Research reportAntinociception and sedation following intracerebroventricular administration of Δ9-tetrahydrocannabinol in female vs. male rats
Research highlights
▶ Supraspinal mechanisms contribute to greater systemic THC effects in females compared to males. ▶ Late proestrus females show enhancement of cannabinoid antinociception. ▶ Sex differences in motoric effects are not mediated by supraspinal mechanisms.
Introduction
Sex differences in the effects of systemically administered cannabinoids have been demonstrated in rodents. Cannabinoids are more potent and in some cases more efficacious in females than males in producing antinociception and altering movement [8], [33], [35], [42]. Cannabinoids also produce greater impairment of spatial learning in female than male rats [7] and are self-administered to a greater extent by female rats than males [12]. In contrast, sex differences in cannabinoid effects are reversed when examining the hyperphagic effects of cannabinoids, such that male rodents are more sensitive than females [9], [27]. Sex differences in behavioral effects of systemically administered THC can be attributed in part to sex differences in pharmacokinetic factors [39], although pharmacodynamic factors may also be involved.
Sex differences in cannabinoid effects are also gonadal steroid hormone-dependent in adults. For example, Wagner and co-workers [17] have shown that estradiol reduces cannabinoid-induced hyperphagia and hypothermia in ovariectomized female guinea pigs. Additionally, our lab has demonstrated that estradiol enhances THC-induced antinociception in ovariectomized female rats, a group difference that is similar to that observed between gonadally intact females in tested in estrus vs. diestrus [8]. Additionally, testosterone attenuates the motoric effects of THC in gonadectomized male rats [8]. Although activational effects of gonadal hormones appear to be responsible for sex differences in antinociceptive and motoric effects of THC following systemic administration, it is not known at what level(s) of the neuraxis these hormone–cannabinoid interactions occur. Cannabinoids may produce antinociception via actions at supraspinal, spinal and peripheral sites [10], [15], [21], [22], [38], [39].
Several studies suggest that the brain is one locus of sex differences in, and gonadal hormone modulation of cannabinoid effects. For example, ovariectomy decreased brain cannabinoid receptor density in female rats, and estradiol treatment of ovariectomized rats increased cannabinoid receptor density [4]. In a separate study by this same group, [3H]CP55,940 bound with greater affinity to brain cannabinoid receptors in males compared to those in females, and cannabinoid receptor density also fluctuated over the estrous cycle, depending on the brain area examined [32]. More recently, Bradshaw and co-workers [5] reported elevated endocannabinoid levels in the brains of female compared to male rats. Endocannabinoid levels were elevated in the pituitary, hypothalamus and striatum of females compared to males, and in all of these brain areas, endocannabinoid levels were estrous stage-dependent. Taken together, these studies suggest that previously observed sex differences in behavioral effects of exogenous cannabinoids might be caused by sexual dimorphism of the brain endocannabinoid system.
To date, studies demonstrating antinociception following supraspinal THC administration have used only male rats [21], [23], [25]. Therefore, the goal of this study was to compare THC's effects in males vs. females after intracerebroventricular (i.c.v.) administration, extending our previous findings using systemic (i.p.) THC administration, to determine if sex differences in antinociceptive and motoric effects are mediated supraspinally. Because estrous stage has been shown to influence females’ behavioral response to systemic THC as well as females’ brain endocannabinoid system, the effects of i.c.v. THC also were compared among females tested in different stages of the estrous cycle.
Section snippets
Subjects
Twenty-four male and 93 female Sprague–Dawley rats, approximately 3–5 months old, were used (bred in-house from Taconic stock, Germantown, NY). Ad libitum access to food and water was provided except during surgery and testing. Rats were housed in a room with a 12:12 h light:dark cycle (lights on at 0600 h), maintained at 21 ± 2 °C. Same-sex pair-housing was implemented until surgery, after which rats were singly housed to avoid damage to the intracranial implant. Animals used in this study were
Baseline responding
Rats were tested twice on each nociceptive test before i.c.v. injection. Baseline tail withdrawal latencies were significantly longer in males (6.63 ± 0.35 s) compared to females (5.21 ± 0.14 s; F(1, 115) = 19.78, P < 0.001). Tail withdrawal latencies in males given vehicle were also significantly longer than those in vehicle-treated females at several time points post-injection (sex × time: F(1, 43) = 6.10, P = 0.018; see Table 1). Tail withdrawal latencies did not differ significantly among vehicle-treated
Discussion
The present study demonstrates that supraspinal mechanisms contribute to sex and estrous stage differences in THC-induced antinociception. Specifically, when THC was administered i.c.v., late proestrous (proestrous–estrous) females showed greater antinociception than estrous females and males. The results also suggest that sex and estrous stage differences in the motoric effects of THC are less influenced by supraspinal mechanisms, as motoric effects of i.c.v. THC did not differ significantly
Acknowledgements
The authors thank Cassidy Kobialka and Audrey Harris for technical assistance. This research was supported by funds provided for medical and biological research by the State of Washington Initiative Measure No. 171. The authors also thank the Washington State University Center for Reproductive Biology and the Achievement Reward for College Scientists Foundation for additional stipend support to A.A.W.
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