Antisense oligodeoxynucleotides to the kappa1 receptor enhance delta9-THC-induced antinociceptive tolerance

Delta-9-tetrahydrocannabinol produces potent antinociceptive effects in mice and rats. Evidence exists for an interaction between the cannabinoids and the kappa receptor subtype, kappa1, in the production of antinociception. Data indicate that delta9-THC induces the release of endogenous dynorphins, the ligand(s) for the kappa receptor. It has been demonstrated that antisense oligodeoxynucleotides directed against the kappa1 receptor attenuate the antinociceptive effects of delta9-THC. The exact mechanism for the expression of cannabinoid tolerance is unknown. Bidirectional cross-tolerance between the kappa opioids and delta9-THC implies that a common mechanism may be responsible for tolerance expression. We tested the hypothesis that the kappa1 receptor is involved in tolerance to delta9-THC. Antisense to the kappa1 receptor has been shown to downregulate the kappa receptor. We observed a significant increase in the ED50 for delta9-THC in antisense-, but not mismatch-treated mice, indicating an increase in tolerance to delta9-THC. Such data indicate that a decrease in kappa receptor number may accompany tolerance to delta9-THC.