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 STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Molecular Pain
Published in: Molecular Pain 1/2009

Open Access 01-12-2009 | Research

Minocycline treatment inhibits microglial activation and alters spinal levels of endocannabinoids in a rat model of neuropathic pain

Authors: Leonardo Guasti, Denise Richardson, Maulik Jhaveri, Khalil Eldeeb, David Barrett, Maurice R Elphick, Stephen PH Alexander, David Kendall, Gregory J Michael, Victoria Chapman

Published in: Molecular Pain | Issue 1/2009

Login to get access

Abstract

Activation of spinal microglia contributes to aberrant pain responses associated with neuropathic pain states. Endocannabinoids (ECs) are present in the spinal cord, and inhibit nociceptive processing; levels of ECs may be altered by microglia which modulate the turnover of endocannabinoids in vitro. Here, we investigate the effect of minocycline, an inhibitor of activated microglia, on levels of the endocannabinoids anandamide and 2-arachidonoylglycerol (2-AG), and the related compound N-palmitoylethanolamine (PEA), in neuropathic spinal cord. Selective spinal nerve ligation (SNL) in rats resulted in mechanical allodynia and the presence of activated microglia in the ipsilateral spinal cord. Chronic daily treatment with minocycline (30 mg/kg, ip for 14 days) significantly reduced the development of mechanical allodynia at days 5, 10 and 14 post-SNL surgery, compared to vehicle-treated SNL rats (P < 0.001). Minocycline treatment also significantly attenuated OX-42 immunoreactivity, a marker of activated microglia, in the ipsilateral (P < 0.001) and contralateral (P < 0.01) spinal cord of SNL rats, compared to vehicle controls. Minocycline treatment significantly (P < 0.01) decreased levels of 2-AG and significantly (P < 0.01) increased levels of PEA in the ipsilateral spinal cord of SNL rats, compared to the contralateral spinal cord. Thus, activation of microglia affects spinal levels of endocannabinoids and related compounds in neuropathic pain states.
Appendix
Available only for authorised users
Literature
1.
Chapman V, Finn DP: Analgesic effects of cannabinoids: sites and mechanisms of action. Reviews in Analgesia 2003, 7: 25–41.CrossRef
2.
3.
Jhaveri MD, Sagar DR, Elmes SJR, Kendall DA, Chapman V: Cannabinoid CB2 receptor-mediated anti-nociception in models of acute and chronic pain. Mol Neurobiol 2007,36(1):26–35.PubMedCrossRef
4.
Yamamoto W, Mikami T, Iwamura H: Involvement of central cannabinoid CB2 receptor in reducing mechanical allodynia in a mouse model of neuropathic pain. Eur J Pharmacol 2008,583(1):56–61.PubMedCrossRef
5.
Yao BB, Hsieh GC, Frost JM, Fan Y, Garrison TR, Daza AV, Grayson GK, Zhu CZ, Pai M, Chandran P, Salyers AK, Wensink EJ, Honore P, Sullivan JP, Dart MJ, Meyer MD: In vitro and in vivo characterization of A-796260: a selective cannabinoid CB2 receptor agonist exhibiting analgesic activity in rodent pain models. Br J Pharmacol 2008,153(2):390–401.PubMedCentralPubMedCrossRef
6.
Sagar DR, Kelly S, Millns PJ, O'Shaughnessey CT, Kendall DA, Chapman V: Inhibitory effects of CB1 and CB2 receptor agonists on responses of DRG neurons and dorsal horn neurons in neuropathic rats. Eur J Neurosci 2005,22(2):371–9.PubMedCrossRef
7.
Zhang J, Hoffert C, Vu HK, Groblewski T, Ahmad S, O'Donnell D: Induction of CB2 receptor expression in the rat spinal cord of neuropathic but not inflammatory chronic pain models. Eur J Neurosci 2003,17(12):2750–4.PubMedCrossRef
8.
Beltramo M, Bernardini N, Bertorelli R, Campanella M, Nicolussi E, Fredduzzi S, Reggiani A: CB2 receptor mediated anti-hyperalgesia: possible direct involvement of neural mechanisms. Eur J Neurosci 2006, 23: 1530–1538.PubMedCrossRef
9.
Romero-Sandoval A, Nutile-McMenemy N, DeLeo JA: Spinal microglial and perivascular cell cannabinoid receptor type 2 activation reduces behavioral hypersensitivity without tolerance after peripheral nerve injury. Anesthesiology 2008,108(4):722–34.PubMedCentralPubMedCrossRef
10.
Wotherspoon G, Fox A, McIntyre P, Colley S, Bevan S, Winter J: Peripheral nerve injury induces cannabinoid receptor 2 protein expression in rat sensory neurons. Neuroscience 2005,135(1):235–45.PubMedCrossRef
11.
