Abstract

Intrathecal administration of Δ⁹-tetrahydrocannabinol (Δ⁹-THC) but not the cannabinoid agonist CP55,940 enhances the antinociception produced by morphine. In addition, CP55,940- and Δ⁹-THC-induced antinociception is blocked by the kappa opioid antagonist norbinaltorphimine, and both cannabinoids are cross-tolerant to kappa agonists but do not act directly at the kappa receptor. Previous work in our laboratory has implicated dynorphins in the antinociceptive effects of Δ⁹-THC and its enhancement of morphine-induced antinociception. The goal of the present study was to evaluate the role of dynorphins in the antinociceptive effects of CP55,940 at the spinal level. Pretreatment of mice with antisera to dynorphin A(1–17), dynorphin A(1–8) or α-neoendorphin, all of which have been shown to retain specificity for blockade of their respective peptide in vivo, blocked the antinociceptive effects of Δ⁹-THC but not CP55,940. Dynorphin B produced antinociceptive effects on intrathecal administration to mice. Like CP55,940, dynorphin B failed to enhance the antinociceptive effects of morphine, whereas dynorphin A(1–17) and α-neoendorphin enhanced the antinociceptive effects of morphine. Using spinal catheterization of the rat, CP55,940 administration was shown to produce a significant release of dynorphin B concurrent with the production of antinociception. Our data suggest that CP55,940 induces a release of spinal dynorphin B that contributes at least in part to its antinociceptive effects in the spinal cord.