buprenorphine buccal film in patients with moderate-to-severe chronic pain requiring around-the-clock opioids. J Pain Res. 2017;10:233–40.PubMedPubMedCentralCrossRef
20.
go back to reference Hazle MC, Saxon AJ, Hill KP. Buprenorphine in safety-sensitive positions. Am J Drug Alcohol Abuse. 2022;48(3):255–9.PubMedCrossRef Hazle MC, Saxon AJ, Hill KP. Buprenorphine in safety-sensitive positions. Am J Drug Alcohol Abuse. 2022;48(3):255–9.PubMedCrossRef
21.
go back to reference Kamei J, Saitoh A, Suzuki T, Misawa M, Nagase H, Kasuya Y. Buprenorphine exerts its antinociceptive activity via mu 1-opioid receptors. Life Sci. 1995;56(15):PL285–90.PubMedCrossRef Kamei J, Saitoh A, Suzuki T, Misawa M, Nagase H, Kasuya Y. Buprenorphine exerts its antinociceptive activity via mu 1-opioid receptors. Life Sci. 1995;56(15):PL285–90.PubMedCrossRef
22.
go back to reference Walsh SL, Preston KL, Stitzer ML, Cone EJ, Bigelow GE. Clinical pharmacology of buprenorphine: ceiling effects at high doses. Clin Pharmacol Ther. 1994;55(5):569–80.PubMedCrossRef Walsh SL, Preston KL, Stitzer ML, Cone EJ, Bigelow GE. Clinical pharmacology of buprenorphine: ceiling effects at high doses. Clin Pharmacol Ther. 1994;55(5):569–80.PubMedCrossRef
23.
go back to reference Bhivandkar S, Sarfraz Z, Jain L, Bachu A, Malo PK, Hsu M, et al. Therapeutic potential of buprenorphine in depression: a meta-analysis of current evidence. J Clin Med Res. 2024;16(2–3):46–55.PubMedPubMedCentralCrossRef Bhivandkar S, Sarfraz Z, Jain L, Bachu A, Malo PK, Hsu M, et al. Therapeutic potential of buprenorphine in depression: a meta-analysis of current evidence. J Clin Med Res. 2024;16(2–3):46–55.PubMedPubMedCentralCrossRef
24.
go back to reference Johnson RE, Fudala PJ, Payne R. Buprenorphine: considerations for pain management. J Pain Symptom Manag. 2005;29(3):297–326.CrossRef Johnson RE, Fudala PJ, Payne R. Buprenorphine: considerations for pain management. J Pain Symptom Manag. 2005;29(3):297–326.CrossRef
25.
go back to reference Del Pozo B, Atkins D, Andraka-Christou B, Wightman R, Clark MH, Huynh P, et al. Buprenorphine involvement in opioid overdose deaths: a retrospective analysis of postmortem toxicology in Marion County, Indiana, 2015–2021. Drug Alcohol Depend Rep. 2023;6:100131.PubMedPubMedCentralCrossRef Del Pozo B, Atkins D, Andraka-Christou B, Wightman R, Clark MH, Huynh P, et al. Buprenorphine involvement in opioid overdose deaths: a retrospective analysis of postmortem toxicology in Marion County, Indiana, 2015–2021. Drug Alcohol Depend Rep. 2023;6:100131.PubMedPubMedCentralCrossRef
26.
go back to reference Villiger JW, Taylor KM. Buprenorphine: high-affinity binding to dorsal spinal cord. J Neurochem. 1982;38(6):1771–3.PubMedCrossRef Villiger JW, Taylor KM. Buprenorphine: high-affinity binding to dorsal spinal cord. J Neurochem. 1982;38(6):1771–3.PubMedCrossRef
27.
go back to reference Villiger JW, Taylor KM. Buprenorphine : characteristics of binding sites in the rat central nervous system. Life Sci. 1981;29(26):2699–708.PubMedCrossRef Villiger JW, Taylor KM. Buprenorphine : characteristics of binding sites in the rat central nervous system. Life Sci. 1981;29(26):2699–708.PubMedCrossRef
28.
go back to reference Boas RA, Villiger JW. Clinical actions of fentanyl and buprenorphine. The significance of receptor binding. Br J Anaesth. 1985;57(2):192–6.PubMedCrossRef Boas RA, Villiger JW. Clinical actions of fentanyl and buprenorphine. The significance of receptor binding. Br J Anaesth. 1985;57(2):192–6.PubMedCrossRef
29.
go back to reference Bidlack JM, Knapp BI, Deaver DR, Plotnikava M, Arnelle D, Wonsey AM, et al. In vitro pharmacological characterization of buprenorphine, samidorphan, and combinations being developed as an adjunctive treatment of major depressive disorder. J Pharmacol Exp Ther. 2018;367(2):267–81.PubMedCrossRef Bidlack JM, Knapp BI, Deaver DR, Plotnikava M, Arnelle D, Wonsey AM, et al. In vitro pharmacological characterization of buprenorphine, samidorphan, and combinations being developed as an adjunctive treatment of major depressive disorder. J Pharmacol Exp Ther. 2018;367(2):267–81.PubMedCrossRef
30.
go back to reference Zamani N, Buckley NA, Hassanian-Moghaddam H. Buprenorphine to reverse respiratory depression from methadone overdose in opioid-dependent patients: a prospective randomized trial. Crit Care. 2020;24(1):44.PubMedPubMedCentralCrossRef Zamani N, Buckley NA, Hassanian-Moghaddam H. Buprenorphine to reverse respiratory depression from methadone overdose in opioid-dependent patients: a prospective randomized trial. Crit Care. 2020;24(1):44.PubMedPubMedCentralCrossRef
31.
go back to reference Zamani N, Hassanian-Moghaddam H. Intravenous buprenorphine: a substitute for naloxone in methadone-overdosed patients? Ann Emerg Med. 2017;69(6):737–9.PubMedCrossRef Zamani N, Hassanian-Moghaddam H. Intravenous buprenorphine: a substitute for naloxone in methadone-overdosed patients? Ann Emerg Med. 2017;69(6):737–9.PubMedCrossRef
32.
go back to reference Zamani N, Hassanian-Moghaddam H, Bayat AH, Haghparast A, Shadnia S, Rahimi M, et al. Reversal of opioid overdose syndrome in morphine-dependent rats using buprenorphine. Toxicol Lett. 2015;232(3):590–4.PubMedCrossRef Zamani N, Hassanian-Moghaddam H, Bayat AH, Haghparast A, Shadnia S, Rahimi M, et al. Reversal of opioid overdose syndrome in morphine-dependent rats using buprenorphine. Toxicol Lett. 2015;232(3):590–4.PubMedCrossRef
33.
go back to reference Olofsen E, Algera MH, Moss L, Dobbins RL, Groeneveld GJ, van Velzen M, et al. Modeling buprenorphine reduction of fentanyl-induced respiratory depression. JCI Insight. 2022;7(9):e156973.PubMedPubMedCentralCrossRef Olofsen E, Algera MH, Moss L, Dobbins RL, Groeneveld GJ, van Velzen M, et al. Modeling buprenorphine reduction of fentanyl-induced respiratory depression. JCI Insight. 2022;7(9):e156973.PubMedPubMedCentralCrossRef
34.
go back to reference Yassen A, Olofsen E, Kan J, Dahan A, Danhof M. Pharmacokinetic-pharmacodynamic modeling of the effectiveness and safety of buprenorphine and fentanyl in rats. Pharm Res. 2008;25(1):183–93.PubMedCrossRef Yassen A, Olofsen E, Kan J, Dahan A, Danhof M. Pharmacokinetic-pharmacodynamic modeling of the effectiveness and safety of buprenorphine and fentanyl in rats. Pharm Res. 2008;25(1):183–93.PubMedCrossRef
35.
go back to reference Yassen A, Olofsen E, Romberg R, Sarton E, Teppema L, Danhof M, et al. Mechanism-based PK/PD modeling of the respiratory depressant effect of buprenorphine and fentanyl in healthy volunteers. Clin Pharmacol Ther. 2007;81(1):50–8.PubMedCrossRef Yassen A, Olofsen E, Romberg R, Sarton E, Teppema L, Danhof M, et al. Mechanism-based PK/PD modeling of the respiratory depressant effect of buprenorphine and fentanyl in healthy volunteers. Clin Pharmacol Ther. 2007;81(1):50–8.PubMedCrossRef
36.
go back to reference Oakley B, Wilson H, Hayes V, Lintzeris N. Managing opioid withdrawal precipitated by buprenorphine with buprenorphine. Drug Alcohol Rev. 2021;40(4):567–71.PubMedPubMedCentralCrossRef Oakley B, Wilson H, Hayes V, Lintzeris N. Managing opioid withdrawal precipitated by buprenorphine with buprenorphine. Drug Alcohol Rev. 2021;40(4):567–71.PubMedPubMedCentralCrossRef
37.
go back to reference Quattlebaum THN, Kiyokawa M, Murata KA. A case of buprenorphine-precipitated withdrawal managed with high-dose buprenorphine. Fam Pract. 2022;39(2):292–4.PubMedCrossRef Quattlebaum THN, Kiyokawa M, Murata KA. A case of buprenorphine-precipitated withdrawal managed with high-dose buprenorphine. Fam Pract. 2022;39(2):292–4.PubMedCrossRef
38.
go back to reference Brogdon H, Facer KL, Cox EJ, Carlson RH Jr, Wurzel JF 3rd. Rapid transition to buprenorphine in a patient with methadone-related QTc interval prolongation. J Addict Med. 2022;16(4):488–91.PubMedCrossRef Brogdon H, Facer KL, Cox EJ, Carlson RH Jr, Wurzel JF 3rd. Rapid transition to buprenorphine in a patient with methadone-related QTc interval prolongation. J Addict Med. 2022;16(4):488–91.PubMedCrossRef
39.
go back to reference Urban V, Sullivan R. Buprenorphine rescue from naltrexone-induced opioid withdrawal during relatively rapid detoxification from high-dose methadone: a novel approach. Psychiatry (Edgmont). 2008;5(4):56–8.PubMed Urban V, Sullivan R. Buprenorphine rescue from naltrexone-induced opioid withdrawal during relatively rapid detoxification from high-dose methadone: a novel approach. Psychiatry (Edgmont). 2008;5(4):56–8.PubMed
40.
go back to reference Ward HB, Barnett BS, Suzuki J. Rapid transition from methadone to buprenorphine using naltrexone-induced withdrawal: a case report. Subst Abus. 2019;40(2):140–5.PubMedPubMedCentralCrossRef Ward HB, Barnett BS, Suzuki J. Rapid transition from methadone to buprenorphine using naltrexone-induced withdrawal: a case report. Subst Abus. 2019;40(2):140–5.PubMedPubMedCentralCrossRef
41.
go back to reference Randall A, Hull I, Martin SA. Enhancing patient choice: using self-administered intranasal naloxone for novel rapid buprenorphine initiation. J Addict Med. 2023;17(2):237–40.PubMedCrossRef Randall A, Hull I, Martin SA. Enhancing patient choice: using self-administered intranasal naloxone for novel rapid buprenorphine initiation. J Addict Med. 2023;17(2):237–40.PubMedCrossRef
42.
go back to reference Hamata B, Griesdale D, Hann J, Rezazadeh-Azar P. Rapid micro-induction of buprenorphine/naloxone for opioid use disorder in a critically ill intubated patient: a case report. J Addict Med. 2020;14(6):514–7.PubMedCrossRef Hamata B, Griesdale D, Hann J, Rezazadeh-Azar P. Rapid micro-induction of buprenorphine/naloxone for opioid use disorder in a critically ill intubated patient: a case report. J Addict Med. 2020;14(6):514–7.PubMedCrossRef
43.
go back to reference Lee DS, Hann JE, Klaire SS, Nikoo M, Negraeff MD, Rezazadeh-Azar P. Rapid induction of buprenorphine/naloxone for chronic pain using a microdosing regimen: a case report. A A Pract. 2020;14(2):44–7.PubMedPubMedCentralCrossRef Lee DS, Hann JE, Klaire SS, Nikoo M, Negraeff MD, Rezazadeh-Azar P. Rapid induction of buprenorphine/naloxone for chronic pain using a microdosing regimen: a case report. A A Pract. 2020;14(2):44–7.PubMedPubMedCentralCrossRef
44.
go back to reference Tzschentke TM. Behavioral pharmacology of buprenorphine, with a focus on preclinical models of reward and addiction. Psychopharmacology. 2002;161(1):1–16.PubMedCrossRef Tzschentke TM. Behavioral pharmacology of buprenorphine, with a focus on preclinical models of reward and addiction. Psychopharmacology. 2002;161(1):1–16.PubMedCrossRef
45.
go back to reference Spreen LA, Dittmar EN, Quirk KC, Smith MA. Buprenorphine initiation strategies for opioid use disorder and pain management: a systematic review. Pharmacotherapy. 2022;42(5):411–27.PubMedPubMedCentralCrossRef Spreen LA, Dittmar EN, Quirk KC, Smith MA. Buprenorphine initiation strategies for opioid use disorder and pain management: a systematic review. Pharmacotherapy. 2022;42(5):411–27.PubMedPubMedCentralCrossRef
46.
go back to reference Quirk K, Stevenson M. Buprenorphine microdosing for the pain and palliative care clinician. J Palliat Med. 2022;25(1):145–54.PubMedCrossRef Quirk K, Stevenson M. Buprenorphine microdosing for the pain and palliative care clinician. J Palliat Med. 2022;25(1):145–54.PubMedCrossRef
47.
