title: Physiological evidence of a postsynaptic inhibition of the tail flick reflex by a cannabinoid receptor agonist.
abstract: Current evidence indicates that cannabinoids are antinociceptive and this effect is in part mediated by spinal mechanisms. Anatomical studies have localized cannabinoid CB(1) receptors to pre- and postsynaptic sites within the spinal cord. However, behavioural tests have not clearly indicated the relative importance of each of these sites. In this study, the tail flick test was used as a model of acute pain in the rat to determine the site of action of WIN 55,212-2 ((R)-(+)-[2,3-dihydro-5-methyl-3[(4-morpholinyl)methyl]pyrolo[1,2,3-de]-1,4-benzoxazinyl]-(1-naphthalenyl)methanone mesylate), a synthetic cannabinoid receptor agonist. WIN 55,212-2 (3 mg/kg, i.p.) increased the latency of tail withdrawal from a noxious radiant heat source, indicating it is antinociceptive in this model. Using the same paradigm, WIN 55,212-2 was then tested against the synaptically-induced nociceptive hypersensitivity in response to noxious thermal stimulation of the tail (hot water tail immersion). WIN 55,212-2 blocked this hypersensitivity, confirming a spinal site of action of the cannabinoid receptor agonist. Further, WIN 55,212-2 blocked the nociceptive hypersensitivity induced by intrathecal administration of substance P. As substance P acts on postsynaptic tachykinin NK1 receptors in the dorsal horn of the spinal cord, the data are interpreted to suggest that WIN 55,212-2 expressed its anti-hypersensitivity effects at least partially via a postsynaptic site of action; the data do not rule out a presynaptic site of action. This study suggests that cannabinoids may induce analgesia via a postsynaptic site of action in the spinal cord, as well as the possibility that they may interact with substance P signaling.
authors.affiliation: Department of Psychiatry, McGill University, 1033 Pine Avenue West, Montreal, Quebec, Canada H3A 1A1. dablehl@mcmaster.ca
authors.forename: Liliane J
authors.initials: LJ
authors.lastname: Dableh
authors.forename: Kiran
authors.initials: K
authors.lastname: Yashpal
authors.forename: James L
authors.initials: JL
authors.lastname: Henry
mesh_terms: D000700:Analgesics / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D048588:Benzoxazines / Q000494:pharmacology* / Q000627:therapeutic use; D063386:Cannabinoid Receptor Agonists; D006358:Hot Temperature; D008297:Male; D009025:Morpholines / Q000494:pharmacology* / Q000627:therapeutic use; D009281:Naphthalenes / Q000494:pharmacology* / Q000627:therapeutic use; D009433:Neural Inhibition / Q000187:drug effects*; D018377:Neurotransmitter Agents / Q000494:pharmacology; D009619:Nociceptors / Q000378:metabolism; D010146:Pain / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D010147:Pain Measurement / Q000187:drug effects; D010812:Physical Stimulation; D051381:Rats; D017207:Rats, Sprague-Dawley; D018040:Receptors, Neurokinin-1 / Q000378:metabolism; D012018:Reflex / Q000187:drug effects*; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology; D013373:Substance P / Q000494:pharmacology; D055366:Synaptic Potentials / Q000187:drug effects*; D013623:Tail / Q000187:drug effects* / Q000502:physiology; D013997:Time Factors
chemical_list: D000700:Analgesics; D048588:Benzoxazines; D063386:Cannabinoid Receptor Agonists; D009025:Morpholines; D009281:Naphthalenes; D018377:Neurotransmitter Agents; D018040:Receptors, Neurokinin-1; D013373:Substance P; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone