Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2018

Open Access 01-12-2018 | Research

Preemptive intrathecal administration of endomorphins relieves inflammatory pain in male mice via inhibition of p38 MAPK signaling and regulation of inflammatory cytokines

Authors: Ting Zhang, Nan Zhang, Run Zhang, Weidong Zhao, Yong Chen, Zilong Wang, Biao Xu, Mengna Zhang, Xuerui Shi, Qinqin Zhang, Yuanyuan Guo, Jian Xiao, Dan Chen, Quan Fang

Published in: Journal of Neuroinflammation | Issue 1/2018

Login to get access

Abstract

Background

Preemptive administration of analgesic drugs reduces perceived pain and prolongs duration of antinociceptive action. Whereas several lines of evidence suggest that endomorphins, the endogenous mu-opioid agonists, attenuate acute and chronic pain at the spinal level, their preemptive analgesic effects remain to be determined. In this study, we evaluated the anti-allodynic activities of endomorphins and explored their mechanisms of action after preemptive administration in a mouse model of inflammatory pain.

Methods

The anti-allodynic activities of preemptive intrathecal administration of endomorphin-1 and endomorphin-2 were investigated in complete Freund’s adjuvant (CFA)-induced inflammatory pain model and paw incision-induced postoperative pain model. The modulating effects of endomorphins on the expression of p38 mitogen-activated protein kinase (p38 MAPK) and inflammatory mediators in dorsal root ganglion (DRG) of CFA-treated mice were assayed by real-time reverse transcription-polymerase chain reaction (RT-PCR), Western blotting, or immunofluorescence staining.

Results

Preemptive intrathecal injection of endomorphins dose-dependently attenuated CFA-induced mechanical allodynia via the mu-opioid receptor and significantly reversed paw incision-induced allodynia. In addition, CFA-caused increase of phosphorylated p38 MAPK in DRG was dramatically reduced by preemptive administration of endomorphins. Repeated intrathecal application of the specific p38 MAPK inhibitor SB203580 reduced CFA-induced mechanical allodynia as well. Further RT-PCR assay showed that endomorphins regulated the mRNA expression of inflammatory cytokines in DRGs induced by peripheral inflammation.