49.
go back to reference Goldfrank L, Weisman RS, Errick JK, Lo MW. A dosing nomogram for continuous infusion intravenous naloxone. Ann Emerg Med. 1986;15(5):566–70.PubMedCrossRef Goldfrank L, Weisman RS, Errick JK, Lo MW. A dosing nomogram for continuous infusion intravenous naloxone. Ann Emerg Med. 1986;15(5):566–70.PubMedCrossRef
50.
go back to reference Pallasch TJ, Gill CJ. Naloxone-associated morbidity and mortality. Oral Surg Oral Med Oral Pathol. 1981;52(6):602–3.PubMedCrossRef Pallasch TJ, Gill CJ. Naloxone-associated morbidity and mortality. Oral Surg Oral Med Oral Pathol. 1981;52(6):602–3.PubMedCrossRef
51.
go back to reference Huang P, Chen C, Mague SD, Blendy JA, Liu-Chen LY. A common single nucleotide polymorphism A118G of the mu opioid receptor alters its N-glycosylation and protein stability. Biochem J. 2012;441(1):379–86.PubMedCrossRef Huang P, Chen C, Mague SD, Blendy JA, Liu-Chen LY. A common single nucleotide polymorphism A118G of the mu opioid receptor alters its N-glycosylation and protein stability. Biochem J. 2012;441(1):379–86.PubMedCrossRef
52.
go back to reference Mura E, Govoni S, Racchi M, Carossa V, Ranzani GN, Allegri M, et al. Consequences of the 118A>G polymorphism in the OPRM1 gene: translation from bench to bedside? J Pain Res. 2013;6:331–53.PubMedPubMedCentralCrossRef Mura E, Govoni S, Racchi M, Carossa V, Ranzani GN, Allegri M, et al. Consequences of the 118A>G polymorphism in the OPRM1 gene: translation from bench to bedside? J Pain Res. 2013;6:331–53.PubMedPubMedCentralCrossRef
53.
go back to reference Meaden CW, Mozeika A, Asri R, Santos CD. A review of the existing literature on buprenorphine pharmacogenomics. Pharmacogenomics J. 2021;21(2):128–39.PubMedCrossRef Meaden CW, Mozeika A, Asri R, Santos CD. A review of the existing literature on buprenorphine pharmacogenomics. Pharmacogenomics J. 2021;21(2):128–39.PubMedCrossRef
54.
go back to reference Marrone GF, Grinnell SG, Lu Z, Rossi GC, Le Rouzic V, Xu J, et al. Truncated mu opioid GPCR variant involvement in opioid-dependent and opioid-independent pain modulatory systems within the CNS. Proc Natl Acad Sci USA. 2016;113(13):3663–8.PubMedPubMedCentralCrossRef Marrone GF, Grinnell SG, Lu Z, Rossi GC, Le Rouzic V, Xu J, et al. Truncated mu opioid GPCR variant involvement in opioid-dependent and opioid-independent pain modulatory systems within the CNS. Proc Natl Acad Sci USA. 2016;113(13):3663–8.PubMedPubMedCentralCrossRef
55.
go back to reference Grinnell SG, Ansonoff M, Marrone GF, Lu Z, Narayan A, Xu J, et al. Mediation of buprenorphine analgesia by a combination of traditional and truncated mu opioid receptor splice variants. Synapse. 2016;70(10):395–407.PubMedPubMedCentralCrossRef Grinnell SG, Ansonoff M, Marrone GF, Lu Z, Narayan A, Xu J, et al. Mediation of buprenorphine analgesia by a combination of traditional and truncated mu opioid receptor splice variants. Synapse. 2016;70(10):395–407.PubMedPubMedCentralCrossRef
56.
go back to reference Majumdar S, Grinnell S, Le Rouzic V, Burgman M, Polikar L, Ansonoff M, et al. Truncated G protein-coupled mu opioid receptor MOR-1 splice variants are targets for highly potent opioid analgesics lacking side effects. Proc Natl Acad Sci USA. 2011;108(49):19778–83.PubMedPubMedCentralCrossRef Majumdar S, Grinnell S, Le Rouzic V, Burgman M, Polikar L, Ansonoff M, et al. Truncated G protein-coupled mu opioid receptor MOR-1 splice variants are targets for highly potent opioid analgesics lacking side effects. Proc Natl Acad Sci USA. 2011;108(49):19778–83.PubMedPubMedCentralCrossRef
57.
go back to reference Islam A, Rahman MA, Brenner MB, Moore A, Kellmyer A, Buechler HM, et al. Abuse liability, anti-nociceptive, and discriminative stimulus properties of IBNtxA. ACS Pharmacol Transl Sci. 2020;3(5):907–20.PubMedPubMedCentralCrossRef Islam A, Rahman MA, Brenner MB, Moore A, Kellmyer A, Buechler HM, et al. Abuse liability, anti-nociceptive, and discriminative stimulus properties of IBNtxA. ACS Pharmacol Transl Sci. 2020;3(5):907–20.PubMedPubMedCentralCrossRef
58.
go back to reference Zaki PA, Keith DE Jr, Brine GA, Carroll FI, Evans CJ. Ligand-induced changes in surface mu-opioid receptor number: relationship to G protein activation? J Pharmacol Exp Ther. 2000;292(3):1127–34.PubMedCrossRef Zaki PA, Keith DE Jr, Brine GA, Carroll FI, Evans CJ. Ligand-induced changes in surface mu-opioid receptor number: relationship to G protein activation? J Pharmacol Exp Ther. 2000;292(3):1127–34.PubMedCrossRef
59.
go back to reference Sittl R, Nuijten M, Nautrup BP. Changes in the prescribed daily doses of transdermal fentanyl and transdermal buprenorphine during treatment of patients with cancer and noncancer pain in Germany: results of a retrospective cohort study. Clin Ther. 2005;27(7):1022–31.PubMedCrossRef Sittl R, Nuijten M, Nautrup BP. Changes in the prescribed daily doses of transdermal fentanyl and transdermal buprenorphine during treatment of patients with cancer and noncancer pain in Germany: results of a retrospective cohort study. Clin Ther. 2005;27(7):1022–31.PubMedCrossRef
60.
go back to reference Sittl R, Likar R, Nautrup BP. Equipotent doses of transdermal fentanyl and transdermal buprenorphine in patients with cancer and noncancer pain: results of a retrospective cohort study. Clin Ther. 2005;27(2):225–37.PubMedCrossRef Sittl R, Likar R, Nautrup BP. Equipotent doses of transdermal fentanyl and transdermal buprenorphine in patients with cancer and noncancer pain: results of a retrospective cohort study. Clin Ther. 2005;27(2):225–37.PubMedCrossRef
61.
go back to reference Zhang T, Xu J, Pan YX. A Truncated six transmembrane splice variant MOR-1G enhances expression of the full-length seven transmembrane mu-opioid receptor through heterodimerization. Mol Pharmacol. 2020;98(4):518–27.PubMedPubMedCentralCrossRef Zhang T, Xu J, Pan YX. A Truncated six transmembrane splice variant MOR-1G enhances expression of the full-length seven transmembrane mu-opioid receptor through heterodimerization. Mol Pharmacol. 2020;98(4):518–27.PubMedPubMedCentralCrossRef
62.
go back to reference Singleton S, Dieterle C, Walker DJ, Runeberg T, Oswald AS, Rosenqvist G, et al. Activation of mu receptors by SR-17018 through a distinctive mechanism. Neuropharmacology. 2024;258: 110093.PubMedCrossRef Singleton S, Dieterle C, Walker DJ, Runeberg T, Oswald AS, Rosenqvist G, et al. Activation of mu receptors by SR-17018 through a distinctive mechanism. Neuropharmacology. 2024;258: 110093.PubMedCrossRef
63.
go back to reference Singleton S, Baptista-Hon DT, Edelsten E, McCaughey KS, Camplisson E, Hales TG. TRV130 partial agonism and capacity to induce anti-nociceptive tolerance revealed through reducing available mu-opioid receptor number. Br J Pharmacol. 2021;178(8):1855–68.PubMedCrossRef Singleton S, Baptista-Hon DT, Edelsten E, McCaughey KS, Camplisson E, Hales TG. TRV130 partial agonism and capacity to induce anti-nociceptive tolerance revealed through reducing available mu-opioid receptor number. Br J Pharmacol. 2021;178(8):1855–68.PubMedCrossRef
65.
go back to reference Neubig RR, Spedding M, Kenakin T, Christopoulos A, International Union of Pharmacology Committee on Receptor N, Drug C. International Union of Pharmacology Committee on receptor nomenclature and drug classification. XXXVIII. Update on terms and symbols in quantitative pharmacology. Pharmacol Rev. 2003;55(4):597–606.PubMedCrossRef Neubig RR, Spedding M, Kenakin T, Christopoulos A, International Union of Pharmacology Committee on Receptor N, Drug C. International Union of Pharmacology Committee on receptor nomenclature and drug classification. XXXVIII. Update on terms and symbols in quantitative pharmacology. Pharmacol Rev. 2003;55(4):597–606.PubMedCrossRef
66.
go back to reference Lee KO, Akil H, Woods JH, Traynor JR. Differential binding properties of oripavines at cloned mu- and delta-opioid receptors. Eur J Pharmacol. 1999;378(3):323–30.PubMedCrossRef Lee KO, Akil H, Woods JH, Traynor JR. Differential binding properties of oripavines at cloned mu- and delta-opioid receptors. Eur J Pharmacol. 1999;378(3):323–30.PubMedCrossRef
67.
go back to reference Traynor JR, Nahorski SR. Modulation by mu-opioid agonists of guanosine-5’-O-(3-[35S]thio)triphosphate binding to membranes from human neuroblastoma SH-SY5Y cells. Mol Pharmacol. 1995;47(4):848–54.PubMedCrossRef Traynor JR, Nahorski SR. Modulation by mu-opioid agonists of guanosine-5’-O-(3-[35S]thio)triphosphate binding to membranes from human neuroblastoma SH-SY5Y cells. Mol Pharmacol. 1995;47(4):848–54.PubMedCrossRef
68.
go back to reference Selley DE, Liu Q, Childers SR. Signal transduction correlates of mu opioid agonist intrinsic efficacy: receptor-stimulated [35S]GTP gamma S binding in mMOR-CHO cells and rat thalamus. J Pharmacol Exp Ther. 1998;285(2):496–505.PubMedCrossRef Selley DE, Liu Q, Childers SR. Signal transduction correlates of mu opioid agonist intrinsic efficacy: receptor-stimulated [35S]GTP gamma S binding in mMOR-CHO cells and rat thalamus. J Pharmacol Exp Ther. 1998;285(2):496–505.PubMedCrossRef
69.
go back to reference Huang P, Kehner GB, Cowan A, Liu-Chen LY. Comparison of pharmacological activities of buprenorphine and norbuprenorphine: norbuprenorphine is a potent opioid agonist. J Pharmacol Exp Ther. 2001;297(2):688–95.PubMedCrossRef Huang P, Kehner GB, Cowan A, Liu-Chen LY. Comparison of pharmacological activities of buprenorphine and norbuprenorphine: norbuprenorphine is a potent opioid agonist. J Pharmacol Exp Ther. 2001;297(2):688–95.PubMedCrossRef
70.
go back to reference Raynor K, Kong H, Mestek A, Bye LS, Tian M, Liu J, et al. Characterization of the cloned human mu opioid receptor. J Pharmacol Exp Ther. 1995;272(1):423–8.PubMedCrossRef Raynor K, Kong H, Mestek A, Bye LS, Tian M, Liu J, et al. Characterization of the cloned human mu opioid receptor. J Pharmacol Exp Ther. 1995;272(1):423–8.PubMedCrossRef
71.
go back to reference Blake AD, Bot G, Freeman JC, Reisine T. Differential opioid agonist regulation of the mouse mu opioid receptor. J Biol Chem. 1997;272(2):782–90.PubMedCrossRef Blake AD, Bot G, Freeman JC, Reisine T. Differential opioid agonist regulation of the mouse mu opioid receptor. J Biol Chem. 1997;272(2):782–90.PubMedCrossRef
72.
go back to reference Sanchez-Blazquez P, Rodriguez-Diaz M, DeAntonio I, Garzon J. Endomorphin-1 and endomorphin-2 show differences in their activation of mu opioid receptor-regulated G proteins in supraspinal antinociception in mice. J Pharmacol Exp Ther. 1999;291(1):12–8.PubMedCrossRef Sanchez-Blazquez P, Rodriguez-Diaz M, DeAntonio I, Garzon J. Endomorphin-1 and endomorphin-2 show differences in their activation of mu opioid receptor-regulated G proteins in supraspinal antinociception in mice. J Pharmacol Exp Ther. 1999;291(1):12–8.PubMedCrossRef
73.
go back to reference Sanchez-Blazquez P, Gomez-Serranillos P, Garzon J. Agonists determine the pattern of G-protein activation in mu-opioid receptor-mediated supraspinal analgesia. Brain Res Bull. 2001;54(2):229–35.PubMedCrossRef Sanchez-Blazquez P, Gomez-Serranillos P, Garzon J. Agonists determine the pattern of G-protein activation in mu-opioid receptor-mediated supraspinal analgesia. Brain Res Bull. 2001;54(2):229–35.PubMedCrossRef
74.
go back to reference Wheeler-Aceto H, Cowan A. Buprenorphine and morphine cause antinociception by different transduction mechanisms. Eur J Pharmacol. 1991;195(3):411–3.PubMedCrossRef Wheeler-Aceto H, Cowan A. Buprenorphine and morphine cause antinociception by different transduction mechanisms. Eur J Pharmacol. 1991;195(3):411–3.PubMedCrossRef
75.
go back to reference Saidak Z, Blake-Palmer K, Hay DL, Northup JK, Glass M. Differential activation of G-proteins by mu-opioid receptor agonists. Br J Pharmacol. 2006;147(6):671–80.PubMedPubMedCentralCrossRef Saidak Z, Blake-Palmer K, Hay DL, Northup JK, Glass M. Differential activation of G-proteins by mu-opioid receptor agonists. Br J Pharmacol. 2006;147(6):671–80.PubMedPubMedCentralCrossRef
76.
go back to reference Sutcliffe KJ, Henderson G, Kelly E, Sessions RB. Drug binding poses relate structure with efficacy in the mu opioid receptor. J Mol Biol. 2017;429(12):1840–51.PubMedPubMedCentralCrossRef Sutcliffe KJ, Henderson G, Kelly E, Sessions RB. Drug binding poses relate structure with efficacy in the mu opioid receptor. J Mol Biol. 2017;429(12):1840–51.PubMedPubMedCentralCrossRef
77.
go back to reference Mercadante S, Porzio G, Fulfaro F, Aielli F, Verna L, Ficorella C, et al. Switching from transdermal drugs: an observational “N of 1” study of fentanyl and buprenorphine. J Pain Symptom Manag. 2007;34(5):532–8.CrossRef Mercadante S, Porzio G, Fulfaro F, Aielli F, Verna L, Ficorella C, et al. Switching from transdermal drugs: an observational “N of 1” study of fentanyl and buprenorphine. J Pain Symptom Manag. 2007;34(5):532–8.CrossRef
78.
go back to reference Skaer TL. Dosing considerations with transdermal formulations of fentanyl and buprenorphine for the treatment of cancer pain. J Pain Res. 2014;7:495–503.PubMedPubMedCentralCrossRef Skaer TL. Dosing considerations with transdermal formulations of fentanyl and buprenorphine for the treatment of cancer pain. J Pain Res. 2014;7:495–503.PubMedPubMedCentralCrossRef
79.
go back to reference Benredjem B, Gallion J, Pelletier D, Dallaire P, Charbonneau J, Cawkill D, et al. Exploring use of unsupervised clustering to associate signaling profiles of GPCR ligands to clinical response. Nat Commun. 2019;10(1):4075.PubMedPubMedCentralCrossRef Benredjem B, Gallion J, Pelletier D, Dallaire P, Charbonneau J, Cawkill D, et al. Exploring use of unsupervised clustering to associate signaling profiles of GPCR ligands to clinical response. Nat Commun. 2019;10(1):4075.PubMedPubMedCentralCrossRef
80.
go back to reference Onfroy L, Galandrin S, Pontier SM, Seguelas MH, N’Guyen D, Senard JM, et al. G protein stoichiometry dictates biased agonism through distinct receptor-G protein partitioning. Sci Rep. 2017;7(1):7885.PubMedPubMedCentralCrossRef Onfroy L, Galandrin S, Pontier SM, Seguelas MH, N’Guyen D, Senard JM, et al. G protein stoichiometry dictates biased agonism through distinct receptor-G protein partitioning. Sci Rep. 2017;7(1):7885.PubMedPubMedCentralCrossRef
81.
go back to reference Montandon G, Ren J, Victoria NC, Liu H, Wickman K, Greer JJ, et al. G-protein-gated inwardly rectifying potassium channels modulate respiratory depression by opioids. Anesthesiology. 2016;124(3):641–50.PubMedCrossRef Montandon G, Ren J, Victoria NC, Liu H, Wickman K, Greer JJ, et al. G-protein-gated inwardly rectifying potassium channels modulate respiratory depression by opioids. Anesthesiology. 2016;124(3):641–50.PubMedCrossRef
82.
go back to reference Bettinger J, Batista Quevedo H, Cleary J. Emerging pharmacologic mechanisms of buprenorphine to explain experience of analgesia versus adverse effects. J Opioid Manag. 2021;17(7):21–31.PubMedCrossRef Bettinger J, Batista Quevedo H, Cleary J. Emerging pharmacologic mechanisms of buprenorphine to explain experience of analgesia versus adverse effects. J Opioid Manag. 2021;17(7):21–31.PubMedCrossRef
83.
go back to reference Qu Q, Huang W, Aydin D, Paggi JM, Seven AB, Wang H, et al. Insights into distinct signaling profiles of the microOR activated by diverse agonists. Nat Chem Biol. 2023;19(4):423–30.PubMedCrossRef Qu Q, Huang W, Aydin D, Paggi JM, Seven AB, Wang H, et al. Insights into distinct signaling profiles of the microOR activated by diverse agonists. Nat Chem Biol. 2023;19(4):423–30.PubMedCrossRef
84.
85.
go back to reference Chavkin C, Goldstein A. Opioid receptor reserve in normal and morphine-tolerant guinea pig ileum myenteric plexus. Proc Natl Acad Sci USA. 1984;81(22):7253–7.PubMedPubMedCentralCrossRef Chavkin C, Goldstein A. Opioid receptor reserve in normal and morphine-tolerant guinea pig ileum myenteric plexus. Proc Natl Acad Sci USA. 1984;81(22):7253–7.PubMedPubMedCentralCrossRef
86.
go back to reference Baptista-Hon DT, Smith M, Singleton S, Antonides LH, Nic Daeid N, McKenzie C, et al. Activation of mu-opioid receptors by MT-45 (1-cyclohexyl-4-(1,2-diphenylethyl)piperazine) and its fluorinated derivatives. Br J Pharmacol. 2020;177(15):3436–48.PubMedPubMedCentralCrossRef Baptista-Hon DT, Smith M, Singleton S, Antonides LH, Nic Daeid N, McKenzie C, et al. Activation of mu-opioid receptors by MT-45 (1-cyclohexyl-4-(1,2-diphenylethyl)piperazine) and its fluorinated derivatives. Br J Pharmacol. 2020;177(15):3436–48.PubMedPubMedCentralCrossRef
87.
go back to reference Tso PH, Wong YH. Molecular basis of opioid dependence: role of signal regulation by G-proteins. Clin Exp Pharmacol Physiol. 2003;30(5–6):307–16.PubMedCrossRef Tso PH, Wong YH. Molecular basis of opioid dependence: role of signal regulation by G-proteins. Clin Exp Pharmacol Physiol. 2003;30(5–6):307–16.PubMedCrossRef
88.
go back to reference Masuho I, Ostrovskaya O, Kramer GM, Jones CD, Xie K, Martemyanov KA. Distinct profiles of functional discrimination among G proteins determine the actions of G protein-coupled receptors. Sci Signal. 2015;8(405):ra123.PubMedPubMedCentralCrossRef Masuho I, Ostrovskaya O, Kramer GM, Jones CD, Xie K, Martemyanov KA. Distinct profiles of functional discrimination among G proteins determine the actions of G protein-coupled receptors. Sci Signal. 2015;8(405):ra123.PubMedPubMedCentralCrossRef
89.
go back to reference Masuho I, Itoh M, Itoh H, Saitoh O. The mechanism of membrane-translocation of regulator of G-protein signaling (RGS) 8 induced by Galpha expression. J Neurochem. 2004;88(1):161–8.PubMedCrossRef Masuho I, Itoh M, Itoh H, Saitoh O. The mechanism of membrane-translocation of regulator of G-protein signaling (RGS) 8 induced by Galpha expression. J Neurochem. 2004;88(1):161–8.PubMedCrossRef
90.
go back to reference Clark MJ, Linderman JJ, Traynor JR. Endogenous regulators of G protein signaling differentially modulate full and partial mu-opioid agonists at adenylyl cyclase as predicted by a collision coupling model. Mol Pharmacol. 2008;73(5):1538–48.PubMedCrossRef Clark MJ, Linderman JJ, Traynor JR. Endogenous regulators of G protein signaling differentially modulate full and partial mu-opioid agonists at adenylyl cyclase as predicted by a collision coupling model. Mol Pharmacol. 2008;73(5):1538–48.PubMedCrossRef
91.
go back to reference Virk MS, Arttamangkul S, Birdsong WT, Williams JT. Buprenorphine is a weak partial agonist that inhibits opioid receptor desensitization. J Neurosci. 2009;29(22):7341–8.PubMedPubMedCentralCrossRef Virk MS, Arttamangkul S, Birdsong WT, Williams JT. Buprenorphine is a weak partial agonist that inhibits opioid receptor desensitization. J Neurosci. 2009;29(22):7341–8.PubMedPubMedCentralCrossRef
92.
go back to reference McPherson J, Rivero G, Baptist M, Llorente J, Al-Sabah S, Krasel C, et al. mu-opioid receptors: correlation of agonist efficacy for signalling with ability to activate internalization. Mol Pharmacol. 2010;78(4):756–66.PubMedPubMedCentralCrossRef McPherson J, Rivero G, Baptist M, Llorente J, Al-Sabah S, Krasel C, et al. mu-opioid receptors: correlation of agonist efficacy for signalling with ability to activate internalization. Mol Pharmacol. 2010;78(4):756–66.PubMedPubMedCentralCrossRef
93.
go back to reference Just S, Illing S, Trester-Zedlitz M, Lau EK, Kotowski SJ, Miess E, et al. Differentiation of opioid drug effects by hierarchical multi-site phosphorylation. Mol Pharmacol. 2013;83(3):633–9.PubMedPubMedCentralCrossRef Just S, Illing S, Trester-Zedlitz M, Lau EK, Kotowski SJ, Miess E, et al. Differentiation of opioid drug effects by hierarchical multi-site phosphorylation. Mol Pharmacol. 2013;83(3):633–9.PubMedPubMedCentralCrossRef
94.
go back to reference Koch T, Widera A, Bartzsch K, Schulz S, Brandenburg LO, Wundrack N, et al. Receptor endocytosis counteracts the development of opioid tolerance. Mol Pharmacol. 2005;67(1):280–7.PubMedCrossRef Koch T, Widera A, Bartzsch K, Schulz S, Brandenburg LO, Wundrack N, et al. Receptor endocytosis counteracts the development of opioid tolerance. Mol Pharmacol. 2005;67(1):280–7.PubMedCrossRef
95.
go back to reference Schulz S, Mayer D, Pfeiffer M, Stumm R, Koch T, Hollt V. Morphine induces terminal micro-opioid receptor desensitization by sustained phosphorylation of serine-375. EMBO J. 2004;23(16):3282–9.PubMedPubMedCentralCrossRef Schulz S, Mayer D, Pfeiffer M, Stumm R, Koch T, Hollt V. Morphine induces terminal micro-opioid receptor desensitization by sustained phosphorylation of serine-375. EMBO J. 2004;23(16):3282–9.PubMedPubMedCentralCrossRef
96.
go back to reference Lutfy K, Eitan S, Bryant CD, Yang YC, Saliminejad N, Walwyn W, et al. Buprenorphine-induced antinociception is mediated by mu-opioid receptors and compromised by concomitant activation of opioid receptor-like receptors. J Neurosci. 2003;23(32):10331–7.PubMedPubMedCentralCrossRef Lutfy K, Eitan S, Bryant CD, Yang YC, Saliminejad N, Walwyn W, et al. Buprenorphine-induced antinociception is mediated by mu-opioid receptors and compromised by concomitant activation of opioid receptor-like receptors. J Neurosci. 2003;23(32):10331–7.PubMedPubMedCentralCrossRef
97.
go back to reference Melief EJ, Miyatake M, Bruchas MR, Chavkin C. Ligand-directed c-Jun N-terminal kinase activation disrupts opioid receptor signaling. Proc Natl Acad Sci USA. 2010;107(25):11608–13.PubMedPubMedCentralCrossRef Melief EJ, Miyatake M, Bruchas MR, Chavkin C. Ligand-directed c-Jun N-terminal kinase activation disrupts opioid receptor signaling. Proc Natl Acad Sci USA. 2010;107(25):11608–13.PubMedPubMedCentralCrossRef
98.
go back to reference Bruchas MR, Yang T, Schreiber S, Defino M, Kwan SC, Li S, et al. Long-acting kappa opioid antagonists disrupt receptor signaling and produce noncompetitive effects by activating c-Jun N-terminal kinase. J Biol Chem. 2007;282(41):29803–11.PubMedCrossRef Bruchas MR, Yang T, Schreiber S, Defino M, Kwan SC, Li S, et al. Long-acting kappa opioid antagonists disrupt receptor signaling and produce noncompetitive effects by activating c-Jun N-terminal kinase. J Biol Chem. 2007;282(41):29803–11.PubMedCrossRef
99.
go back to reference Negus SS, Bidlack JM, Mello NK, Furness MS, Rice KC, Brandt MR. Delta opioid antagonist effects of buprenorphine in rhesus monkeys. Behav Pharmacol. 2002;13(7):557–70.PubMedCrossRef Negus SS, Bidlack JM, Mello NK, Furness MS, Rice KC, Brandt MR. Delta opioid antagonist effects of buprenorphine in rhesus monkeys. Behav Pharmacol. 2002;13(7):557–70.PubMedCrossRef
100.
go back to reference Belcheva MM, Ho MT, Ignatova EG, Jefcoat LB, Barg J, Vogel Z, et al. Buprenorphine differentially alters opioid receptor adaptation in rat brain regions. J Pharmacol Exp Ther. 1996;277(3):1322–7.PubMedCrossRef Belcheva MM, Ho MT, Ignatova EG, Jefcoat LB, Barg J, Vogel Z, et al. Buprenorphine differentially alters opioid receptor adaptation in rat brain regions. J Pharmacol Exp Ther. 1996;277(3):1322–7.PubMedCrossRef
101.
go back to reference Romero DV, Partilla JS, Zheng QX, Heyliger SO, Ni Q, Rice KC, et al. Opioid peptide receptor studies. 12. Buprenorphine is a potent and selective mu/kappa antagonist in the [35S]-GTP-gamma-S functional binding assay. Synapse. 1999;34(2):83–94.PubMedCrossRef Romero DV, Partilla JS, Zheng QX, Heyliger SO, Ni Q, Rice KC, et al. Opioid peptide receptor studies. 12. Buprenorphine is a potent and selective mu/kappa antagonist in the [35S]-GTP-gamma-S functional binding assay. Synapse. 1999;34(2):83–94.PubMedCrossRef
102.
go back to reference Zhang X, Bao L, Guan JS. Role of delivery and trafficking of delta-opioid peptide receptors in opioid analgesia and tolerance. Trends Pharmacol Sci. 2006;27(6):324–9.PubMedCrossRef Zhang X, Bao L, Guan JS. Role of delivery and trafficking of delta-opioid peptide receptors in opioid analgesia and tolerance. Trends Pharmacol Sci. 2006;27(6):324–9.PubMedCrossRef
103.
go back to reference Zhao GM, Wu D, Soong Y, Shimoyama M, Berezowska I, Schiller PW, et al. Profound spinal tolerance after repeated exposure to a highly selective mu-opioid peptide agonist: role of delta-opioid receptors. J Pharmacol Exp Ther. 2002;302(1):188–96.PubMedCrossRef Zhao GM, Wu D, Soong Y, Shimoyama M, Berezowska I, Schiller PW, et al. Profound spinal tolerance after repeated exposure to a highly selective mu-opioid peptide agonist: role of delta-opioid receptors. J Pharmacol Exp Ther. 2002;302(1):188–96.PubMedCrossRef
104.
go back to reference Rady JJ, Holmes BB, Portoghese PS, Fujimoto JM. Morphine tolerance in mice changes response of heroin from mu to delta opioid receptors. Proc Soc Exp Biol Med. 2000;224(2):93–101.PubMed Rady JJ, Holmes BB, Portoghese PS, Fujimoto JM. Morphine tolerance in mice changes response of heroin from mu to delta opioid receptors. Proc Soc Exp Biol Med. 2000;224(2):93–101.PubMed
105.
go back to reference Abdelhamid EE, Sultana M, Portoghese PS, Takemori AE. Selective blockage of delta opioid receptors prevents the development of morphine tolerance and dependence in mice. J Pharmacol Exp Ther. 1991;258(1):299–303.PubMedCrossRef Abdelhamid EE, Sultana M, Portoghese PS, Takemori AE. Selective blockage of delta opioid receptors prevents the development of morphine tolerance and dependence in mice. J Pharmacol Exp Ther. 1991;258(1):299–303.PubMedCrossRef
106.
go back to reference Russell RD, Leslie JB, Su YF, Watkins WD, Chang KJ. Continuous intrathecal opioid analgesia: tolerance and cross-tolerance of mu and delta spinal opioid receptors. J Pharmacol Exp Ther. 1987;240(1):150–8.PubMedCrossRef Russell RD, Leslie JB, Su YF, Watkins WD, Chang KJ. Continuous intrathecal opioid analgesia: tolerance and cross-tolerance of mu and delta spinal opioid receptors. J Pharmacol Exp Ther. 1987;240(1):150–8.PubMedCrossRef
107.
go back to reference Klenowski P, Morgan M, Bartlett SE. The role of delta-opioid receptors in learning and memory underlying the development of addiction. Br J Pharmacol. 2015;172(2):297–310.PubMedCrossRef Klenowski P, Morgan M, Bartlett SE. The role of delta-opioid receptors in learning and memory underlying the development of addiction. Br J Pharmacol. 2015;172(2):297–310.PubMedCrossRef
108.
go back to reference Requana Aradas A, Djaboub Y, McCort-Tranchepain I, Hajasova Z, Clemenceau L, Canestrelli C, et al. Activation of the mu-delta opioid receptor heteromers blocks morphine rewarding effects. Int J Neuropsychopharmacol. 2023;26(7):513–21.PubMedPubMedCentralCrossRef Requana Aradas A, Djaboub Y, McCort-Tranchepain I, Hajasova Z, Clemenceau L, Canestrelli C, et al. Activation of the mu-delta opioid receptor heteromers blocks morphine rewarding effects. Int J Neuropsychopharmacol. 2023;26(7):513–21.PubMedPubMedCentralCrossRef
109.
go back to reference Kranzler HR, Lynch KG, Crist RC, Hartwell E, Le Moigne A, Laffont CM, et al. A delta-opioid receptor gene polymorphism moderates the therapeutic response to extended-release buprenorphine in opioid use disorder. Int J Neuropsychopharmacol. 2021;24(2):89–96.PubMedCrossRef Kranzler HR, Lynch KG, Crist RC, Hartwell E, Le Moigne A, Laffont CM, et al. A delta-opioid receptor gene polymorphism moderates the therapeutic response to extended-release buprenorphine in opioid use disorder. Int J Neuropsychopharmacol. 2021;24(2):89–96.PubMedCrossRef
110.
go back to reference Negus SS, St Onge CM, Lee YK, Li M, Rice KC, Zhang Y. Effects of selective and mixed-action kappa and delta opioid receptor agonists on pain-related behavioral depression in mice. Molecules. 2024;29(14):3331.PubMedPubMedCentralCrossRef Negus SS, St Onge CM, Lee YK, Li M, Rice KC, Zhang Y. Effects of selective and mixed-action kappa and delta opioid receptor agonists on pain-related behavioral depression in mice. Molecules. 2024;29(14):3331.PubMedPubMedCentralCrossRef
111.
go back to reference Richards EM, Mathews DC, Luckenbaugh DA, Ionescu DF, Machado-Vieira R, Niciu MJ, et al. A randomized, placebo-controlled pilot trial of the delta opioid receptor agonist AZD2327 in anxious depression. Psychopharmacology. 2016;233(6):1119–30.PubMedPubMedCentralCrossRef Richards EM, Mathews DC, Luckenbaugh DA, Ionescu DF, Machado-Vieira R, Niciu MJ, et al. A randomized, placebo-controlled pilot trial of the delta opioid receptor agonist AZD2327 in anxious depression. Psychopharmacology. 2016;233(6):1119–30.PubMedPubMedCentralCrossRef
112.
go back to reference Perrine SA, Sheikh IS, Nwaneshiudu CA, Schroeder JA, Unterwald EM. Withdrawal from chronic administration of cocaine decreases delta opioid receptor signaling and increases anxiety- and depression-like behaviors in the rat. Neuropharmacology. 2008;54(2):355–64.PubMedCrossRef Perrine SA, Sheikh IS, Nwaneshiudu CA, Schroeder JA, Unterwald EM. Withdrawal from chronic administration of cocaine decreases delta opioid receptor signaling and increases anxiety- and depression-like behaviors in the rat. Neuropharmacology. 2008;54(2):355–64.PubMedCrossRef
113.
go back to reference Jutkiewicz EM, Baladi MG, Folk JE, Rice KC, Woods JH. The convulsive and electroencephalographic changes produced by nonpeptidic delta-opioid agonists in rats: comparison with pentylenetetrazol. J Pharmacol Exp Ther. 2006;317(3):1337–48.PubMedCrossRef Jutkiewicz EM, Baladi MG, Folk JE, Rice KC, Woods JH. The convulsive and electroencephalographic changes produced by nonpeptidic delta-opioid agonists in rats: comparison with pentylenetetrazol. J Pharmacol Exp Ther. 2006;317(3):1337–48.PubMedCrossRef
114.
go back to reference Gupta A, Mulder J, Gomes I, Rozenfeld R, Bushlin I, Ong E, et al. Increased abundance of opioid receptor heteromers after chronic morphine administration. Sci Signal. 2010;3(131):ra54.PubMedPubMedCentralCrossRef Gupta A, Mulder J, Gomes I, Rozenfeld R, Bushlin I, Ong E, et al. Increased abundance of opioid receptor heteromers after chronic morphine administration. Sci Signal. 2010;3(131):ra54.PubMedPubMedCentralCrossRef
115.
go back to reference Decaillot FM, Rozenfeld R, Gupta A, Devi LA. Cell surface targeting of mu-delta opioid receptor heterodimers by RTP4. Proc Natl Acad Sci USA. 2008;105(41):16045–50.PubMedPubMedCentralCrossRef Decaillot FM, Rozenfeld R, Gupta A, Devi LA. Cell surface targeting of mu-delta opioid receptor heterodimers by RTP4. Proc Natl Acad Sci USA. 2008;105(41):16045–50.PubMedPubMedCentralCrossRef
116.
go back to reference Gomes I, Jordan BA, Gupta A, Trapaidze N, Nagy V, Devi LA. Heterodimerization of mu and delta opioid receptors: a role in opiate synergy. J Neurosci. 2000;20(22):RC110.PubMedPubMedCentralCrossRef Gomes I, Jordan BA, Gupta A, Trapaidze N, Nagy V, Devi LA. Heterodimerization of mu and delta opioid receptors: a role in opiate synergy. J Neurosci. 2000;20(22):RC110.PubMedPubMedCentralCrossRef
117.
go back to reference Milan-Lobo L, Enquist J, van Rijn RM, Whistler JL. Anti-analgesic effect of the mu/delta opioid receptor heteromer revealed by ligand-biased antagonism. PLoS ONE. 2013;8(3): e58362.PubMedPubMedCentralCrossRef Milan-Lobo L, Enquist J, van Rijn RM, Whistler JL. Anti-analgesic effect of the mu/delta opioid receptor heteromer revealed by ligand-biased antagonism. PLoS ONE. 2013;8(3): e58362.PubMedPubMedCentralCrossRef
118.
go back to reference Rozenfeld R, Abul-Husn NS, Gomez I, Devi LA. An emerging role for the delta opioid receptor in the regulation of mu opioid receptor function. Sci World J. 2007;7:64–73.CrossRef Rozenfeld R, Abul-Husn NS, Gomez I, Devi LA. An emerging role for the delta opioid receptor in the regulation of mu opioid receptor function. Sci World J. 2007;7:64–73.CrossRef
119.
go back to reference Bao F, Li CL, Chen XQ, Lu YJ, Bao L, Zhang X. Clinical opioids differentially induce co-internalization of mu- and delta-opioid receptors. Mol Pain. 2018;14:1744806918769492.PubMedPubMedCentralCrossRef Bao F, Li CL, Chen XQ, Lu YJ, Bao L, Zhang X. Clinical opioids differentially induce co-internalization of mu- and delta-opioid receptors. Mol Pain. 2018;14:1744806918769492.PubMedPubMedCentralCrossRef
120.
go back to reference Nitsche JF, Schuller AG, King MA, Zengh M, Pasternak GW, Pintar JE. Genetic dissociation of opiate tolerance and physical dependence in delta-opioid receptor-1 and preproenkephalin knock-out mice. J Neurosci. 2002;22(24):10906–13.PubMedPubMedCentralCrossRef Nitsche JF, Schuller AG, King MA, Zengh M, Pasternak GW, Pintar JE. Genetic dissociation of opiate tolerance and physical dependence in delta-opioid receptor-1 and preproenkephalin knock-out mice. J Neurosci. 2002;22(24):10906–13.PubMedPubMedCentralCrossRef
121.
go back to reference Keresztes A, Olson K, Nguyen P, Lopez-Pier MA, Hecksel R, Barker NK, et al. Antagonism of the mu-delta opioid receptor heterodimer enhances opioid antinociception by activating Src and calcium/calmodulin-dependent protein kinase II signaling. Pain. 2022;163(1):146–58.PubMedPubMedCentralCrossRef Keresztes A, Olson K, Nguyen P, Lopez-Pier MA, Hecksel R, Barker NK, et al. Antagonism of the mu-delta opioid receptor heterodimer enhances opioid antinociception by activating Src and calcium/calmodulin-dependent protein kinase II signaling. Pain. 2022;163(1):146–58.PubMedPubMedCentralCrossRef
122.
go back to reference Daniels DJ, Lenard NR, Etienne CL, Law PY, Roerig SC, Portoghese PS. Opioid-induced tolerance and dependence in mice is modulated by the distance between pharmacophores in a bivalent ligand series. Proc Natl Acad Sci USA. 2005;102(52):19208–13.PubMedPubMedCentralCrossRef Daniels DJ, Lenard NR, Etienne CL, Law PY, Roerig SC, Portoghese PS. Opioid-induced tolerance and dependence in mice is modulated by the distance between pharmacophores in a bivalent ligand series. Proc Natl Acad Sci USA. 2005;102(52):19208–13.PubMedPubMedCentralCrossRef
123.
go back to reference Lenard NR, Daniels DJ, Portoghese PS, Roerig SC. Absence of conditioned place preference or reinstatement with bivalent ligands containing mu-opioid receptor agonist and delta-opioid receptor antagonist pharmacophores. Eur J Pharmacol. 2007;566(1–3):75–82.PubMedCrossRef Lenard NR, Daniels DJ, Portoghese PS, Roerig SC. Absence of conditioned place preference or reinstatement with bivalent ligands containing mu-opioid receptor agonist and delta-opioid receptor antagonist pharmacophores. Eur J Pharmacol. 2007;566(1–3):75–82.PubMedCrossRef
124.
go back to reference Cueva JP, Roche C, Ostovar M, Kumar V, Clark MJ, Hillhouse TM, et al. C7beta-methyl analogues of the orvinols: the discovery of kappa opioid antagonists with nociceptin/orphanin FQ peptide (NOP) receptor partial agonism and low, or zero, efficacy at mu opioid receptors. J Med Chem. 2015;58(10):4242–9.PubMedPubMedCentralCrossRef Cueva JP, Roche C, Ostovar M, Kumar V, Clark MJ, Hillhouse TM, et al. C7beta-methyl analogues of the orvinols: the discovery of kappa opioid antagonists with nociceptin/orphanin FQ peptide (NOP) receptor partial agonism and low, or zero, efficacy at mu opioid receptors. J Med Chem. 2015;58(10):4242–9.PubMedPubMedCentralCrossRef
125.
go back to reference Greedy BM, Bradbury F, Thomas MP, Grivas K, Cami-Kobeci G, Archambeau A, et al. Orvinols with mixed kappa/mu opioid receptor agonist activity. J Med Chem. 2013;56(8):3207–16.PubMedPubMedCentralCrossRef Greedy BM, Bradbury F, Thomas MP, Grivas K, Cami-Kobeci G, Archambeau A, et al. Orvinols with mixed kappa/mu opioid receptor agonist activity. J Med Chem. 2013;56(8):3207–16.PubMedPubMedCentralCrossRef
126.
go back to reference Santos EJ, Nassehi N, Bow EW, Chambers DR, Gutman ES, Jacobson AE, et al. Role of efficacy as a determinant of locomotor activation by mu-opioid receptor (MOR) ligands in female and male mice. II. Effects of novel MOR-selective phenylmorphans with high-to-low MOR efficacy. Pharmacol Res Perspect. 2023;11(4):e01111.PubMedPubMedCentralCrossRef Santos EJ, Nassehi N, Bow EW, Chambers DR, Gutman ES, Jacobson AE, et al. Role of efficacy as a determinant of locomotor activation by mu-opioid receptor (MOR) ligands in female and male mice. II. Effects of novel MOR-selective phenylmorphans with high-to-low MOR efficacy. Pharmacol Res Perspect. 2023;11(4):e01111.PubMedPubMedCentralCrossRef
127.
go back to reference Su TP. Further demonstration of kappa opioid binding sites in the brain: evidence for heterogeneity. J Pharmacol Exp Ther. 1985;232(1):144–8.PubMedCrossRef Su TP. Further demonstration of kappa opioid binding sites in the brain: evidence for heterogeneity. J Pharmacol Exp Ther. 1985;232(1):144–8.PubMedCrossRef
128.
go back to reference Young AM, Stephens KR, Hein DW, Woods JH. Reinforcing and discriminative stimulus properties of mixed agonist-antagonist opioids. J Pharmacol Exp Ther. 1984;229(1):118–26.PubMedCrossRef Young AM, Stephens KR, Hein DW, Woods JH. Reinforcing and discriminative stimulus properties of mixed agonist-antagonist opioids. J Pharmacol Exp Ther. 1984;229(1):118–26.PubMedCrossRef
129.
go back to reference Zhu J, Luo LY, Li JG, Chen C, Liu-Chen LY. Activation of the cloned human kappa opioid receptor by agonists enhances [35S]GTPgammaS binding to membranes: determination of potencies and efficacies of ligands. J Pharmacol Exp Ther. 1997;282(2):676–84.PubMedCrossRef Zhu J, Luo LY, Li JG, Chen C, Liu-Chen LY. Activation of the cloned human kappa opioid receptor by agonists enhances [35S]GTPgammaS binding to membranes: determination of potencies and efficacies of ligands. J Pharmacol Exp Ther. 1997;282(2):676–84.PubMedCrossRef
130.
go back to reference Pick CG, Peter Y, Schreiber S, Weizman R. Pharmacological characterization of buprenorphine, a mixed agonist-antagonist with kappa 3 analgesia. Brain Res. 1997;744(1):41–6.PubMedCrossRef Pick CG, Peter Y, Schreiber S, Weizman R. Pharmacological characterization of buprenorphine, a mixed agonist-antagonist with kappa 3 analgesia. Brain Res. 1997;744(1):41–6.PubMedCrossRef
131.
go back to reference Olianas MC, Concas D, Onali P. Agonist activity of naloxone benzoylhydrazone at recombinant and native opioid receptors. Br J Pharmacol. 2006;147(4):360–70.PubMedPubMedCentralCrossRef Olianas MC, Concas D, Onali P. Agonist activity of naloxone benzoylhydrazone at recombinant and native opioid receptors. Br J Pharmacol. 2006;147(4):360–70.PubMedPubMedCentralCrossRef
132.
go back to reference Cox V, Clarke S, Czyzyk T, Ansonoff M, Nitsche J, Hsu MS, et al. Autoradiography in opioid triple knockout mice reveals opioid and opioid receptor like binding of naloxone benzoylhydrazone. Neuropharmacology. 2005;48(2):228–35.PubMedCrossRef Cox V, Clarke S, Czyzyk T, Ansonoff M, Nitsche J, Hsu MS, et al. Autoradiography in opioid triple knockout mice reveals opioid and opioid receptor like binding of naloxone benzoylhydrazone. Neuropharmacology. 2005;48(2):228–35.PubMedCrossRef
133.
go back to reference Pan YX, Bolan E, Pasternak GW. Dimerization of morphine and orphanin FQ/nociceptin receptors: generation of a novel opioid receptor subtype. Biochem Biophys Res Commun. 2002;297(3):659–63.PubMedCrossRef Pan YX, Bolan E, Pasternak GW. Dimerization of morphine and orphanin FQ/nociceptin receptors: generation of a novel opioid receptor subtype. Biochem Biophys Res Commun. 2002;297(3):659–63.PubMedCrossRef
134.
go back to reference Richards ML, Sadee W. Buprenorphine is an antagonist at the varkappa opioid receptor. Pharm Res. 1985;2(4):178–81.PubMedCrossRef Richards ML, Sadee W. Buprenorphine is an antagonist at the varkappa opioid receptor. Pharm Res. 1985;2(4):178–81.PubMedCrossRef
135.
go back to reference Leander JD. Buprenorphine has potent kappa opioid receptor antagonist activity. Neuropharmacology. 1987;26(9):1445–7.PubMedCrossRef Leander JD. Buprenorphine has potent kappa opioid receptor antagonist activity. Neuropharmacology. 1987;26(9):1445–7.PubMedCrossRef
136.
go back to reference Negus SS, Picker MJ, Dykstra LA. Kappa antagonist effects of buprenorphine in the rat drug-discrimination procedure. NIDA Res Monogr. 1989;95:518–9.PubMed Negus SS, Picker MJ, Dykstra LA. Kappa antagonist effects of buprenorphine in the rat drug-discrimination procedure. NIDA Res Monogr. 1989;95:518–9.PubMed
137.
go back to reference Negus SS, Picker MJ, Dykstra LA. Kappa antagonist properties of buprenorphine in non-tolerant and morphine-tolerant rats. Psychopharmacology. 1989;98(1):141–3.PubMedCrossRef Negus SS, Picker MJ, Dykstra LA. Kappa antagonist properties of buprenorphine in non-tolerant and morphine-tolerant rats. Psychopharmacology. 1989;98(1):141–3.PubMedCrossRef
138.
go back to reference Bruchas MR, Land BB, Chavkin C. The dynorphin/kappa opioid system as a modulator of stress-induced and pro-addictive behaviors. Brain Res. 2010;1314:44–55.PubMedCrossRef Bruchas MR, Land BB, Chavkin C. The dynorphin/kappa opioid system as a modulator of stress-induced and pro-addictive behaviors. Brain Res. 2010;1314:44–55.PubMedCrossRef
139.
140.
go back to reference Schlosburg JE, Whitfield TW Jr, Park PE, Crawford EF, George O, Vendruscolo LF, et al. Long-term antagonism of kappa opioid receptors prevents escalation of and increased motivation for heroin intake. J Neurosci. 2013;33(49):19384–92.PubMedPubMedCentralCrossRef Schlosburg JE, Whitfield TW Jr, Park PE, Crawford EF, George O, Vendruscolo LF, et al. Long-term antagonism of kappa opioid receptors prevents escalation of and increased motivation for heroin intake. J Neurosci. 2013;33(49):19384–92.PubMedPubMedCentralCrossRef
141.
go back to reference Fava M, Mazzone E, Freeman M, Flynn M, Judge H, Hoeppner B, et al. Double-blind, placebo-controlled, proof-of-concept trial of a kappa-selective opioid receptor antagonist augmentation in treatment-resistant depression. Ann Clin Psychiatry. 2020;32(4):18–26.PubMed Fava M, Mazzone E, Freeman M, Flynn M, Judge H, Hoeppner B, et al. Double-blind, placebo-controlled, proof-of-concept trial of a kappa-selective opioid receptor antagonist augmentation in treatment-resistant depression. Ann Clin Psychiatry. 2020;32(4):18–26.PubMed
142.
go back to reference Fiatcoski F, Jesus CHA, de Melo TJ, Chichorro JG, Kopruszinski CM. Sex differences in descending control of nociception (DCN) responses after chronic orofacial pain induction in rats and the contribution of kappa opioid receptors. Behav Brain Res. 2024;459: 114789.PubMedCrossRef Fiatcoski F, Jesus CHA, de Melo TJ, Chichorro JG, Kopruszinski CM. Sex differences in descending control of nociception (DCN) responses after chronic orofacial pain induction in rats and the contribution of kappa opioid receptors. Behav Brain Res. 2024;459: 114789.PubMedCrossRef
144.
go back to reference Liu SS, Pickens S, Burma NE, Ibarra-Lecue I, Yang H, Xue L, et al. Kappa opioid receptors drive a tonic aversive component of chronic pain. J Neurosci. 2019;39(21):4162–78.PubMedCrossRef Liu SS, Pickens S, Burma NE, Ibarra-Lecue I, Yang H, Xue L, et al. Kappa opioid receptors drive a tonic aversive component of chronic pain. J Neurosci. 2019;39(21):4162–78.PubMedCrossRef
145.
go back to reference Chartoff EH, Ebner SR, Sparrow A, Potter D, Baker PM, Ragozzino ME, et al. Relative timing between kappa opioid receptor activation and cocaine determines the impact on reward and dopamine release. Neuropsychopharmacology. 2016;41(4):989–1002.PubMedCrossRef Chartoff EH, Ebner SR, Sparrow A, Potter D, Baker PM, Ragozzino ME, et al. Relative timing between kappa opioid receptor activation and cocaine determines the impact on reward and dopamine release. Neuropsychopharmacology. 2016;41(4):989–1002.PubMedCrossRef
146.
go back to reference Vanderah TW. Delta and kappa opioid receptors as suitable drug targets for pain. Clin J Pain. 2010;26(Suppl 10):S10–5.PubMedCrossRef Vanderah TW. Delta and kappa opioid receptors as suitable drug targets for pain. Clin J Pain. 2010;26(Suppl 10):S10–5.PubMedCrossRef
147.
go back to reference Navratilova E, Ji G, Phelps C, Qu C, Hein M, Yakhnitsa V, et al. Kappa opioid signaling in the central nucleus of the amygdala promotes disinhibition and aversiveness of chronic neuropathic pain. Pain. 2019;160(4):824–32.PubMedPubMedCentralCrossRef Navratilova E, Ji G, Phelps C, Qu C, Hein M, Yakhnitsa V, et al. Kappa opioid signaling in the central nucleus of the amygdala promotes disinhibition and aversiveness of chronic neuropathic pain. Pain. 2019;160(4):824–32.PubMedPubMedCentralCrossRef
148.
go back to reference Nylander I, Vlaskovska M, Terenius L. Brain dynorphin and enkephalin systems in Fischer and Lewis rats: effects of morphine tolerance and withdrawal. Brain Res. 1995;683(1):25–35.PubMedCrossRef Nylander I, Vlaskovska M, Terenius L. Brain dynorphin and enkephalin systems in Fischer and Lewis rats: effects of morphine tolerance and withdrawal. Brain Res. 1995;683(1):25–35.PubMedCrossRef
149.
