ANTISENSE OLIGODEOXYNUCLEOTIDES TO THE KAPPA(1) RECEPTOR ENHANCE DELTA(9)-THC-INDUCED ANTINOCICEPTIVE TOLERANCE

Delta-9-tetrahydrocannabinol produces potent antinociceptive effects i n mice and rats. Evidence exists for an interaction between the cannab inoids and the kappa receptor subtype, kappa, in the production of ant inociception. Data indicate that Delta(9)-THC induces the release of e ndogenous dynorphins, the ligand(s)for the kappa receptor. It has been demonstrated that antisense oligodeoxynucleotides directed against th e kappa, receptor attenuate the antinociceptive effects of Delta(9)-TH C. The exact mechanism for the expression of cannabinoid tolerance is unknown. Bidirectional cross-tolerance between the kappa opioids and D elta(9)-THC implies that a common mechanism may be responsible for tol erance expression. We tested the hypothesis that the kappa(1) receptor is involved in tolerance to Delta(9)-THC. Antisense to the kappa(1) r eceptor has been shown to downregulate the kappa receptor. We observed a significant increase in the ED50 for Delta(9)-THC in antisense-, bu t not mismatch-treated mice, indicating an increase in tolerance to De lta(9)-THC. Such data indicate that a decrease in kappa receptor numbe r may accompany tolerance to Delta(9)-THC. (C) 1998 Elsevier Science I nc.