Ovarian hormone modulation of cannabinoid antinociception and cannabinoid receptor density in female rats

Abstract

Estrous cycle-related fluctuations in delta-9-tetrahydrocannabinol (THC)-induced antinociception have been observed in the rat. The aim of this study was to determine which of the major ovarian hormones, estradiol (E2) or progesterone (P4), modulates the antinociceptive and motoric effects of supraspinally administered THC, and whether changes in brain cannabinoid receptors (CBr) are associated with hormone modulation of THC's behavioral effects. Female rats were ovariectomized (OVX) and implanted with a cannula guide into the lateral ventricle. Vehicle (oil) or hormones (E2 or P4, or both) were administered on Days 3 and 7 after surgery. On the morning or late afternoon of Day 8 or 9, vehicle (1:1:8 ethanol:cremaphor:saline) or THC (100 μg) was administered intracerebroventricularly. Antinociception was measured using paw pressure and tail withdrawal tests at 5-180 min post-injection. Horizontal locomotion was examined in 5-min periods at 15-180 min post-injection, and catalepsy was measured at 15 and 30 min post-injection. Brain tissue was taken from separate groups of oil+oil- and E2+P4-treated females for [3H]SR141716A binding, to examine hormone effects on CBr in structures known to mediate THC's behavioral effects. THC produced antinociception on both tests, reduced locomotor activity, and produced minimal catalepsy. E2 (with or without P4) enhanced THC-induced paw pressure antinociception. Neither hormone significantly altered THC's effects on the tail withdrawal or motoric tests. CBr density in the periaqueductal gray (PAG) and caudate putamen (CPu) was increased and decreased, respectively, in E2+P4-treated females compared to oil-treated females on Day 9. Within the CPu, CBr affinity was increased in females tested on Day 8 compared to those tested on Day 9, and hormone treatment also increased affinity compared to oil treatment. Hormone treatment did not significantly alter CBr density or affinity in hypothalamus, amygdala or cerebellum.These results demonstrate that the ovarian hormone E2 (alone or with P4) enhances females' sensitivity to supraspinal THC-induced mechanical antinociception, suggesting that E2 is responsible for estrous cycle-related fluctuations in THC sensitivity. Neither ovarian hormone appears to significantly modulate the motoric effects of THC. Ovarian hormone enhancement of THC's antinociceptive effect cannot be explained by changes in CBr density or affinity in the brain areas examined.