Chronic morphine increases the pituitary-adrenocortical response of juvenile rats to mild stress.

We previously reported that chronic exposure of adult male rats to morphine by pellet implantation has no effect on corticosterone secretion but causes a marked testosterone-dependent increase in CBG. In the studies reported here, we examined the effects of chronic morphine on the pituitary-adrenocortical axis of male rats prior to the developmental rise in testosterone. In contrast to adults, morphine had little effect on CBG in peripubertal males. We found nothing remarkable with regard to basal hormone levels; morphine caused only a transient increase in ACTH and corticosterone in juveniles. However, while the pituitary-adrenocortical response to mild stress was normal in adults exposed to morphine, it was markedly increased in juveniles. After 7 days of morphine exposure, the stress response was as much as 2.5 times greater than normal in morphine-treated juveniles. This exaggerated response to stress did not appear to be due to the passive withdrawal of morphine or to an additive effect of stress plus morphine. Instead, morphine may either increase the perceived severity of stressors or decrease sensitivity to the negative feedback effects of stress levels of corticosterone in juvenile males. Either way, there is a striking shift in morphine's effects on the pituitary-adrenocortical axis across development.

Gender-linked differences in the expression of physical dependence in the rat.

In earlier studies, it was shown that there were gender differences in several aspects of the pharmacological profile of morphine, including its antinociceptive activity, discriminative stimulus properties and its reinforcing effects. The purpose of the present studies was to examine whether there might also be gender-related differences in the development of physical dependence, as reflected in the expression of an opiate withdrawal syndrome upon cessation of chronic morphine administration. We found that a more severe spontaneous withdrawal syndrome was produced by chronic morphine injections or morphine pellet implantation in male rats than in females. The duration of the withdrawal syndrome was also longer. In contrast to our observations with spontaneous withdrawal, we found no gender differences in the naloxone-precipitated withdrawal syndrome induced by chronic morphine administration. These observations suggest that there are gender differences only in the expression of the spontaneous withdrawal syndrome, but not in the neuro-adaptive changes associated with the generation of physical dependence as reflected by naloxone-precipitated withdrawal.

Role of steroids in sex differences in morphine-induced analgesia: activational and organizational effects.

The purpose of the present studies was to determine the role of either the organizational or activational sex steroids in mediating the sex differences observed in morphine-induced antinociception in the rat. To examine the organizational aspects, male pups were castrated at postnatal days 1 and 2; females were masculinized by large doses of testosterone on postnatal days 1 and 2. Adult male and female rats were also castrated over a period of 2 months to examine the role of the acute activational effects of the opiates in the already sexually differentiated adult rat brain. The results of these studies demonstrate that there were no alterations in the sex differences in opiate analgesia in castrated adult male and female rats; thus, male- and female-specific responses to opiate-induced antinociception were maintained even in the absence of the acute membrane-mediated effects of sex steroids. On the other hand, in male rats, castrated at postnatal days 1 and 2, the morphine dose-response curve shifted markedly to the right and, in fact, was almost identical to that observed in untreated females. Conversely, in female rats, masculinized by large doses of testosterone early in prenatal life, the morphine dose-response curve shifted to the left, yielding a dose-response curve that resembled that in normal males. These results strongly suggest that the sex differences that have been observed in morphine-induced analgesia are due to the organizational effects of sex steroids in the developing rat brain, rather than their acute activational effects in adulthood.