Gonadal hormones do not alter the development of antinociceptive tolerance to delta-9-tetrahydrocannabinol in adult rats.
The purpose of this study was to determine whether sex differences in the development of antinociceptive tolerance to delta-9-tetrahydrocannabinol (THC) are due to activational effects of gonadal hormones. Rats were sham-gonadectomized (sham-GDX) or gonadectomized (GDX). GDX females received no hormone replacement (GDX0), estradiol (GDXE2), progesterone (GDXP4), or both (GDXE2P4). GDX male rats received no hormone (GDX0) or testosterone (GDXT). Two weeks later, antinociceptive potency of THC was determined (pre-chronic test) on the warm water tail withdrawal and paw pressure assays. Vehicle or a sex-specific THC dose (females, 5.7mgkg, males, 9.9mgkg) was administered twice-daily for 9days, then the THC dose-effect curves were re-determined (post-chronic test). On the pre-chronic test (both assays), THC was more potent in sham-GDX females than males, and gonadectomy did not alter this sex difference. In GDX females, P4 significantly decreased THCs antinociceptive potency, whereas E2 had no effect. In GDX males, T did not alter THCs antinociceptive potency. After chronic THC treatment, THCs antinociceptive potency was decreased more in sham-GDX females than males, on the tail withdrawal test this sex difference in tolerance was not altered in GDX or hormone-treated groups. These results suggest that greater antinociceptive tolerance in females, which occurred despite females receiving 40% less THC than males, is not due to activational effects of gonadal hormones.