Conclusions

Our findings reveal a novel mechanism by which preemptive treatment of endomorphins attenuates inflammatory pain through regulating the production of inflammatory cytokines in DRG neurons via inhibition of p38 MAPK phosphorylation.
Appendix
Available only for authorised users
Literature
1.
Zadina JE, Hackler L, Ge LJ, Kastin AJ. A potent and selective endogenous agonist for the mu-opiate receptor. Nature. 1997;386:499–502.CrossRef
2.
Hao S, Wolfe D, Glorioso JC, Mata M, Fink DJ. Effects of transgene-mediated endomorphin-2 in inflammatory pain. Eur J Pain. 2009;13:380–6.CrossRef
3.
Xie H, Woods JH, Traynor JR, Ko MC. The spinal antinociceptive effects of endomorphins in rats: behavioral and G protein functional studies. Anesth Analg. 2008;106:1873–81.CrossRef
4.
Przewlocka B, Mika J, Labuz D, Toth G, Przewlocki R. Spinal analgesic action of endomorphins in acute, inflammatory and neuropathic pain in rats. Eur J Pharmacol. 1999;367:189–96.CrossRef
5.
Soignier RD, Vaccarino AL, Brennan AM, Kastin AJ, Zadina JE. Analgesic effects of endomorphin-1 and endomorphin-2 in the formalin test in mice. Life Sci. 2000;67:907–12.CrossRef
6.
McDougall JJ, Baker CL, Hermann PM. Attenuation of knee joint inflammation by peripherally administered endomorphin-1. J Mol Neurosci. 2004;22:125–37.CrossRef
7.
Feehan AK, Morgenweck J, Zhang X, Amgott-Kwan AT, Zadina JE. Novel endomorphin analogs are more potent and longer-lasting analgesics in neuropathic, inflammatory, postoperative, and visceral pain relative to morphine. J Pain. 2017;18:1526–41.PubMed
8.
Mousa SA, Machelska H, Schafer M, Stein C. Immunohistochemical localization of endomorphin-1 and endomorphin-2 in immune cells and spinal cord in a model of inflammatory pain. J Neuroimmunol. 2002;126:5–15.CrossRef
9.
Obara I, Przewlocki R, Przewlocka B. Local peripheral effects of mu-opioid receptor agonists in neuropathic pain in rats. Neurosci Lett. 2004;360:85–9.CrossRef
10.
Przewlocki R, Labuz D, Mika J, Przewlocka B, Tomboly C, Toth G. Pain inhibition by endomorphins. Ann N Y Acad Sci. 1999;897:154–64.CrossRef
11.
Czapla MA, Gozal D, Alea OA, Beckerman RC, Zadina JE. Differential cardiorespiratory effects of endomorphin 1, endomorphin 2, DAMGO, and morphine. Am J Respir Crit Care Med. 2000;162:994–9.CrossRef
12.
Wilson AM, Soignier RD, Zadina JE, Kastin AJ, Nores WL, Olson RD, Olson GA. Dissociation of analgesic and rewarding effects of endomorphin-1 in rats. Peptides. 2000;21:1871–4.CrossRef
13.
Mizoguchi H, Watanabe H, Hayashi T, Sakurada W, Sawai T, Fujimura T, Sakurada T, Sakurada S. Possible involvement of dynorphin A-(1-17) release via mu1-opioid receptors in spinal antinociception by endomorphin-2. J Pharmacol Exp Ther. 2006;317:362–8.CrossRef
14.
Wu HE, Hung KC, Mizoguchi H, Fujimoto JM, Tseng LF. Acute antinociceptive tolerance and asymmetric cross-tolerance between endomorphin-1 and endomorphin-2 given intracerebroventricularly in the mouse. J Pharmacol Exp Ther. 2001;299:1120–5.PubMed
15.
Basbaum AI, Bautista DM, Scherrer G, Julius D. Cellular and molecular mechanisms of pain. Cell. 2009;139:267–84.CrossRef
16.
Woolf CJ. Evidence for a central component of post-injury pain hypersensitivity. Nature. 1983;306:686–8.CrossRef
17.
Chen Y, Sommer C. Activation of the nociceptin opioid system in rat sensory neurons produces antinociceptive effects in inflammatory pain: involvement of inflammatory mediators. J Neurosci Res. 2007;85:1478–88.CrossRef
18.
Gu ZH, Wang B, Kou ZZ, Bai Y, Chen T, Dong YL, Li H, Li YQ. Endomorphins: promising endogenous opioid peptides for the development of novel analgesics. Neurosignals. 2017;25:98–116.CrossRef
19.
