The role of endogenous opioid peptides (EOP) in the neuroendocrine control of primate gonadotropin and PRL secretion was studied in nonrestrained adult male rhesus monkeys. Morphine (0.5-1.0 mg/kg) was used as the prototype opiate, beta-endorphin (beta-END; 10-20 micrograms/kg) and [D-Ala2,D-Leu5] enkephalin (DADLE; 5-20 micrograms/kg) were used as representatives of EOP, and naloxone (0.5-2.0 mg/kg) was used as an opiate receptor blocker. Drugs were administered and blood was collected (at 20-min intervals for 4 h) through an indwelling jugular catheter. LH and PRL levels were measured in plasma by RIA. Intravenous administration of morphine (1.0 mg/kg) and DADLE (10 micrograms/kg) produced decreases in LH levels of 64% and 40%, respectively. These decreases occurred within 1 h after drug injections and lasted for approximately 3 h. beta-END had no effect on LH levels. Naloxone, at all doses studied, significantly increased LH levels (5- to 8-fold). The LH rises occurred within 20 min and lasted for up to 2 h. Both morphine and beta-END produced immediate increases in PRL, which remained elevated for 3 h. DADLE did not alter PRL levels. Naloxone (1.0 and 2.0 mg/kg) decreased PRL concentrations (45% and 60%, respectively). Pretreatment with morphine or DADLE did not alter the LH response to GnRH (100 micrograms) stimulation, indicating a hypothalamic site of action for the opioid inhibition of LH release. Naloxone administration reversed the inhibitory effects of morphine and DADLE on LH. The stimulatory effect of morphine on PRL levels was also reversed by naloxone. These studies further define the postulated physiological role of EOP in primate reproductive neuroendocrinology. Based on receptor selectivities of these opioid agonists, the inhibition of LH may be mediated by delta-receptors, whereas PRL release appears to be mu-mediated.
This study examines the role of dynorphin-A(1-13) and dynorphin-A(1-10)-amide in the neuroendocrine regulation of anterior pituitary hormones in nonrestrained, adult male rhesus monkeys. The effects of these opioids on plasma concentrations of prolactin (PRL), luteinizing hormone (LH), follicle-stimulating hormone (FSH), thyrotropin (TSH) and growth hormone (GH) were assessed. Intravenous administration of dynorphin-A(1–13), 1–120 µg/kg, significantly increased plasma PRL levels. Average maximal increases of 90–230% occurred within 5 min and levels remained significantly elevated for up to 120 min. PRL response reached a plateau following the 30 µg/kg dose. Dynorphin-A(1–13) had no observable effects on plasma concentrations of LH, FSH, TSH or GH at any dose level studied. Administration of dynorphin-A(1–10)-amide produced significant dose-dependent increases in plasma PRL concentrations. Dose levels of 1–120 µg/kg produced mean peak increases from 100 to 230%, 5–10 min postadministration. Dynorphin-A(1–10)-amide had no significant effect on plasma concentrations of LH, FSH, TSH or GH. The increases in plasma PRL concentrations induced by dynorphin-A were naloxone-reversible. These results indicate a selective effect of dynorphin-A on the regulatory mechanisms of PRL secretion over that of other anterior pituitary hormones.
Plasma androgen levels studied following the injection of the opioid agonists morphine sulfate (0.5-1.0 mg/kg), beta-endorphin (10-20 mg/kg), and [D-Ala2, D-Leu5]-enkephalin (DADLE; 5-20 micrograms/kg), and the opioid receptor antagonist naloxone (0.5-2.0 mg/kg) in nonrestrained adult male rhesus monkeys. Drugs were administered and blood samples were collected through indwelling jugular catheters. Morphine (1.0 mg/kg) and DADLE (10.0 micrograms/kg) decreased androgen levels by 70% and 34%, respectively. Significant decreases occurred 80 minutes after drug injections, and levels remained depressed for 180 minutes; beta-endorphin (20 micrograms/kg) produced no effect on androgen levels. Treatment with naloxone (0.5 mg/kg-2.0 mg/kg) alone produced marked increases in androgen levels. Peak hormone levels occurred 80 minutes after naloxone administration and remained elevated for up to 2 hours. The depressant effects of morphine and DADLE on androgen levels were completely reversed by the administration of naloxone (1.0 mg/kg). In monkeys pretreated with hCG, neither morphine (1.0 mg/kg) nor DADLE (20 micrograms-kg) had any effect on androgen levels for up to 3 hours after opioid administration. Administration of morphine or endogenous opioid peptides exerts negative effects on androgen levels, whereas antagonism or endogenous or exogenous opiates by naloxone results in increases in circulating androgens. These results support a physiologic role of the endogenous opioid peptides in primate reproductive function.
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