The selective
kappa opioid receptor antagonist
nor-binaltorphimine (
nor-BNI) has been shown to modulate
cannabinoid-induced antinociception by delta 9-tetrahydrocannabinol (delta 9-THC). However, it is not known whether
nor-BNI blocks other pharmacological effects of delta 9-THC or if this is a specific action of
nor-BNI. Studies were conducted in which pretreatment with
nor-BNI (2, 10 and 20 micrograms i.t.) selectively blocked delta 9-THC-induced antinociception while not significantly affecting other commonly observed
cannabinoid actions, which included
hypothermia, hypoactivity and
catalepsy. Chronic administration studies were performed to determine if cross tolerance could be established between delta 9-THC and the highly specific
kappa opioid receptor agonists,
U-50,488H and
CI-977. The chronic delta 9-THC-treated groups were significantly tolerant, not only to i.t. delta 9-THC-induced antinociception in the tail-flick test, but also to i.t. U-50,488 and
CI-977 compared with those treated chronically with vehicle. They were not cross tolerant to either
DAMGO or
DPDPE. Dose-response curves were generated for both delta 9-THC (i.t.) and
CI-977 (i.t.) in mice tolerant to delta 9-THC and
CI-977. Parallel shifts to the right of the delta 9-THC dose-response curves were observed in animals tolerant to delta 9-THC and also in animals tolerant to
CI-977. Animals tolerant to
CI-977 also demonstrated parallel shifts of the dose-response curves of both delta 9-THC and
CI-977. This study demonstrated that
cannabinoid actions can be distinguished from each other. The pharmacological separation of antinociception from the other
cannabinoid-induced actions implies that it may have a mechanism distinct from other effects. In addition, this study indicates that delta 9-THC and the kappa
opioid agonists may share a common mechanism of action in the production of antinociception and that a possible interaction exists between i.t. administered
cannabinoid compounds and the
kappa opioid receptor.