Li JL, Ding YQ, Li YQ, Li JS, Nomura S, Kaneko T, Mizuno N. Immunocytochemical localization of mu-opioid receptor in primary afferent neurons containing substance P or calcitonin gene-related peptide. A light and electron microscope study in the rat. Brain Res. 1998;794:347–52.CrossRef
20.
Greenwell TN, Martin-Schild S, Inglis FM, Zadina JE. Colocalization and shared distribution of endomorphins with substance P, calcitonin gene-related peptide, gamma-aminobutyric acid, and the mu opioid receptor. J Comp Neurol. 2007;503:319–33.CrossRef
21.
Borzsei R, Pozsgai G, Bagoly T, Elekes K, Pinter E, Szolcsanyi J, Helyes Z. Inhibitory action of endomorphin-1 on sensory neuropeptide release and neurogenic inflammation in rats and mice. Neuroscience. 2008;152:82–8.CrossRef
22.
Abbadie C, Bhangoo S, De Koninck Y, Malcangio M, Melik-Parsadaniantz S, White FA. Chemokines and pain mechanisms. Brain Res Rev. 2009;60:125–34.CrossRef
23.
DeLeo JAY, Yezierski RP. The role of neuroinflammation and neuroimmune activation in persistent pain. Pain. 2001;90:1–6.CrossRef
24.
Kawasaki Y, Zhang L, Cheng JK, Ji RR. Cytokine mechanisms of central sensitization: distinct and overlapping role of interleukin-1beta, interleukin-6, and tumor necrosis factor-alpha in regulating synaptic and neuronal activity in the superficial spinal cord. J Neurosci. 2008;28:5189–94.CrossRef
25.
Ji RR, Gereau RWT, Malcangio M, Strichartz GR. MAP kinase and pain. Brain Res Rev. 2009;60:135–48.CrossRef
26.
Svensson CI, Marsala M, Westerlund A, Calcutt NA, Campana WM, Freshwater JD, Catalano R, Feng Y, Protter AA, Scott B, Yaksh TL. Activation of p38 mitogen-activated protein kinase in spinal microglia is a critical link in inflammation-induced spinal pain processing. J Neurochem. 2003;86:1534–44.CrossRef
27.
Azuma Y, Ohura K. Endomorphin-2 modulates productions of TNF-alpha, IL-1beta, IL-10, and IL-12, and alters functions related to innate immune of macrophages. Inflammation. 2002;26:223–32.CrossRef
28.
Azuma Y, Ohura K. Endomorphins 1 and 2 inhibit IL-10 and IL-12 production and innate immune functions, and potentiate NF-kappa B DNA binding in THP-1 differentiated to macrophage-like cells. Scand J Immunol. 2002;56:260–9.CrossRef
29.
Li WY, Yang JJ, Zhu SH, Liu HJ, Xu JG. Endomorphins and ohmefentanyl in the inhibition of immunosuppressant function in rat peritoneal macrophages: an experimental in vitro study. Curr Ther Res Clin Exp. 2008;69:56–64.CrossRef
30.
Li ZH, Chu NS, Shan LD, Gong S, Yin QZ, Jiang XH. Inducible expression of functional mu opioid receptors in murine dendritic cells. J NeuroImmune Pharmacol. 2009;4:359–67.CrossRef
31.
Liu J, Yan L, Niu R, Tian L, Zhang Q, Quan J, Liu H, Wei S, Guo Q. Protection effect of endomorphins on advanced glycation end products induced injury in endothelial cells. J Diabetes Res. 2013; 2013:105780.
32.
Wang ZL, Li N, Wang P, Tang HH, Han ZL, Song JJ, Li XH, Yu HP, Zhang T, Zhang R, et al. Pharmacological characterization of EN-9, a novel chimeric peptide of endomorphin-2 and neuropeptide FF that produces potent antinociceptive activity and limited tolerance. Neuropharmacology. 2016;108:364–72.CrossRef
33.
Kilkenny C, Browne W, Cuthill IC, Emerson M, Altman DG, Group NCRRGW. Animal research: reporting in vivo experiments: the ARRIVE guidelines. Br J Pharmacol. 2010;160:1577–9.CrossRef
34.
Hylden JL, Wilcox GL. Intrathecal morphine in mice: a new technique. Eur J Pharmacol. 1980;67:313–6.CrossRef
35.
Stein C, Millan MJ, Herz A. Unilateral inflammation of the hindpaw in rats as a model of prolonged noxious-stimulation - alterations in behavior and nociceptive thresholds. Pharmacol Biochem Behav. 1988;31:445–51.CrossRef
36.
Clark JD, Qiao YL, Li XQ, Shi XY, Angst MS, Yeomans DC. Blockade of the complement C5a receptor reduces incisional allodynia, edema, and cytokine expression. Anesthesiology. 2006;104:1274–82.CrossRef