go back to reference Nylander I, Vlaskovska M, Terenius L. The effects of morphine treatment and morphine withdrawal on the dynorphin and enkephalin systems in Sprague-Dawley rats. Psychopharmacology. 1995;118(4):391–400.PubMedCrossRef Nylander I, Vlaskovska M, Terenius L. The effects of morphine treatment and morphine withdrawal on the dynorphin and enkephalin systems in Sprague-Dawley rats. Psychopharmacology. 1995;118(4):391–400.PubMedCrossRef
150.
go back to reference Pfeiffer A, Brantl V, Herz A, Emrich HM. Psychotomimesis mediated by kappa opiate receptors. Science. 1986;233(4765):774–6.PubMedCrossRef Pfeiffer A, Brantl V, Herz A, Emrich HM. Psychotomimesis mediated by kappa opiate receptors. Science. 1986;233(4765):774–6.PubMedCrossRef
151.
go back to reference Marchette RCN, Gregory-Flores A, Tunstall BJ, Carlson ER, Jackson SN, Sulima A, et al. kappa-Opioid receptor antagonism reverses heroin withdrawal-induced hyperalgesia in male and female rats. Neurobiol Stress. 2021;14: 100325.PubMedPubMedCentralCrossRef Marchette RCN, Gregory-Flores A, Tunstall BJ, Carlson ER, Jackson SN, Sulima A, et al. kappa-Opioid receptor antagonism reverses heroin withdrawal-induced hyperalgesia in male and female rats. Neurobiol Stress. 2021;14: 100325.PubMedPubMedCentralCrossRef
152.
go back to reference Chavkin C, Koob GF. Dynorphin, dysphoria, and dependence: the stress of addiction. Neuropsychopharmacology. 2016;41(1):373–4.PubMedCrossRef Chavkin C, Koob GF. Dynorphin, dysphoria, and dependence: the stress of addiction. Neuropsychopharmacology. 2016;41(1):373–4.PubMedCrossRef
153.
go back to reference Whitfield TW Jr, Schlosburg JE, Wee S, Gould A, George O, Grant Y, et al. kappa Opioid receptors in the nucleus accumbens shell mediate escalation of methamphetamine intake. J Neurosci. 2015;35(10):4296–305.PubMedPubMedCentralCrossRef Whitfield TW Jr, Schlosburg JE, Wee S, Gould A, George O, Grant Y, et al. kappa Opioid receptors in the nucleus accumbens shell mediate escalation of methamphetamine intake. J Neurosci. 2015;35(10):4296–305.PubMedPubMedCentralCrossRef
154.
155.
go back to reference Walker BM, Koob GF. Pharmacological evidence for a motivational role of kappa-opioid systems in ethanol dependence. Neuropsychopharmacology. 2008;33(3):643–52.PubMedCrossRef Walker BM, Koob GF. Pharmacological evidence for a motivational role of kappa-opioid systems in ethanol dependence. Neuropsychopharmacology. 2008;33(3):643–52.PubMedCrossRef
156.
go back to reference Ji G, Presto P, Kiritoshi T, Chen Y, Navratilova E, Porreca F, et al. Chemogenetic manipulation of amygdala kappa opioid receptor neurons modulates amygdala neuronal activity and neuropathic pain behaviors. Cells. 2024;13(8):705.PubMedPubMedCentralCrossRef Ji G, Presto P, Kiritoshi T, Chen Y, Navratilova E, Porreca F, et al. Chemogenetic manipulation of amygdala kappa opioid receptor neurons modulates amygdala neuronal activity and neuropathic pain behaviors. Cells. 2024;13(8):705.PubMedPubMedCentralCrossRef
157.
go back to reference Navratilova E, Qu C, Ji G, Neugebauer V, Guerrero M, Rosen H, et al. Opposing effects on descending control of nociception by micro and kappa opioid receptors in the anterior cingulate cortex. Anesthesiology. 2024;140(2):272–83.PubMedCrossRef Navratilova E, Qu C, Ji G, Neugebauer V, Guerrero M, Rosen H, et al. Opposing effects on descending control of nociception by micro and kappa opioid receptors in the anterior cingulate cortex. Anesthesiology. 2024;140(2):272–83.PubMedCrossRef
158.
go back to reference Ito H, Navratilova E, Vagnerova B, Watanabe M, Kopruszinski C, Moreira de Souza LH, et al. Chronic pain recruits hypothalamic dynorphin/kappa opioid receptor signalling to promote wakefulness and vigilance. Brain. 2023;146(3):1186–99.PubMedCrossRef Ito H, Navratilova E, Vagnerova B, Watanabe M, Kopruszinski C, Moreira de Souza LH, et al. Chronic pain recruits hypothalamic dynorphin/kappa opioid receptor signalling to promote wakefulness and vigilance. Brain. 2023;146(3):1186–99.PubMedCrossRef
159.
go back to reference Bruchas MR, Land BB, Aita M, Xu M, Barot SK, Li S, et al. Stress-induced p38 mitogen-activated protein kinase activation mediates kappa-opioid-dependent dysphoria. J Neurosci. 2007;27(43):11614–23.PubMedPubMedCentralCrossRef Bruchas MR, Land BB, Aita M, Xu M, Barot SK, Li S, et al. Stress-induced p38 mitogen-activated protein kinase activation mediates kappa-opioid-dependent dysphoria. J Neurosci. 2007;27(43):11614–23.PubMedPubMedCentralCrossRef
160.
go back to reference de Laat B, Nabulsi N, Huang Y, O’Malley SS, Froehlich JC, Morris ED, et al. Occupancy of the kappa opioid receptor by naltrexone predicts reduction in drinking and craving. Mol Psychiatry. 2021;26(9):5053–60.PubMedCrossRef de Laat B, Nabulsi N, Huang Y, O’Malley SS, Froehlich JC, Morris ED, et al. Occupancy of the kappa opioid receptor by naltrexone predicts reduction in drinking and craving. Mol Psychiatry. 2021;26(9):5053–60.PubMedCrossRef
161.
go back to reference de Laat B, Goldberg A, Shi J, Tetrault JM, Nabulsi N, Zheng MQ, et al. The kappa opioid receptor is associated with naltrexone-induced reduction of drinking and craving. Biol Psychiatry. 2019;86(11):864–71.PubMedCrossRef de Laat B, Goldberg A, Shi J, Tetrault JM, Nabulsi N, Zheng MQ, et al. The kappa opioid receptor is associated with naltrexone-induced reduction of drinking and craving. Biol Psychiatry. 2019;86(11):864–71.PubMedCrossRef
162.
go back to reference Koob GF. Anhedonia, hyperkatifeia, and negative reinforcement in substance use disorders. Curr Top Behav Neurosci. 2022;58:147–65.PubMedCrossRef Koob GF. Anhedonia, hyperkatifeia, and negative reinforcement in substance use disorders. Curr Top Behav Neurosci. 2022;58:147–65.PubMedCrossRef
163.
go back to reference Shurman J, Koob GF, Gutstein HB. Opioids, pain, the brain, and hyperkatifeia: a framework for the rational use of opioids for pain. Pain Med. 2010;11(7):1092–8.PubMedCrossRef Shurman J, Koob GF, Gutstein HB. Opioids, pain, the brain, and hyperkatifeia: a framework for the rational use of opioids for pain. Pain Med. 2010;11(7):1092–8.PubMedCrossRef
164.
go back to reference Kakko J, Alho H, Baldacchino A, Molina R, Nava FA, Shaya G. Craving in opioid use disorder: from neurobiology to clinical practice. Front Psychiatry. 2019;10:592.PubMedPubMedCentralCrossRef Kakko J, Alho H, Baldacchino A, Molina R, Nava FA, Shaya G. Craving in opioid use disorder: from neurobiology to clinical practice. Front Psychiatry. 2019;10:592.PubMedPubMedCentralCrossRef
165.
go back to reference Cameron CM, Nieto S, Bosler L, Wong M, Bishop I, Mooney L, et al. Mechanisms underlying the anti-suicidal treatment potential of buprenorphine. Adv Drug Alcohol Res. 2021;1:10009.PubMedPubMedCentralCrossRef Cameron CM, Nieto S, Bosler L, Wong M, Bishop I, Mooney L, et al. Mechanisms underlying the anti-suicidal treatment potential of buprenorphine. Adv Drug Alcohol Res. 2021;1:10009.PubMedPubMedCentralCrossRef
166.
go back to reference Pirino BE, Kelley AM, Karkhanis AN, Barson JR. A critical review of effects on ethanol intake of the dynorphin/kappa opioid receptor system in the extended amygdala: from inhibition to stimulation. Alcohol Clin Exp Res (Hoboken). 2023;47(6):1027–38.PubMedPubMedCentralCrossRef Pirino BE, Kelley AM, Karkhanis AN, Barson JR. A critical review of effects on ethanol intake of the dynorphin/kappa opioid receptor system in the extended amygdala: from inhibition to stimulation. Alcohol Clin Exp Res (Hoboken). 2023;47(6):1027–38.PubMedPubMedCentralCrossRef
167.
go back to reference Flores-Ramirez FJ, Illenberger JM, Pascasio G, Terenius L, Martin-Fardon R. LY2444296, a kappa-opioid receptor antagonist, selectively reduces alcohol drinking in male and female Wistar rats with a history of alcohol dependence. Sci Rep. 2024;14(1):5804.PubMedPubMedCentralCrossRef Flores-Ramirez FJ, Illenberger JM, Pascasio G, Terenius L, Martin-Fardon R. LY2444296, a kappa-opioid receptor antagonist, selectively reduces alcohol drinking in male and female Wistar rats with a history of alcohol dependence. Sci Rep. 2024;14(1):5804.PubMedPubMedCentralCrossRef
168.
go back to reference Nava F, Manzato E, Leonardi C, Lucchini A. Opioid maintenance therapy suppresses alcohol intake in heroin addicts with alcohol dependence: preliminary results of an open randomized study. Prog Neuropsychopharmacol Biol Psychiatry. 2008;32(8):1867–72.PubMedCrossRef Nava F, Manzato E, Leonardi C, Lucchini A. Opioid maintenance therapy suppresses alcohol intake in heroin addicts with alcohol dependence: preliminary results of an open randomized study. Prog Neuropsychopharmacol Biol Psychiatry. 2008;32(8):1867–72.PubMedCrossRef
169.
go back to reference Riblet NB, Young-Xu Y, Shiner B, Schnurr PP, Watts BV. The efficacy and safety of buprenorphine for the treatment of depression: a systematic review and meta-analysis. J Psychiatr Res. 2023;161:393–401.PubMedPubMedCentralCrossRef Riblet NB, Young-Xu Y, Shiner B, Schnurr PP, Watts BV. The efficacy and safety of buprenorphine for the treatment of depression: a systematic review and meta-analysis. J Psychiatr Res. 2023;161:393–401.PubMedPubMedCentralCrossRef
170.
go back to reference Ahmadi J, Mansoori A, Mosavat SH, Bazrafshan A. Comparison of ketamine with buprenorphine as adjunctive therapy in the treatment of comorbid major depressive disorder and opium use disorders: a randomized controlled trial. Int J Psychiatry Med. 2023;59:521–35.PubMedCrossRef Ahmadi J, Mansoori A, Mosavat SH, Bazrafshan A. Comparison of ketamine with buprenorphine as adjunctive therapy in the treatment of comorbid major depressive disorder and opium use disorders: a randomized controlled trial. Int J Psychiatry Med. 2023;59:521–35.PubMedCrossRef
171.
go back to reference Kissler JL, Sirohi S, Reis DJ, Jansen HT, Quock RM, Smith DG, et al. The one-two punch of alcoholism: role of central amygdala dynorphins/kappa-opioid receptors. Biol Psychiatry. 2014;75(10):774–82.PubMedCrossRef Kissler JL, Sirohi S, Reis DJ, Jansen HT, Quock RM, Smith DG, et al. The one-two punch of alcoholism: role of central amygdala dynorphins/kappa-opioid receptors. Biol Psychiatry. 2014;75(10):774–82.PubMedCrossRef
172.
go back to reference Margolis EB, Karkhanis AN. Dopaminergic cellular and circuit contributions to kappa opioid receptor mediated aversion. Neurochem Int. 2019;129: 104504.PubMedPubMedCentralCrossRef Margolis EB, Karkhanis AN. Dopaminergic cellular and circuit contributions to kappa opioid receptor mediated aversion. Neurochem Int. 2019;129: 104504.PubMedPubMedCentralCrossRef
173.
go back to reference Miller JM, Zanderigo F, Purushothaman PD, DeLorenzo C, Rubin-Falcone H, Ogden RT, et al. Kappa opioid receptor binding in major depression: a pilot study. Synapse. 2018;72(9): e22042.PubMedPubMedCentralCrossRef Miller JM, Zanderigo F, Purushothaman PD, DeLorenzo C, Rubin-Falcone H, Ogden RT, et al. Kappa opioid receptor binding in major depression: a pilot study. Synapse. 2018;72(9): e22042.PubMedPubMedCentralCrossRef
174.
go back to reference Dogra S, Kumar A, Umrao D, Sahasrabuddhe AA, Yadav PN. Chronic Kappa opioid receptor activation modulates NR2B: implication in treatment resistant depression. Sci Rep. 2016;6:33401.PubMedPubMedCentralCrossRef Dogra S, Kumar A, Umrao D, Sahasrabuddhe AA, Yadav PN. Chronic Kappa opioid receptor activation modulates NR2B: implication in treatment resistant depression. Sci Rep. 2016;6:33401.PubMedPubMedCentralCrossRef
175.
go back to reference Ukai M, Suzuki M, Mamiya T. Effects of U-50,488H, a kappa-opioid receptor agonist, on the learned helplessness model of depression in mice. J Neural Transm (Vienna). 2002;109(9):1221–5.PubMedCrossRef Ukai M, Suzuki M, Mamiya T. Effects of U-50,488H, a kappa-opioid receptor agonist, on the learned helplessness model of depression in mice. J Neural Transm (Vienna). 2002;109(9):1221–5.PubMedCrossRef
176.