Cabral GA, Harmon KN, Carlisle SJ: Cannabinoid-mediated inhibition of inducible nitric oxide production by rat microglial cells: evidence for CB1 receptor participation. Adv Exp Med Biol 2001, 493: 207–14.PubMedCrossRef
12.
Cabral GA, Raborn ES, Griffin L, Dennis J, Marciano-Cabral F: CB2 receptors in the brain: role in central immune function. Br J Pharmacol 2008, 153: 240–51.PubMedCentralPubMedCrossRef
13.
14.
Narita M, Yoshida T, Nakajima M, Narita M, Miyatake M, Takagi T, Yajima Y, Suzuki Tyr2006: Direct evidence for spinal cord microglia in the development of a neuropathic pain-like state in mice. J Neurochem 2006, 97: 1337–1348.PubMedCrossRef
15.
Bye N, Habgood MD, Callaway JK, Malakooti N, Potter A, Kossmann T, Morganti-Kossmann MC: Transient neuroprotection by minocycline following traumatic brain injury is associated with attenuated microglial activation but no changes in cell apoptosis or neutrophil infiltration. Exp Neurol 2007, 204: 220–233.PubMedCrossRef
16.
Choi Y, Kim H-S, Shin KY, Kim EM, Kim M, Kim HS, Park CH, Jeong YH, Yoo J, Lee JP, Chang KA, Kim S, Suh YH: Minocycline attenuates neuronal cell death and improves cognitive impairment in Alzheimer's disease models. Neuropsychopharmacology. 2007,32(11):2393–2404.PubMedCrossRef
17.
Raghavendra V, Tanga F, DeLeo JA: Inhibition of microglial activation attenuates the development but not existing hypersensitivity in a rat model of neuropathy. J Pharmacol Exp Ther 2003,306(2):624–30.PubMedCrossRef
18.
Ledeboer A, Sloane EM, Milligan ED, Frank MG, Mahony JH, Maier SF, Watkins LR: Minocycline attenuates mechanical allodynia and proinflammatory cytokine expression in rat models of pain facilitation. Pain 2005,115(1–2):71–83.PubMedCrossRef
19.
Piao ZG, Cho IH, Park CK, Hong JP, Choi SY, Lee SJ, Lee S, Park K, Kim JS, Oh SB: Activation of glia and microglial p38 MAPK in medullary dorsal horn contributes to tactile hypersensitivity following trigeminal sensory nerve injury. Pain 2006,121(3):219–31.PubMedCrossRef
20.
Wallace VC, Blackbeard J, Segerdahl AR, Hasnie F, Pheby T, McMahon SB, Rice AS: Characterization of rodent models of HIV-gp120 and anti-retroviral-associated neuropathic pain. Brain 2007,130(Pt 10):2688–702.PubMedCentralPubMedCrossRef
21.
Carrier EJ, Kearn CS, Barkmeier AJ, Breese NM, Yang W, Nithipatikom K, Pfister SL, Campbell WB, Hillard CJ: Cultured rat microglial cells synthesize the endocannabinoid 2-arachidonylglycerol, which increases proliferation via a CB2 receptor-dependent mechanism. Mol Pharmacol 2004,65(4):999–1007.PubMedCrossRef
22.
Muccioli GG, Xu C, Odah E, Cudaback E, Cisneros JA, Lambert DM, López Rodríguez ML, Bajjalieh S, Stella N: Identification of a novel endocannabinoid-hydrolyzing enzyme expressed by microglial cells. J Neurosci 2007,27(11):2883–9.PubMedCrossRef
23.
Petrosino S, Palazzo E, de Novellis V, Bisogno T, Rossi F, Maione S, Di Marzo V: Changes in spinal and supraspinal endocananbinoid levels in neuropathic rats. Neuropharmacology. 2007,52(2):415–422.PubMedCrossRef
24.
Schomacher M, Muller HD, Sommer C, Schwab S, Schabitz WR: Endocannabinoids mediate neuroprotection after transient focal cerebral ischemia. Brain Res 2008, 1240: 213–220.PubMedCrossRef
25.
Leung D, Saghatelian A, Simon GM, Cravatt BF: Inactivation of N-acyl phosphatidylethanolamine phospholipase D reveals multiple mechanisms for the biosynthesis of endocannabinoids. Biochemistry 2006,45(15):4720–4726.PubMedCentralPubMedCrossRef
26.
27.
Walter L, Franklin A, Witting A, Wade C, Xie Y, Kunos G, Mackie K, Stella N: Nonpsychotropic cannabinoid receptors regulate microglial cell migration. J Neurosci 2003,23(4):1398–405.PubMed
28.
Blackbeard J, O'Dea KP, Wallace VC, Segerdahl A, Pheby T, Takata M, Field MJ, Rice AS: Quantification of the rat spinal microglial response to peripheral nerve injury as revealed by immunohistochemical image analysis and flow cytometry. J Neurosci Methods 2007,164(2):207–17.PubMedCentralPubMedCrossRef
29.
Clark AK, Gentry C, Bradbury EJ, McMahon SB, Malcangio M: Role of spinal microglia in rat models of peripheral nerve injury and inflammation. Eur J Pain 2007, 11: 223–230.PubMedCrossRef
30.
Tsuda M, Inoue K, Salter MW: Neuropathic pain and spinal microglia: a big problem from molecules in small glia. Trends Neurosci. 2005,28(2):101–107.PubMedCrossRef
31.