37.
Liang DY, Li X, Shi X, Sun Y, Sahbaie P, Li WW, Clark JD. The complement component C5a receptor mediates pain and inflammation in a postsurgical pain model. Pain. 2012;153:366–72.CrossRef
38.
Sun Y, Li XQ, Sahbaie P, Shi XY, Li WW, Liang DY, Clark JD. miR-203 regulates nociceptive sensitization after incision by controlling phospholipase A2 activating protein expression. Anesthesiology. 2012;117:626–38.CrossRef
39.
Chen Y, Kanju P, Fang Q, Lee SH, Parekh PK, Lee W, Moore C, Brenner D, Gereau RWT, Wang F, Liedtke W. TRPV4 is necessary for trigeminal irritant pain and functions as a cellular formalin receptor. Pain. 2014;155:2662–72.CrossRef
40.
Chen JJ, Dai L, Zhao LX, Zhu X, Cao S, Gao YJ. Intrathecal curcumin attenuates pain hypersensitivity and decreases spinal neuroinflammation in rat model of monoarthritis. Sci Rep. 2015;5:10278.CrossRef
41.
Ji RR, Zhang Q, Law PY, Low HH, Elde R, Hokfelt T. Expression of mu-, delta-, and kappa-opioid receptor-like immunoreactivities in rat dorsal root ganglia after carrageenan-induced inflammation. J Neurosci. 1995;15:8156–66.CrossRef
42.
Chen Y, Geis C, Sommer C. Activation of TRPV1 contributes to morphine tolerance: involvement of the mitogen-activated protein kinase signaling pathway. J Neurosci. 2008;28:5836–45.CrossRef
43.
Zhang JM, An J. Cytokines, inflammation, and pain. Int Anesthesiol Clin. 2007;45:27–37.CrossRef
44.
Zadina JE, Nilges MR, Morgenweck J, Zhang X, Hackler L, Fasold MB. Endomorphin analog analgesics with reduced abuse liability, respiratory depression, motor impairment, tolerance, and glial activation relative to morphine. Neuropharmacology. 2016;105:215–27.CrossRef
45.
Yamamoto T, Ohtori S, Chiba T. Effects of pre-emptively administered nociceptin on the development of thermal hyperalgesia induced by two models of experimental mononeuropathy in the rat. Brain Res. 2000;871:192–200.CrossRef
46.
Woolf CJ, Chong MS. Preemptive analgesia--treating postoperative pain by preventing the establishment of central sensitization. Anesth Analg. 1993;77:362–79.CrossRef
47.
Przewlocki R, Hassan AH, Lason W, Epplen C, Herz A, Stein C. Gene expression and localization of opioid peptides in immune cells of inflamed tissue: functional role in antinociception. Neuroscience. 1992;48:491–500.CrossRef
48.
Sakurada S, Hayashi T, Yuhki M, Orito T, Zadina JE, Kastin AJ, Fujimura T, Murayama K, Sakurada C, Sakurada T, et al. Differential antinociceptive effects induced by intrathecally administered endomorphin-1 and endomorphin-2 in the mouse. Eur J Pharmacol. 2001;427:203–10.CrossRef
49.
Puehler W, Zollner C, Brack A, Shaqura MA, Krause H, Schafer M, Stein C. Rapid upregulation of mu opioid receptor mRNA in dorsal root ganglia in response to peripheral inflammation depends on neuronal conduction. Neuroscience. 2004;129:473–9.CrossRef
50.
Jin SX, Zhuang ZY, Woolf CJ, Ji RR. p38 mitogen-activated protein kinase is activated after a spinal nerve ligation in spinal cord microglia and dorsal root ganglion neurons and contributes to the generation of neuropathic pain. J Neurosci. 2003;23:4017–22.CrossRef
51.
Tsuda M, Mizokoshi A, Shigemoto-Mogami Y, Koizumi S, Inoue K. Activation of p38 mitogen-activated protein kinase in spinal hyperactive microglia contributes to pain hypersensitivity following peripheral nerve injury. Glia. 2004;45:89–95.CrossRef
52.
Zhuang ZY, Gerner P, Woolf CJ, Ji RR. ERK is sequentially activated in neurons, microglia, and astrocytes by spinal nerve ligation and contributes to mechanical allodynia in this neuropathic pain model. Pain. 2005;114:149–59.CrossRef
53.
