Background: Although spinal cannabinoid (CB) receptor agonist (WIN 55,212-2) has been shown to encounter various models of pain, the role of two subtypes of cannabinoid receptor for the antinociceptive effect of cannabinoids has not investigated at the spinal level. Spinal alpha-2 receptor agonist (clonidine) and cholinesterse inhibitor (neostigmine) are also active in the modulation of nociception. The author examined the properties of drug interaction after intrathecal coadministration of WIN 55,212-2-clonidine, and intrathecal WIN 55,212-2-neostigmine, and further clarified the role of CB1 and CB2 receptors in cannabinoids antinociception. Methods: Catheters were inserted into the intrathecal space of male SD rats. 50 fA of 5% formalin solution was injected into the hindpaw to induce the pain. Isobolographic analysis was used for evaluation of pharmacological interaction. Results: Intrathecal 55,212-2, clonidine and neostigmine dose-dependent% suppressed the flinching observed during phase 1 and phase 2 in the formalin test. Isobolographic analysis revealed a synergistic interaction after intrathecal delivery of WIN 55,212-2-clonidine or WIN 55,212-2-neostigmine mixture in both phases. The antinociceptive effect of WIN 55,212-2 was antagonized by AM 251 but not by AM 630. No antinociceptive effect was seen after intrathecal administration of JWH 133. Conclusions* Intrathecal 55,212-2, clonidine and neostigmine attenuate the facilitated state and acute pain. WIN 55,212-2 interacts synergistically with either clonidine or neostigmine. The antinociception of WIN 55,212-2 is mediated through only CB1 receptor at the spinal level.

Keywords55,212-2, Clonidine, Neostigmine, Formalin test, Rat