177.
go back to reference Kallupi M, Wee S, Edwards S, Whitfield TW Jr, Oleata CS, Luu G, et al. Kappa opioid receptor-mediated dysregulation of gamma-aminobutyric acidergic transmission in the central amygdala in cocaine addiction. Biol Psychiatry. 2013;74(7):520–8.PubMedPubMedCentralCrossRef Kallupi M, Wee S, Edwards S, Whitfield TW Jr, Oleata CS, Luu G, et al. Kappa opioid receptor-mediated dysregulation of gamma-aminobutyric acidergic transmission in the central amygdala in cocaine addiction. Biol Psychiatry. 2013;74(7):520–8.PubMedPubMedCentralCrossRef
178.
go back to reference Wang YH, Sun JF, Tao YM, Chi ZQ, Liu JG. The role of kappa-opioid receptor activation in mediating antinociception and addiction. Acta Pharmacol Sin. 2010;31(9):1065–70.PubMedPubMedCentralCrossRef Wang YH, Sun JF, Tao YM, Chi ZQ, Liu JG. The role of kappa-opioid receptor activation in mediating antinociception and addiction. Acta Pharmacol Sin. 2010;31(9):1065–70.PubMedPubMedCentralCrossRef
179.
go back to reference Shippenberg TS. The dynorphin/kappa opioid receptor system: a new target for the treatment of addiction and affective disorders? Neuropsychopharmacology. 2009;34(1):247.PubMedCrossRef Shippenberg TS. The dynorphin/kappa opioid receptor system: a new target for the treatment of addiction and affective disorders? Neuropsychopharmacology. 2009;34(1):247.PubMedCrossRef
180.
go back to reference van der Venne P, Balint A, Drews E, Parzer P, Resch F, Koenig J, et al. Pain sensitivity and plasma beta-endorphin in adolescent non-suicidal self-injury. J Affect Disord. 2021;278:199–208.PubMedCrossRef van der Venne P, Balint A, Drews E, Parzer P, Resch F, Koenig J, et al. Pain sensitivity and plasma beta-endorphin in adolescent non-suicidal self-injury. J Affect Disord. 2021;278:199–208.PubMedCrossRef
181.
go back to reference Cakin Memik N, Hunc F, Kalayci S, Demir N, Senturk E, Yildiz Gundogdu O, et al. Assessment of plasma-endogenous opioid neuropeptide levels and psychometric properties of non-suicidal self-injury in adolescents. Arch Suicide Res. 2023;27(2):749–68.PubMedCrossRef Cakin Memik N, Hunc F, Kalayci S, Demir N, Senturk E, Yildiz Gundogdu O, et al. Assessment of plasma-endogenous opioid neuropeptide levels and psychometric properties of non-suicidal self-injury in adolescents. Arch Suicide Res. 2023;27(2):749–68.PubMedCrossRef
182.
go back to reference Johnson BN, McKernan LC, Bruehl S. A theoretical endogenous opioid neurobiological framework for co-occurring pain, trauma, and non-suicidal self-injury. Curr Pain Headache Rep. 2022;26(6):405–14.PubMedPubMedCentralCrossRef Johnson BN, McKernan LC, Bruehl S. A theoretical endogenous opioid neurobiological framework for co-occurring pain, trauma, and non-suicidal self-injury. Curr Pain Headache Rep. 2022;26(6):405–14.PubMedPubMedCentralCrossRef
183.
go back to reference Norelli LJ, Smith HS, Sher L, Blackwood TA. Buprenorphine in the treatment of non-suicidal self-injury: a case series and discussion of the literature. Int J Adolesc Med Health. 2013;25(3):323–30.PubMedCrossRef Norelli LJ, Smith HS, Sher L, Blackwood TA. Buprenorphine in the treatment of non-suicidal self-injury: a case series and discussion of the literature. Int J Adolesc Med Health. 2013;25(3):323–30.PubMedCrossRef
184.
go back to reference Spagnolo B, Calo G, Polgar WE, Jiang F, Olsen CM, Berzetei-Gurske I, et al. Activities of mixed NOP and mu-opioid receptor ligands. Br J Pharmacol. 2008;153(3):609–19.PubMedCrossRef Spagnolo B, Calo G, Polgar WE, Jiang F, Olsen CM, Berzetei-Gurske I, et al. Activities of mixed NOP and mu-opioid receptor ligands. Br J Pharmacol. 2008;153(3):609–19.PubMedCrossRef
185.
go back to reference Zaveri N, Polgar WE, Olsen CM, Kelson AB, Grundt P, Lewis JW, et al. Characterization of opiates, neuroleptics, and synthetic analogs at ORL1 and opioid receptors. Eur J Pharmacol. 2001;428(1):29–36.PubMedPubMedCentralCrossRef Zaveri N, Polgar WE, Olsen CM, Kelson AB, Grundt P, Lewis JW, et al. Characterization of opiates, neuroleptics, and synthetic analogs at ORL1 and opioid receptors. Eur J Pharmacol. 2001;428(1):29–36.PubMedPubMedCentralCrossRef
186.
go back to reference Wnendt S, Kruger T, Janocha E, Hildebrandt D, Englberger W. Agonistic effect of buprenorphine in a nociceptin/OFQ receptor-triggered reporter gene assay. Mol Pharmacol. 1999;56(2):334–8.PubMedCrossRef Wnendt S, Kruger T, Janocha E, Hildebrandt D, Englberger W. Agonistic effect of buprenorphine in a nociceptin/OFQ receptor-triggered reporter gene assay. Mol Pharmacol. 1999;56(2):334–8.PubMedCrossRef
187.
go back to reference Adapa ID, Toll L. Relationship between binding affinity and functional activity of nociceptin/orphanin FQ. Neuropeptides. 1997;31(5):403–8.PubMedCrossRef Adapa ID, Toll L. Relationship between binding affinity and functional activity of nociceptin/orphanin FQ. Neuropeptides. 1997;31(5):403–8.PubMedCrossRef
188.
go back to reference Bloms-Funke P, Gillen C, Schuettler AJ, Wnendt S. Agonistic effects of the opioid buprenorphine on the nociceptin/OFQ receptor. Peptides. 2000;21(7):1141–6.PubMedCrossRef Bloms-Funke P, Gillen C, Schuettler AJ, Wnendt S. Agonistic effects of the opioid buprenorphine on the nociceptin/OFQ receptor. Peptides. 2000;21(7):1141–6.PubMedCrossRef
189.
go back to reference Hakomaki H, Eskola S, Kokki H, Lehtonen M, Rasanen J, Laaksonen S, et al. Central nervous system distribution of buprenorphine in pregnant sheep, fetuses and newborn lambs after continuous transdermal and single subcutaneous extended-release dosing. Eur J Pharm Sci. 2022;178: 106283.PubMedCrossRef Hakomaki H, Eskola S, Kokki H, Lehtonen M, Rasanen J, Laaksonen S, et al. Central nervous system distribution of buprenorphine in pregnant sheep, fetuses and newborn lambs after continuous transdermal and single subcutaneous extended-release dosing. Eur J Pharm Sci. 2022;178: 106283.PubMedCrossRef
190.
go back to reference Hakomaki H, Kokki H, Lehtonen M, Rasanen J, Voipio HM, Ranta VP, et al. Maternal and fetal buprenorphine pharmacokinetics in pregnant sheep during transdermal patch dosing: Buprenorphine pharmacokinetics in pregnant sheep. Eur J Pharm Sci. 2021;165: 105936.PubMedCrossRef Hakomaki H, Kokki H, Lehtonen M, Rasanen J, Voipio HM, Ranta VP, et al. Maternal and fetal buprenorphine pharmacokinetics in pregnant sheep during transdermal patch dosing: Buprenorphine pharmacokinetics in pregnant sheep. Eur J Pharm Sci. 2021;165: 105936.PubMedCrossRef
191.
go back to reference Hakomaki H, Kokki H, Lehtonen M, Ranta VP, Rasanen J, Voipio HM, et al. Pharmacokinetics of buprenorphine in pregnant sheep after intravenous injection. Pharmacol Res Perspect. 2021;9(2): e00726.PubMedPubMedCentralCrossRef Hakomaki H, Kokki H, Lehtonen M, Ranta VP, Rasanen J, Voipio HM, et al. Pharmacokinetics of buprenorphine in pregnant sheep after intravenous injection. Pharmacol Res Perspect. 2021;9(2): e00726.PubMedPubMedCentralCrossRef
192.
go back to reference Jensen ML, Foster D, Upton R, Grant C, Martinez A, Somogyi A. Comparison of cerebral pharmacokinetics of buprenorphine and norbuprenorphine in an in vivo sheep model. Xenobiotica. 2007;37(4):441–57.PubMedCrossRef Jensen ML, Foster D, Upton R, Grant C, Martinez A, Somogyi A. Comparison of cerebral pharmacokinetics of buprenorphine and norbuprenorphine in an in vivo sheep model. Xenobiotica. 2007;37(4):441–57.PubMedCrossRef
193.
go back to reference Ding Z, Raffa RB. Identification of an additional supraspinal component to the analgesic mechanism of action of buprenorphine. Br J Pharmacol. 2009;157(5):831–43.PubMedPubMedCentralCrossRef Ding Z, Raffa RB. Identification of an additional supraspinal component to the analgesic mechanism of action of buprenorphine. Br J Pharmacol. 2009;157(5):831–43.PubMedPubMedCentralCrossRef
194.
go back to reference Khroyan TV, Zaveri NT, Polgar WE, Orduna J, Olsen C, Jiang F, et al. SR 16435 [1-(1-(bicyclo[3.3.1]nonan-9-yl)piperidin-4-yl)indolin-2-one], a novel mixed nociceptin/orphanin FQ/mu-opioid receptor partial agonist: analgesic and rewarding properties in mice. J Pharmacol Exp Ther. 2007;320(2):934–43.PubMedCrossRef Khroyan TV, Zaveri NT, Polgar WE, Orduna J, Olsen C, Jiang F, et al. SR 16435 [1-(1-(bicyclo[3.3.1]nonan-9-yl)piperidin-4-yl)indolin-2-one], a novel mixed nociceptin/orphanin FQ/mu-opioid receptor partial agonist: analgesic and rewarding properties in mice. J Pharmacol Exp Ther. 2007;320(2):934–43.PubMedCrossRef
195.
go back to reference Kiguchi N, Ding H, Ko MC. Therapeutic potentials of NOP and MOP receptor coactivation for the treatment of pain and opioid abuse. J Neurosci Res. 2022;100(1):191–202.PubMedCrossRef Kiguchi N, Ding H, Ko MC. Therapeutic potentials of NOP and MOP receptor coactivation for the treatment of pain and opioid abuse. J Neurosci Res. 2022;100(1):191–202.PubMedCrossRef
196.
go back to reference Murphy NP, Ly HT, Maidment NT. Intracerebroventricular orphanin FQ/nociceptin suppresses dopamine release in the nucleus accumbens of anaesthetized rats. Neuroscience. 1996;75(1):1–4.PubMedCrossRef Murphy NP, Ly HT, Maidment NT. Intracerebroventricular orphanin FQ/nociceptin suppresses dopamine release in the nucleus accumbens of anaesthetized rats. Neuroscience. 1996;75(1):1–4.PubMedCrossRef
197.
go back to reference Murphy NP, Maidment NT. Orphanin FQ/nociceptin modulation of mesolimbic dopamine transmission determined by microdialysis. J Neurochem. 1999;73(1):179–86.PubMedCrossRef Murphy NP, Maidment NT. Orphanin FQ/nociceptin modulation of mesolimbic dopamine transmission determined by microdialysis. J Neurochem. 1999;73(1):179–86.PubMedCrossRef
198.
go back to reference Wang F, Shen W, Cai Y, Zhang X, Du H, Lai M, et al. Buprenorphine reduces methamphetamine intake and drug seeking behavior via activating nociceptin/orphanin FQ peptide receptor in rats. Front Psychiatry. 2022;13: 983595.PubMedPubMedCentralCrossRef Wang F, Shen W, Cai Y, Zhang X, Du H, Lai M, et al. Buprenorphine reduces methamphetamine intake and drug seeking behavior via activating nociceptin/orphanin FQ peptide receptor in rats. Front Psychiatry. 2022;13: 983595.PubMedPubMedCentralCrossRef
199.