Macey TA, Lowe JD, Chavkin C. Mu opioid receptor activation of ERK1/2 is GRK3 and arrestin dependent in striatal neurons. J Biol Chem. 2006;281:34515–24.CrossRef
54.
Belcheva MM, Haas PD, Tan Y, Heaton VM, Coscia CJ. The fibroblast growth factor receptor is at the site of convergence between mu-opioid receptor and growth factor signaling pathways in rat C6 glioma cells. J Pharmacol Exp Ther. 2002;303:909–18.CrossRef
55.
Messmer D, Hatsukari I, Hitosugi N, Schmidt-Wolf IGH, Singhal PC. Morphine reciprocally regulates IL-10 and IL-12 production by monocyte-derived human dendritic cells and enhances T cell activation. Mol Med. 2006;12:284–90.PubMedPubMedCentral
56.
Ji RR, Nackley A, Huh Y, Terrando N, Maixner W. Neuroinflammation and central sensitization in chronic and widespread pain. Anesthesiology. 2018;129:343–66.CrossRef
57.
Ji RR, Xu ZZ, Gao YJ. Emerging targets in neuroinflammation-driven chronic pain. Nat Rev Drug Discov. 2014;13:533–48.CrossRef
58.
DeLeo JA, Yezierski RP. The role of neuroinflammation and neuroimmune activation in persistent pain. Pain. 2001;90:1–6.CrossRef
59.
Hanisch UK. Microglia as a source and target of cytokines. Glia. 2002;40:140–55.CrossRef
60.
Xu JT, Xin WJ, Zang Y, Wu CY, Liu XG. The role of tumor necrosis factor-alpha in the neuropathic pain induced by lumbar 5 ventral root transection in rat. Pain. 2006;123:306–21.CrossRef
61.
Sweitzer S, Martin D, DeLeo JA. Intrathecal interleukin-1 receptor antagonist in combination with soluble tumor necrosis factor receptor exhibits an anti-allodynic action in a rat model of neuropathic pain. Neuroscience. 2001;103:529–39.CrossRef
62.
Ji RR, Berta T, Nedergaard M. Glia and pain: is chronic pain a gliopathy? Pain. 2013;154(Suppl 1):S10–28.CrossRef
63.
Kiguchi N, Maeda T, Kobayashi Y, Fukazawa Y, Kishioka S. Macrophage inflammatory protein-1alpha mediates the development of neuropathic pain following peripheral nerve injury through interleukin-1beta up-regulation. Pain. 2010;149:305–15.CrossRef
64.
Old EA, Nadkarni S, Grist J, Gentry C, Bevan S, Kim KW, Mogg AJ, Perretti M, Malcangio M. Monocytes expressing CX3CR1 orchestrate the development of vincristine-induced pain. J Clin Invest. 2014;124:2023–36.CrossRef
65.
Melik Parsadaniantz S, Rivat C, Rostene W, Reaux-Le Goazigo A. Opioid and chemokine receptor crosstalk: a promising target for pain therapy? Nat Rev Neurosci. 2015;16:69–78.CrossRef
Metadata
Title
Preemptive intrathecal administration of endomorphins relieves inflammatory pain in male mice via inhibition of p38 MAPK signaling and regulation of inflammatory cytokines
Authors
Ting Zhang
Nan Zhang
Run Zhang
Weidong Zhao
Yong Chen
Zilong Wang
Biao Xu
Mengna Zhang
Xuerui Shi
Qinqin Zhang
Yuanyuan Guo
Jian Xiao
Dan Chen
Quan Fang
Publication date
01-12-2018
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2018
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/s12974-018-1358-3

Other articles of this Issue 1/2018

Journal of Neuroinflammation 1/2018 Go to the issue

Research

The glycoprotein GPNMB attenuates astrocyte inflammatory responses through the CD44 receptor

Research

Age-related deregulation of TDP-43 after stroke enhances NF-κB-mediated inflammation and neuronal damage

Research

Laquinimod protects the optic nerve and retina in an experimental autoimmune encephalomyelitis model

Research

Lymphotoxin β receptor-mediated NFκB signaling promotes glial lineage differentiation and inhibits neuronal lineage differentiation in mouse brain neural stem/progenitor cells

Research

Peripheral myeloid cells contribute to brain injury in male neonatal mice

Research

Intracellular inflammatory and antioxidant pathways in postmortem frontal cortex of subjects with major depression: effect of antidepressants