Sex differences in antinociceptive and motoric effects of cannabinoids.

Cannabinoids are currently used for the treatment of excessive weight loss and nausea; however, there are very few studies that have examined cannabinoid effects in females of any species. A previous study has shown that there are sex differences in cannabinoid pharmacokinetics in rats, suggesting that there could be sex differences in cannabinoid-induced behaviors. To address this issue, Delta9-tetrahydrocannabinol, 11-hydroxy-Delta9-tetrahydrocannabinol (natural cannabinoids) or (-)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)-phenyl]-trans-4-(3-hydroxypropyl)cyclohexanol) (CP55940, a synthetic cannabinoid) was administered i.p. to male and female Sprague-Dawley rats, who were tested on the 50 degrees C warm water tail withdrawal, paw pressure, catalepsy bar and spontaneous locomotor activity tests at various times post-injection. At the doses tested, all three cannabinoid agonists produced greater effects in females than males in two or more behavioral tests. This study demonstrates that there are sex differences in the behavioral effects of cannabinoids in the rat.

Receptor-selective antagonism of opioid antinociception in female versus male rats.

This study was conducted to determine whether sex differences in opioid antinociception may be explained by sex differences in opioid receptor activation. The time course, dose-effect and selectivity of antagonists that have been previously shown to be relatively mu (beta-funaltrexamine, beta-FNA), kappa (norbinaltorphimine, norBNI), or delta (naltrindole, NTI) receptor selective in male animals were compared in female and male Sprague-Dawley rats using a 52 degrees C hotplate test. In both sexes, beta-FNA (10 or 20 microg intracerebroventricularly [i.c.v.]) dose-dependently blocked the antinociceptive effects of fentanyl (0.056 mg/kg subcutaneously); antagonism was observed 24 h after beta-FNA, and diminished within 7-14 days. In both sexes, norBNI (1 or 10 microg i.c.v.) dose-dependently blocked the antinociceptive effects of U69,593 (1.0 mg/kg subcutaneously); antagonism was maximal by 1-3 days post-norBNI and lasted longer than 56 days. NTI (1 or 10 microg i.c.v.) dose-dependently blocked the antinociceptive effects of [D-Pen2, D-Pen5]enkephalin (DPDPE, 100 nmol i.c.v.) in both sexes; however, the duration of action of NTI was shorter in females than in males. The antinociceptive effects of the mu receptor-preferring agonists fentanyl, morphine and buprenorphine were significantly and dose-dependently antagonized by beta-FNA, but not by norBNI or NTI, in both sexes. Beta-FNA antagonism was significantly greater in females compared with males given morphine, but not fentanyl or buprenorphine. The antinociceptive effects of the kappa receptor-preferring agonists U69,593 and U50,488 were significantly and dose-dependently antagonized by norBNI; U50,488 but not U69,593 was also antagonized to a lesser extent by NTI and beta-FNA, in both sexes. The antinociceptive effect of the delta receptor-preferring agonist SNC 80 was significantly antagonized by NTI, but not by norBNI or beta-FNA, in both sexes. The sex difference in beta-FNA antagonism of morphine suggests that there may be sex differences in functional mu opioid receptor reserve or signal transduction; however, the lack of consistency across all mu agonists weakens this hypothesis. Overall, the opioids tested had very similar receptor selectivity in male and female subjects.

Comparison of sodium transport processes of human and rat erythrocytes in hypertension.

Erythrocytes of normotensive and hypertensive humans, as well as Sprague-Dawley, Wistar-Kyoto and spontaneously hypertensive rats, were prepared to have similar ionic compositions adequate for determining the activities of lithium-sodium (Li-Na) countertransport and sodium (Na) pump. The rate of Li-Na countertransport was significantly higher in erythrocytes of hypertensive subjects. This activity was not detected in rat erythrocytes, at two different ages, and over a six-fold of lithium (Li) content. Activities of Na pump were not significantly different among various groups. Human cells, in general, had a higher activity than rat cells; among rat cells, spontaneously hypertensive rats had a higher rate of sodium pump. Both Na-independent Li efflux and ouabain-insensitive Na efflux were significantly higher in rat erythrocytes than in human cells. Thus, employing the same methods, we have determined that while the properties of Na pump were similar in human and rat erythrocytes, Li-Na countertransport did not operate in the erythrocytes of either normotensive or hypertensive rats.