Central opioid modulation of breathing dynamics in the fetal lamb: effects of [D-Pen2,D-Pen5]-enkephalin and partial antagonism by naltrindole.

The effects of opiates on fetal breathing movements (FBM) have been shown to be complicated, with stimulation at low doses and suppression at higher doses. Recent studies have shown that morphine-induced stimulation of FBM can be blocked by naloxonazine (NALZ), suggesting action at the mu 1 opioid receptor. To examine the role of delta receptors in modulating FBM, the effects of [D-Pen2,D-Pen5]-enkephalin (DPDPE) on breathing dynamics were studied in fetal lambs with chronically implanted diaphragmatic electromyographic electrodes. DPDPE given i.c.v. (4.6-465 nmol/hr) caused significant time and dose-related increases in the number of breaths/hr and the incidence of fetal breathing movements, without significant changes in blood pH, PCO2 or PO2. Higher doses resulted in an attenuation of the responses, with a significant decrease in breaths/hr at 465 nmol/hr. DPDPE also induced a much more continuous and regular breathing pattern. All DPDPE effects were completely abolished by pretreatment with i.v. naloxone, but were unaffected by naloxonazine pretreatment. Naltrindole did not alter the effects of DPDPE on breath number or incidence of FBM, but blocked the effects on continuity and regularity of the breathing pattern. These results demonstrate that DPDPE stimulates breathing activity as well as alters breathing dynamics in the fetal lamb. The differential sensitivity of these two actions to naltrindole suggest that they may be mediated by different delta receptor subtypes, and that the mu 1 receptor is not involved.