Abstract |
Exogenous cannabinoids are effective in attenuating neuropathic pain behaviors induced by peripheral nerve injury, but the mechanisms of their effectiveness remain unclear. Here we examined the expression of spinal cannabinoid-1-receptors (CB1Rs) following chronic constriction sciatic nerve injury (CCI) and its relation to the effects of a CBR agonist (Win 55,212-2) on neuropathic pain in rats. CCI induced a time-dependent upregulation of spinal CB1Rs primarily within the ipsilateral superficial spinal cord dorsal horn as revealed by both Western blot and immunohistochemistry. This CCI-induced CB1R upregulation was at least in part mediated through tyrosine kinase receptors (Trk), because intrathecal treatment with the Trk inhibitor K252a (1 microg) for postoperative days 1-6 significantly reduced the CB1R upregulation in CCI rats. At the intracellular level, the mitogen-activated protein kinase (ERK-MAPK) inhibitor PD98059 (1 microg) prevented, while the protein kinase C inhibitor chelerythrine (10 microg) partially reduced, the CCI-induced CB1R upregulation when each agent was administered intrathecally for postoperative days 1-6. Importantly, the CCI-induced upregulation of spinal CB1Rs enhanced the effects of Win 55,212-2 on both thermal hyperalgesia and mechanical allodynia, since inhibition of the CB1R upregulation by PD98059 resulted in a significant reduction of the effects of Win 55,212-2 in CCI rats. These results indicate that upregulation of spinal CB1Rs following peripheral nerve injury may contribute to the therapeutic effects of exogenous cannabinoids on neuropathic pain.
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Authors | Grewo Lim, Backil Sung, Ru-Rong Ji, Jianren Mao |
Journal | Pain
(Pain)
Vol. 105
Issue 1-2
Pg. 275-83
(Sep 2003)
ISSN: 0304-3959 [Print] United States |
PMID | 14499445
(Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)
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Chemical References |
- Analgesics
- Benzoxazines
- Enzyme Inhibitors
- Flavonoids
- Morpholines
- Naphthalenes
- Receptors, Cannabinoid
- Receptors, Drug
- (3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone
- Receptor Protein-Tyrosine Kinases
- Protein Kinase C
- Mitogen-Activated Protein Kinases
- 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one
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Topics |
- Analgesics
(pharmacology)
- Animals
- Behavior, Animal
(drug effects)
- Benzoxazines
- Enzyme Inhibitors
(pharmacology)
- Flavonoids
(pharmacology)
- Ligation
- Male
- Mitogen-Activated Protein Kinases
(antagonists & inhibitors)
- Morpholines
(pharmacology)
- Naphthalenes
(pharmacology)
- Neuralgia
(psychology)
- Pain
(psychology)
- Protein Kinase C
(antagonists & inhibitors)
- Rats
- Rats, Sprague-Dawley
- Receptor Protein-Tyrosine Kinases
(antagonists & inhibitors)
- Receptors, Cannabinoid
- Receptors, Drug
(metabolism)
- Sciatic Nerve
(injuries)
- Spinal Cord
(metabolism)
- Time Factors
- Up-Regulation
(drug effects)
- Wounds and Injuries
(complications, metabolism)
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