Sex differences in discriminative stimulus effects of morphine in the rat

Nine female and ten male rats were trained to discriminate 3.0mg/kg s.c. morphine from saline. The six female rats that acquired and maintained the morphine discrimination did so in significantly fewer sessions than the eight males did (28 +/- 5 vs 51 +/- 9 sessions, respectively), and the ED(50) for morphine substitution was significantly lower in females (0.69 +/- 0.15 vs 1.28 +/- 0.20mg/kg). The time course of morphine substitution was approximately equivalent in females and males. The µ agonist fentanyl completely substituted for morphine in both sexes, with no sex difference in potency to substitute for morphine. The µ agonist buprenorphine partially or completely substituted for morphine in all females and five of six males, but at a lower dose in females (ED(50) 0.009 +/- 0.002 vs 0.019 +/- 0.006mg/kg). The delta agonist BW373U86 partially substituted for morphine in both sexes, with no potency differences; the kappa agonist U69,593 and the non-opioid cocaine did not substitute for morphine in either sex. On a test of spontaneous locomotor activity, morphine increased locomotion to a slightly but not significantly greater extent in males than in females. Morphine also produced significantly greater hotplate antinociception in males than in females. Further drug discrimination training with a lower dose of morphine, 1.0mg/kg, decreased the ED(50) for morphine substitution in females and males to 0.26 +/- 0.06 vs 0.45 +/- 0.11mg/kg, respectively (not significant). In a separate group of age-matched rats, there was no sex difference in brain or plasma levels of morphine measured via HPLC 20min post-injection, the pretreatment time used to examine behavioral effects of morphine. The HPLC results, plus the fact that sex differences were not the same for all behavioral effects of morphine, suggest that sex differences in discriminative stimulus effects of morphine are not due to differential pharmacokinetics. The possibility that sex differences in morphine discrimination reflect sex differences in opioid receptor pharmacology, or differential reinforcement between morphine and saline levers for males but not females, is discussed.