SUPPRESSION OF NOXIOUS STIMULUS-EVOKED EXPRESSION OF FOS PROTEIN-LIKEIMMUNOREACTIVITY IN RAT SPINAL-CORD BY A SELECTIVE CANNABINOID AGONIST

In rats, cannabinoids inhibit behavioral responses to noxious stimulat ion with a potency and efficacy similar to that of morphine. However, because cannabinoids depress motor function, it has not been possible to state beyond any doubt that these effects were related to a dampeni ng of noxious sensory input. Therefore, c-fos immunocytochemistry was used to explore the possibility that cannabinoids reduce behavioral re sponses to noxious stimuli by decreasing spinal processing of nocicept ive inputs. Rats received systemic injections of the potent and select ive cannabinoid agonist WIN 55,212-2, the receptor-inactive enantiomer WIN 55,212-3 or vehicle prior to observations in a model of tonic pai n, the formalin test. As demonstrated previously, plantar injections o f formalin led to lifting and licking of the injected paw, with two pe aks of activity occurring at 5 and 30 min after injection. The cannabi noid agonist suppressed these pain responses and produced a reduction in mobility. Immunocytochemical processing of sections with an antibod y to the Fos protein revealed that the cannabinoid markedly suppressed pain-evoked c-fos expression in the superficial and neck regions of t he spinal dorsal horn, but not in the nucleus proprius. Decreased expr ession of c-fos also occurred in the ventral horn. The specificity of this effect and its probable mediation by cannabinoid receptors are su ggested by three findings: (i) the suppression by the drug of both beh avioral and immunocytochemical responses to pain was dose-dependent; ( ii) neither the behavioral nor the immunocytochemical response to the noxious stimulus was significantly affected by the receptor-inactive e nantiomer of the agonist; (iii) animals rendered tolerant to cannabino ids by repeated injections of the agonist showed reduced responses to the drug. These findings suggest that cannabinoids inhibit the spinal processing of nociceptive stimuli and support the notion that endogeno us cannabinoids may act naturally to modify pain transmission within t he central nervous system.