Antinociceptive effects of tetrahydrocannabinol side chain analogs: dependence upon route of administration

The role of flexibility of the alkyl side chain in the tetrahydrocannabinols to cannabinoid activity has been delineated in previous studies with side chain analogs of Δ 8-tetrahydrocannabinol with double or triple bonds. This study investigated the site of antinociceptive action for these analogs through analysis of structure–activity relationships following different routes of administration. In analogs without terminal substitutions, potency was greater following intrathecal (i.t.) injection than with intracerebroventricular (i.c.v.). Further, optimal structural features differed for each route of administration. Absolute position of the double or triple bond best predicted i.t. potency. In contrast, i.c.v. potency was best predicted by the size of the alkyl substituent beyond the point of unsaturation. Terminal substitutions tended to increase i.c.v. potency while decreasing or not affecting i.t. These results suggest that receptor mechanisms for cannabinoid antinociceptive effects differ in brain and spinal cord, although potential pharmacokinetic differences in rate of local distribution cannot be eliminated.