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

The role of flexibility of the alkyl side chain in the tetrahydrocannabinol s to cannabinoid activity has been delineated in previous studies with side chain analogs of Delta(8)-tetrahydrocannabinol with double or triple bonds . This study investigated the site of antinociceptive action for these anal ogs through analysis of structure-activity relationships following differen t routes of administration. In analogs without terminal substitutions, pote ncy was greater following intrathecal (i.t.) injection than with intracereb roventricular (i.c.v.). Further, optimal structural features differed for e ach route of administration. Absolute position of the double or triple bond best predicted i.t. potency. In contrast, i.c.v, potency was best predicte d by the size of the alkyl substituent beyond the point of unsaturation. Te rminal substitutions tended to increase i.c.v. potency while decreasing or not affecting i.t. These results suggest that receptor mechanisms for canna binoid antinociceptive effects differ in brain and spinal cord, although po tential pharmacokinetic differences in rate of local distribution cannot be eliminated. (C) 2000 Elsevier Science B.V. All rights reserved.