Evaluation of nociceptive modulation by spinal and peripheral cannabinoid receptors

Cannabinoids have been widely reported to produce antinociception. However, there are still a number of questions which have yet to be evaluated regarding the involvement of spinal and peripheral cannabinoid systems in the modulation of thermal nociceptive thresholds. In the present work, we evaluated two hypotheses: whether cannabinoids act at a spinal site of action to modulate nociceptive transmission under basal and inflamed conditions and whether cannabinoids act at a peripheral CB{dollar}sb1{dollar} receptor to modulate nociceptive transmission under conditions of inflammation.; We have determined that the spinal CB{dollar}sb1{dollar} cannabinoid receptor tonically modulates basal nociceptive thresholds. Decreasing spinal cannabinoid receptor activity with either an antisense oligonucleotide directed against a portion of the CB{dollar}sb1{dollar} receptor or a CB{dollar}sb1{dollar} receptor antagonist resulted in thermal hyperalgesia. Furthermore, this hyperalgesia was inhibited by co-administration of NMDA antagonists. These results suggest that the spinal cannabinoid receptor may inhibit basal release of glutamate to modulate thermal nociceptive thresholds. Moreover, hypoactivity of this modulation may be involved in the transition from normal to hyperalgesic states.; We have also determined that both spinal and peripheral administration of cannabinoids will produce antihyperalgesia in a carrageenan-model of inflammation. Additionally, peripherally administered cannabinoids inhibit other characteristics of inflammation, including edema and plasma extravasation. One potential mechanism for the antihyperalgesic effects of cannabinoids is the inhibition of neurosecretion from capsaicin-sensitive fibers. We have determined that cannabinoids are capable of inhibiting iCGRP release from both central and peripheral terminals of capsaicin-sensitive fibers. These results suggest that cannabinoid-mediated antihyperalgesia may due to the inhibition of activity of certain nociceptive fibers.; Collectively, our results indicate that spinal cannabinoids modulate basal nociceptive thresholds. Furthermore, spinal cannabinoids are capable of inhibiting hyperalgesia. Peripheral cannabinoids can inhibit hyperalgesia as well as other indices of inflammation such as edema and plasma extravasation. One potential mechanism that integrates these findings is cannabinoid-induced inhibition of neurosecretion from the terminals of capsaicin-sensitive fibers. Accordingly, these results indicate that the cannabinoid system has potential therapeutic utility especially in the treatment of pain and inflammatory disorders.