go back to reference Ciccocioppo R, Economidou D, Rimondini R, Sommer W, Massi M, Heilig M. Buprenorphine reduces alcohol drinking through activation of the nociceptin/orphanin FQ-NOP receptor system. Biol Psychiatry. 2007;61(1):4–12.PubMedCrossRef Ciccocioppo R, Economidou D, Rimondini R, Sommer W, Massi M, Heilig M. Buprenorphine reduces alcohol drinking through activation of the nociceptin/orphanin FQ-NOP receptor system. Biol Psychiatry. 2007;61(1):4–12.PubMedCrossRef
200.
go back to reference Marquez P, Borse J, Nguyen AT, Hamid A, Lutfy K. The role of the opioid receptor-like (ORL1) receptor in motor stimulatory and rewarding actions of buprenorphine and morphine. Neuroscience. 2008;155(3):597–602.PubMedCrossRef Marquez P, Borse J, Nguyen AT, Hamid A, Lutfy K. The role of the opioid receptor-like (ORL1) receptor in motor stimulatory and rewarding actions of buprenorphine and morphine. Neuroscience. 2008;155(3):597–602.PubMedCrossRef
201.
go back to reference Hu E, Calo G, Guerrini R, Ko MC. Long-lasting antinociceptive spinal effects in primates of the novel nociceptin/orphanin FQ receptor agonist UFP-112. Pain. 2010;148(1):107–13.PubMedCrossRef Hu E, Calo G, Guerrini R, Ko MC. Long-lasting antinociceptive spinal effects in primates of the novel nociceptin/orphanin FQ receptor agonist UFP-112. Pain. 2010;148(1):107–13.PubMedCrossRef
202.
go back to reference Lin AP, Ko MC. The therapeutic potential of nociceptin/orphanin FQ receptor agonists as analgesics without abuse liability. ACS Chem Neurosci. 2013;4(2):214–24.PubMedCrossRef Lin AP, Ko MC. The therapeutic potential of nociceptin/orphanin FQ receptor agonists as analgesics without abuse liability. ACS Chem Neurosci. 2013;4(2):214–24.PubMedCrossRef
203.
go back to reference Cremeans CM, Gruley E, Kyle DJ, Ko MC. Roles of mu-opioid receptors and nociceptin/orphanin FQ peptide receptors in buprenorphine-induced physiological responses in primates. J Pharmacol Exp Ther. 2012;343(1):72–81.PubMedPubMedCentralCrossRef Cremeans CM, Gruley E, Kyle DJ, Ko MC. Roles of mu-opioid receptors and nociceptin/orphanin FQ peptide receptors in buprenorphine-induced physiological responses in primates. J Pharmacol Exp Ther. 2012;343(1):72–81.PubMedPubMedCentralCrossRef
204.
go back to reference Takahashi T, Okubo K, Kojima S, Nishikawa H, Takemura M, Tsubota-Matsunami M, et al. Antihyperalgesic effect of buprenorphine involves nociceptin/orphanin FQ peptide-receptor activation in rats with spinal nerve injury-induced neuropathy. J Pharmacol Sci. 2013;122(1):51–4.PubMedCrossRef Takahashi T, Okubo K, Kojima S, Nishikawa H, Takemura M, Tsubota-Matsunami M, et al. Antihyperalgesic effect of buprenorphine involves nociceptin/orphanin FQ peptide-receptor activation in rats with spinal nerve injury-induced neuropathy. J Pharmacol Sci. 2013;122(1):51–4.PubMedCrossRef
205.
go back to reference Yamamoto T, Shono K, Tanabe S. Buprenorphine activates mu and opioid receptor like-1 receptors simultaneously, but the analgesic effect is mainly mediated by mu receptor activation in the rat formalin test. J Pharmacol Exp Ther. 2006;318(1):206–13.PubMedCrossRef Yamamoto T, Shono K, Tanabe S. Buprenorphine activates mu and opioid receptor like-1 receptors simultaneously, but the analgesic effect is mainly mediated by mu receptor activation in the rat formalin test. J Pharmacol Exp Ther. 2006;318(1):206–13.PubMedCrossRef
206.
go back to reference Ding H, Czoty PW, Kiguchi N, Cami-Kobeci G, Sukhtankar DD, Nader MA, et al. A novel orvinol analog, BU08028, as a safe opioid analgesic without abuse liability in primates. Proc Natl Acad Sci USA. 2016;113(37):E5511–8.PubMedPubMedCentralCrossRef Ding H, Czoty PW, Kiguchi N, Cami-Kobeci G, Sukhtankar DD, Nader MA, et al. A novel orvinol analog, BU08028, as a safe opioid analgesic without abuse liability in primates. Proc Natl Acad Sci USA. 2016;113(37):E5511–8.PubMedPubMedCentralCrossRef
207.
go back to reference Ding H, Kiguchi N, Yasuda D, Daga PR, Polgar WE, Lu JJ, et al. A bifunctional nociceptin and mu opioid receptor agonist is analgesic without opioid side effects in nonhuman primates. Sci Transl Med. 2018;10(456):eaar3483.PubMedPubMedCentralCrossRef Ding H, Kiguchi N, Yasuda D, Daga PR, Polgar WE, Lu JJ, et al. A bifunctional nociceptin and mu opioid receptor agonist is analgesic without opioid side effects in nonhuman primates. Sci Transl Med. 2018;10(456):eaar3483.PubMedPubMedCentralCrossRef
208.
go back to reference Kiguchi N, Ding H, Cami-Kobeci G, Sukhtankar DD, Czoty PW, DeLoid HB, et al. BU10038 as a safe opioid analgesic with fewer side-effects after systemic and intrathecal administration in primates. Br J Anaesth. 2019;122(6):e146–56.PubMedPubMedCentralCrossRef Kiguchi N, Ding H, Cami-Kobeci G, Sukhtankar DD, Czoty PW, DeLoid HB, et al. BU10038 as a safe opioid analgesic with fewer side-effects after systemic and intrathecal administration in primates. Br J Anaesth. 2019;122(6):e146–56.PubMedPubMedCentralCrossRef
210.
go back to reference France CP, Jacobson AE, Woods JH. Irreversible and reversible narcotic agonists: discriminative and analgesic effects of buprenorphine, oxymorphazone, and morphine. NIDA Res Monogr. 1984;49:136–42.PubMed France CP, Jacobson AE, Woods JH. Irreversible and reversible narcotic agonists: discriminative and analgesic effects of buprenorphine, oxymorphazone, and morphine. NIDA Res Monogr. 1984;49:136–42.PubMed
211.
212.
go back to reference Dang VC, Chieng BC, Christie MJ. Prolonged stimulation of mu-opioid receptors produces beta-arrestin-2-mediated heterologous desensitization of alpha(2)-adrenoceptor function in locus ceruleus neurons. Mol Pharmacol. 2012;82(3):473–80.PubMedCrossRef Dang VC, Chieng BC, Christie MJ. Prolonged stimulation of mu-opioid receptors produces beta-arrestin-2-mediated heterologous desensitization of alpha(2)-adrenoceptor function in locus ceruleus neurons. Mol Pharmacol. 2012;82(3):473–80.PubMedCrossRef
213.
go back to reference Volpe DA, McMahon Tobin GA, Mellon RD, Katki AG, Parker RJ, Colatsky T, et al. Uniform assessment and ranking of opioid mu receptor binding constants for selected opioid drugs. Regul Toxicol Pharmacol. 2011;59(3):385–90.PubMedCrossRef Volpe DA, McMahon Tobin GA, Mellon RD, Katki AG, Parker RJ, Colatsky T, et al. Uniform assessment and ranking of opioid mu receptor binding constants for selected opioid drugs. Regul Toxicol Pharmacol. 2011;59(3):385–90.PubMedCrossRef
214.
go back to reference Weltrowska G, Lemieux C, Chung NN, Guo JJ, Wilkes BC, Schiller PW. ’Carba’-carfentanil (trans isomer): a mu opioid receptor (MOR) partial agonist with a distinct binding mode. Bioorg Med Chem. 2014;22(17):4581–6.PubMedPubMedCentralCrossRef Weltrowska G, Lemieux C, Chung NN, Guo JJ, Wilkes BC, Schiller PW. ’Carba’-carfentanil (trans isomer): a mu opioid receptor (MOR) partial agonist with a distinct binding mode. Bioorg Med Chem. 2014;22(17):4581–6.PubMedPubMedCentralCrossRef
215.
go back to reference Alt A, McFadyen IJ, Fan CD, Woods JH, Traynor JR. Stimulation of guanosine-5’-o-(3-[35S]thio)triphosphate binding in digitonin-permeabilized C6 rat glioma cells: evidence for an organized association of mu-opioid receptors and G protein. J Pharmacol Exp Ther. 2001;298(1):116–21.PubMedCrossRef Alt A, McFadyen IJ, Fan CD, Woods JH, Traynor JR. Stimulation of guanosine-5’-o-(3-[35S]thio)triphosphate binding in digitonin-permeabilized C6 rat glioma cells: evidence for an organized association of mu-opioid receptors and G protein. J Pharmacol Exp Ther. 2001;298(1):116–21.PubMedCrossRef
216.
go back to reference Dong R, Wang H, Li D, Lang L, Gray F, Liu Y, et al. Pharmacokinetics of sublingual buprenorphine tablets following single and multiple doses in chinese participants with and without opioid use disorder. Drugs R D. 2019;19(3):255–65.PubMedPubMedCentralCrossRef Dong R, Wang H, Li D, Lang L, Gray F, Liu Y, et al. Pharmacokinetics of sublingual buprenorphine tablets following single and multiple doses in chinese participants with and without opioid use disorder. Drugs R D. 2019;19(3):255–65.PubMedPubMedCentralCrossRef
217.
go back to reference Greenwald MK, Johanson CE, Moody DE, Woods JH, Kilbourn MR, Koeppe RA, et al. Effects of buprenorphine maintenance dose on mu-opioid receptor availability, plasma concentrations, and antagonist blockade in heroin-dependent volunteers. Neuropsychopharmacology. 2003;28(11):2000–9.PubMedCrossRef Greenwald MK, Johanson CE, Moody DE, Woods JH, Kilbourn MR, Koeppe RA, et al. Effects of buprenorphine maintenance dose on mu-opioid receptor availability, plasma concentrations, and antagonist blockade in heroin-dependent volunteers. Neuropsychopharmacology. 2003;28(11):2000–9.PubMedCrossRef
218.
go back to reference Olson KM, Duron DI, Womer D, Fell R, Streicher JM. Comprehensive molecular pharmacology screening reveals potential new receptor interactions for clinically relevant opioids. PLoS ONE. 2019;14(6): e0217371.PubMedPubMedCentralCrossRef Olson KM, Duron DI, Womer D, Fell R, Streicher JM. Comprehensive molecular pharmacology screening reveals potential new receptor interactions for clinically relevant opioids. PLoS ONE. 2019;14(6): e0217371.PubMedPubMedCentralCrossRef
219.
go back to reference Cami-Kobeci G, Polgar WE, Khroyan TV, Toll L, Husbands SM. Structural determinants of opioid and NOP receptor activity in derivatives of buprenorphine. J Med Chem. 2011;54(19):6531–7.PubMedPubMedCentralCrossRef Cami-Kobeci G, Polgar WE, Khroyan TV, Toll L, Husbands SM. Structural determinants of opioid and NOP receptor activity in derivatives of buprenorphine. J Med Chem. 2011;54(19):6531–7.PubMedPubMedCentralCrossRef
220.
go back to reference Toll L, Berzetei-Gurske IP, Polgar WE, Brandt SR, Adapa ID, Rodriguez L, et al. Standard binding and functional assays related to medications development division testing for potential cocaine and opiate narcotic treatment medications. NIDA Res Monogr. 1998;178:440–66.PubMed Toll L, Berzetei-Gurske IP, Polgar WE, Brandt SR, Adapa ID, Rodriguez L, et al. Standard binding and functional assays related to medications development division testing for potential cocaine and opiate narcotic treatment medications. NIDA Res Monogr. 1998;178:440–66.PubMed
221.
go back to reference Wood PL, Charleson SE, Lane D, Hudgin RL. Multiple opiate receptors: differential binding of mu, kappa and delta agonists. Neuropharmacology. 1981;20(12A):1215–20.PubMedCrossRef Wood PL, Charleson SE, Lane D, Hudgin RL. Multiple opiate receptors: differential binding of mu, kappa and delta agonists. Neuropharmacology. 1981;20(12A):1215–20.PubMedCrossRef
222.
go back to reference Santos EJ, Giddings AN, Kandil FA, Negus SS. Climbing behavior by mice as an endpoint for preclinical assessment of drug effects in the absence and presence of pain. Front Pain Res (Lausanne). 2023;4:1150236.PubMedPubMedCentralCrossRef Santos EJ, Giddings AN, Kandil FA, Negus SS. Climbing behavior by mice as an endpoint for preclinical assessment of drug effects in the absence and presence of pain. Front Pain Res (Lausanne). 2023;4:1150236.PubMedPubMedCentralCrossRef
Metadata
Title
Buprenorphine Pharmacodynamics: A Bridge to Understanding Buprenorphine Clinical Benefits
Author
Mellar Davis
Publication date
28-01-2025
Publisher
Springer International Publishing
Published in
Drugs / Issue 2/2025
Print ISSN: 0012-6667
Electronic ISSN: 1179-1950
DOI
https://doi.org/10.1007/s40265-024-02128-y