Antihyperalgesic effect of the cannabinoid agonist WIN55,212-2 is mediated through an interaction with spinal metabotropic glutamate-5 receptors in rats.
In the current study, a possible interaction between spinal cord dorsal horn cannabinoid and mGlu5 receptors was evaluated in rats with a peripheral nerve injury. Following unilateral loose ligation of a sciatic nerve, rats developed decreased withdrawal thresholds to noxious pressure (mechanical hyperalgesia) of the ligated but not the unoperated contralateral hind paw. Systemic (subcutaneous) injection of synthetic cannabinoid agonist WIN55,212-2 increased withdrawal thresholds of both the ligated and the unoperated hind paw. Systemic injection of 2-methyl-6-(phenylethynyl)pyradine (MPEP), an antagonist selective for the mGlu5 receptor, did not alter the antinociceptive and antihyperalgesic effects of systemic WIN55,212-2. Intrathecal (i.t.) injection of WIN55,212-2 increased thresholds of the ligated but not the unoperated hind paw. Intrathecal injection of MPEP reversed the antihyperalgesic effect of i.t. WIN55,212-2. Neither systemic nor i.t. injection of MPEP alone altered withdrawal thresholds. These data suggest that the antihyperalgesic effect of WIN55,212-2 is mediated through an interaction with spinal mGlu5 receptors.
Hama
Aldric T
AT
Department of Pharmacology, Merck Research Laboratories, San Diego, CA 92121, USA.
Urban
Mark O
MO
D000818:Animals; D048588:Benzoxazines; D063386:Cannabinoid Receptor Agonists; D002186:Cannabinoids / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D006930:Hyperalgesia / Q000188:drug therapy*; D008297:Male; D009025:Morpholines / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D009281:Naphthalenes / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D010147:Pain Measurement / Q000187:drug effects / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley; D064529:Receptor, Metabotropic Glutamate 5; D043882:Receptors, Cannabinoid / Q000378:metabolism; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism*; D020426:Sciatic Neuropathy / Q000188:drug therapy; D013116:Spinal Cord / Q000187:drug effects* / Q000378:metabolism
D048588:Benzoxazines; D063386:Cannabinoid Receptor Agonists; D002186:Cannabinoids; D009025:Morpholines; D009281:Naphthalenes; D064529:Receptor, Metabotropic Glutamate 5; D043882:Receptors, Cannabinoid; D018094:Receptors, Metabotropic Glutamate; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone