Sex differences in antinociceptive tolerance to delta-9-tetrahydrocannabinol in the rat

Abstract

Background Sex differences in cannabinoid effects have been reported in rodents, with adult females typically being more sensitive than adult males. The present study compared the development of antinociceptive tolerance to delta-9-tetrahydrocannabinol (THC) in adult, gonadally intact female vs. male rats. Methods Cumulative dose-effect curves were obtained for THC (1.0–18 mg/kg i.p.) on warm water tail withdrawal and paw pressure tests. Vehicle or the sex-specific ED80 dose for THC was administered twice daily for 9 days; THC dose-effect curves were then re-determined. Results On the pre-chronic test day, THC was significantly more potent in females than males in producing antinociception on the tail withdrawal and paw pressure tests. After 9 days of twice-daily THC treatment (5.4 mg/kg/injection in females, 7.6 mg/kg/injection in males), THC potency on both tests decreased more in females than males. On the tail withdrawal test, chronic THC produced 4.2- vs. 2.8-fold increases in ED50 values in females vs. males, respectively. On the paw pressure test, chronic THC produced 4.4- vs. 2.9-fold increases in ED50 values in females vs. males, respectively. Chronic THC treatment did not significantly disrupt estrous cycling in females. Conclusions These results demonstrate that – even when sex differences in acute THC potency are controlled for – females develop more antinociceptive tolerance to THC than males. Given the importance of drug tolerance in the development of drug dependence, these results suggest that females may be more vulnerable than males to developing dependence after chronic cannabinoid exposure.

Tolerance to hypothermic and antinoceptive effects of Δ9-tetrahydrocannabinol (THC) vapor inhalation in rats

“…Prior work has shown that female mice develop tolerance to locomotor stimulant effects of THC (i.p.) under conditions under which males do not (Wiley, 2003), that female rats develop tolerance to THC-induced errors on a learning task more slowly than males during chronic injection of 10 mg/kg THC, i.p., (Weed, Filipeanu, Ketchum & Winsauer, 2016) and that female rats develop a greater degree of nociceptive tolerance to THC even when the repeated dose is only 71% as large as the male dose (Wakley, Wiley & Craft, 2014). The study also demonstrated, as in our prior reports (Javadi-Paydar, Nguyen, Grant, Vandewater, Cole & Taffe, 2017;, that so long as intervals of at least 7 days are maintained between THC administration sessions, there is no detectable plasticity of the hypothermic response.…”

“…The latency to withdraw the tail was measured using a stopwatch, and a cutoff of 15 seconds was used to avoid any possible tissue damage (Wakley and Craft, 2011;Wakley et al, 2014). Tail-withdrawal was assessed 35, 60 and 120 minutes after the initiation of inhalation.…”

Sex-dependent effects of cannabis-induced analgesia

“…Recent preclinical studies revealed that although females are more sensitive to cannabinoid-induced antinociception, this effect is restricted to the acute administration of cannabinoids. Under conditions of repeated THC administration, both male and female rats develop tolerance to THC's antinociceptive effects and females develop significantly greater tolerance relative to males (Wakley et al, 2014, 2015). For instance, after repeated daily THC administration, female rats demonstrated a 4.2-fold increase in ED50 values for THC's antinociceptive effects, whereas males demonstrated only a 2.8 fold increase in ED50 values (Wakley et al, 2014).…”

Sex differences in cannabinoid-regulated biology: A focus on energy homeostasis

“…Other contributing factors to these sex differences include the activation of both CB1 and CB2 receptors in females, whereas in males only the CB1 receptors contribute (Craft et al, 2012). The enhanced responsiveness observed in females extends to the development of antinociceptive tolerance upon chronic treatment with THC (Wakley et al, 2014b). Similarly, females are more sensitive, via both CB1 and CB2 receptors, to the ability of THC to counter the allodynia and hyperalgesia observed after a week-long administration of Freund’s adjuvant to the right hind paw than males are via activation of only CB1 receptors (Craft et al, 2013).…”