Cannabinoids have been shown to be very potent analgesic agents. However, their psychomimetic effects have precluded their clinical use. Although their specific neuroanatomical sites of action have not yet been determined, several lines of evidence indicate that they produce antinociception, in part, by spinal action. Assuming that cannabinoid behavioral effects occur by supraspinal mechanism, it may be possible to achieve antinociception without concomitant behavioral effects by administration directly into spinal sites. The initial goal of this study was to determine if administration of the drug into the spinal cord could retain the antinociceptive effects while producing less of the behavioral effects. These results demonstrated the Delta-9-THC is an effective antinociceptive agent by this route although the other behavioral effects are also evident. In order to determine if intrathecal Delta-9-THC was eliciting its effects by action in the brain or at other sites, the drug concentrations in the brain following intrathecal injection of 3H-Delta-9-THC were compared to the concentrations following a range of intravenous doses. Profound analgesia was produced in animals with brain concentrations of 3H- Delta-9-THC less than those following ineffective i.v. doses. This suggests a spinal component to the antinociceptive effect elicited by Delta-9-THC. Possible mechanisms of the cannabinoid-induced antinociception is currently being investigated. It has recently been proposed that the potency of spinally administered analgesics is inversely related to lipophilicity. A correlation coefficient between lipophilicity and ED50 of a wide range of cannabinoid compounds was demonstrated to be 0.76. These results suggest that the lipophilicity of cannabinoids influences their potency in the spinal cord. The highly selective kappa opioid receptor antagonist, nor-binaltorphamine (nor-BNI) has recently been shown to modulate cannabinoid-induced antinociception. Delta-9-THC-induced antinociception could be blocked in animals pretreated with nor- BNI, Several other cannabinoid-induced effects including hypothermia, hypoactivity, and catalepsy were not significantly blocked by nor-BNI. These findings demonstrate that nor-BNI selectively modulates Delta-9-THC-induced antinociception while not significantly affecting other commonly observed cannabinoid actions. This blockade indicates a possible interaction of i.t. administered cannabinoid compounds with the kappa opiate receptors. These results provide further support for a role of kappa receptors in cannabinoid-induced antinociception. In addition, this study provides the first convincing evidence that the antinociceptive effects of the cannabinoids are mediated through mechanisms distinct from those responsible for the behavioral effects.
