Butorphanol-inducedc-Fos production within the paraventricular nucleus of the hypothalamus and activation of the hypothalamic pituitary adrenal axis: Role of the kappa opioid receptor.

摘要

Butorphanol is a mixed opioid agonist/antagonist which displays agonist activity at both the mu and kappa opioid receptors. Previous studies have shown acute peripheral administration of butorphanol results in activation of a subset of neurons within the paraventricular nucleus of the hypothalamus (PVN), as indicated by an increase in production of the cellular protein, c-Fos. Neurons within the PVN govern the activity of the hypothalamic-pituitary-adrenal (HPA) axis. Activation of this axis is the body's primary response to stress. The present study employs a conscious, chronically catheterized rat model to determine the in vivo dose-response relationship between intravenous butorphanol administration and c-Fos production within the PVN and resulting activation of the HPA axis, as determined by increases in plasma corticosterone. Administration of butorphanol resulted in dose-related increases in c-Fos production within the PVN. Increases in c-Fos production within the PVN and increases in plasma corticosterone displayed a nonlinear relationship. The role of the kappa opioid receptor (KOR) in butorphanol-induced PVN c-Fos production was explored by "masking" the KOR within the central nervous system. Pretreatment with nor-BNI (35 pg), a KOR selective antagonist, resulted in a significant reduction of c-Fos production within the PVN of butorphanol-treated animals. Interestingly, these animals did not display decreased plasma corticosterone concentrations. In order to determine if butorphanol is acts at the level of the hypothalamus or at extra-hypothalamic sites, an organotypic hypothalamic slice explant model was employed. Incubation of slice explants in butorphanol (100 nM) significantly increased c-Fos production within the PVN. To assess the role of the peripheral opioid receptors in butorphanol's actions on plasma corticosterone concentrations, either nor-BNI (5.0 mg/kg) or the nonselective opioid receptor antagonist, naloxone (5.0 mg/kg), was administered subcutaneously prior to butorphanol administration. Peripheral pretreatments failed to prevent butorphanol-induced increases in plasma corticosterone. Our results indicate acute administration of butorphanol elicits dose-dependent increases in c-Fos production within the PVN and dose-dependent increases in plasma corticosterone. As opposed to its role in butorphanol-induced increases in plasma corticosterone, the KOR appears to mediate the increase in c-Fos production within the PVN following acute administration of the mixed opioid agonist/antagonist, butorphanol.