Gonzalez JC, Egea J, Del Carmen Godino M, Fernandez-Gomez FJ, Sanchez-Prieto J, Gandia L, Garcia AG, Jordan J, Hernandez-Guijo JM: Neuroprotectant minocycline depresses gluatamatergic neurotransmission and Ca 2+ signalling in hippocampal neurones. Eur J Neurosci 2007, 26: 2481–2495.PubMedCrossRef
32.
Hailer NP: Immunosuppression after traumatic or ischemic CNS damage: it is neuroprotective and illuminates the role of microglial cells. Progress in Neurobiology 2008, 84: 211–233.PubMedCrossRef
33.
Walter L, Franklin A, Witting A, Möller T, Stella N: Astrocytes in culture produce anandamide and other acylethanolamides. J Biol Chem 2002, 277: 20869–20876.PubMedCrossRef
34.
Witting A, Walter L, Wacker J, Möller T, Stella N: P2X7 receptors control 2-arachidonoylglycerol production by microglial cells. Proc Natl Acad Sci USA 2004, 101: 3214–9.PubMedCentralPubMedCrossRef
35.
Lo Verme J, Russo R, La Rana G, Fu J, Farthing J, Mattace-Raso G, Meli R, Hohmann A, Calignano A, Piomelli D: Rapid broad-spectrum analgesia through activation of peroxisome proliferator-activated receptor-α. J Pharmacol Exp Ther. 2006,319(3):1051–1061.CrossRef
36.
Costa B, Comelli F, Bettoni I, Colleoni M, Giagnoni G: The endogenous fatty acid amide, palmitoylethanolamide, has anti-allodynic and anti-hyperalgesic effects in a murine model of neuropathic pain: involvement of CB(1), TRPV1 and PPARgamma receptors and neurotrophic factors. Pain 2008, 139: 541–550.PubMedCrossRef
37.
Calignano A, La Rana G, Giuffrida A, Piomelli D: Control of pain initiation by endogenous cannabinoids. Nature 1998,394(6690):277–81.PubMedCrossRef
38.
Facci L, Dal Toso R, Romanello S, Buriani A, Skaper SD, Leon A: Mast cells express a peripheral cannabinoid receptor with differential sensitivity to anandamide and palmitoylethanolamide. Proc Natl Acad Sci 1995,92(8):3376–80.PubMedCentralPubMedCrossRef
39.
Griffin G, Tao Q, Abood ME: Cloning and pharmacological characterization of the rat CB(2) cannabinoid receptor. J Pharmacol Exp Ther 2000,292(3):886–94.PubMed
40.
Walker JM, Hohmann AG: Cannabinoid mechanisms of pain suppression. Handb Exp Pharmacol 2005, 168: 509–54.PubMedCrossRef
41.
Lo Verme J, Fu J, Astarita G, La Rana G, Russo R, Calignano A, Piomelli D: The nuclear receptor peroxisome proliferator-activated receptor-alpha mediates the anti-inflammatory actions of palmitoylethanolamide. Mol Pharmacol 2005,67(1):15–9.PubMedCrossRef
42.
Kim SH, Chung JM: An experimental model for peripheral neuropathy produced by segmental spinal nerve ligation in the rat. Pain 1992,50(3):355–63.PubMedCrossRef
43.
Richardson D, Ortori CA, Chapman V, Kendall DA, Barrett DA: Quantitative profiling of endocannabinoids and related compounds in rat brain using liquid chromatography-tandem electrospray ionization mass spectrometry. Anal Biochem 2007,360(2):216–26.PubMedCrossRef
44.
Paylor B, Holt S, Fowler CJ: The potency of the fatty acid amide hydrolase inhibitor URB597 is dependent upon the assay pH. Pharmacological Research 2006, 54: 481–485.PubMedCrossRef
Metadata
Title
Minocycline treatment inhibits microglial activation and alters spinal levels of endocannabinoids in a rat model of neuropathic pain
Authors
Leonardo Guasti
Denise Richardson
Maulik Jhaveri
Khalil Eldeeb
David Barrett
Maurice R Elphick
Stephen PH Alexander
David Kendall
Gregory J Michael
Victoria Chapman
Publication date
01-12-2009
Publisher
BioMed Central
Published in
Molecular Pain / Issue 1/2009
Electronic ISSN: 1744-8069
DOI
https://doi.org/10.1186/1744-8069-5-35

Other articles of this Issue 1/2009

Molecular Pain 1/2009 Go to the issue

Research

Increased chemokine signaling in a model of HIV1-associated peripheral neuropathy

Research

Proinflammatory-activated trigeminal satellite cells promote neuronal sensitization: relevance for migraine pathology

Research

Antidepressants inhibit P2X4 receptor function: a possible involvement in neuropathic pain relief

Research

Nociception-induced spatial and temporal plasticity of synaptic connection and function in the hippocampal formation of rats: a multi-electrode array recording

Research

Enhanced pre-synaptic glutamate release in deep-dorsal horn contributes to calcium channel alpha-2-delta-1 protein-mediated spinal sensitization and behavioral hypersensitivity

Short report

NR2B receptor blockade inhibits pain-related sensitization of amygdala neurons