Effect of central naloxone on hormone and blood pressure responses to hemorrhage in conscious sheep

Abstract

The role of the brain opioid system in the control of hypothalamic-pituitary-adrenal activity was studied in 10 conscious sheep with an indwelling cannula in a cerebral lateral ventricle. On separate days, sheep received infusions of artificial CSF (control) and the opiate antagonist, naloxone (100 μg/hr) before and during acute moderate hemorrhage (15 ml/kg over 10 min). Infusion of naloxone before hemorrhage raised plasma ACTH and resulted in a significant increase in cortisol responses to hemorrhage control infusion. In contrast, ACTH and cortisol responses to hemorrhage tended to be blunted by central naloxone infusion. The responses of vasopressin, aldosterone and the catecholamines remained unaffected by naloxone. The fall in blood pressure and the rise in heart rate accompanying hemorrhage were likewise unaltered. These results suggest that brain opioid peptides have an inhibitory effect on basal ACTH secretion but do not play a major role in modulating the hemodynamic or pituitary-adrenal responses to acute moderate hemorrhage in conscious sheep. Numerous studies have established that the brain opioid system is activated by a variety of acute stressors, including hemorrhage (1) and other forms of shock and trauma (2, 3). These same stresses are potent stimuli to ACTH secretion. Several lines of evidence indicate that enkephalins and endorphins may participate directly in the regulation of ACTH secretion. The enkephalin agonist, DAMME, inhibits ACTH in sheep (4) and humans (5), opioid peptides suppress corticotropin-releasing factor (CRF) in vitro (6), and the opiate antagonist naloxone enhances ACTH secretion (7), including the ACTH response to exogenous CRF (8). These findings suggest that the brain opioid system may act to restrain both CRF release and ACTH responsiveness during acute stress. Using conscious sheep with indwelling cannulae in a lateral ventricle, we have examined the effect of central naloxone on the ACTH and neuroendocrine response to acute moderate hemorrhage. Since cardio-depressant effects of brain opioid activation also occur during hemorrhage (2, 9) apparently contributing to the shock syndrome, the hemodynamic response to acute, moderate hemorrhage during central administration of naloxone was also studied.