Opioid depression of respiration in neonatal rats

Abstract

1. The effects of opioid receptor agonists and antagonists on the breathing pattern of neonatal rats were studied. Three experimental approaches were taken. In the first approach, the effects of opioid agonists and antagonists on the spontaneous respiratory neural activity generated by brainstem-spinal cords isolated from neonatal rats aged 0-4 days postnatal (P0-4) maintained in vitro were studied. Secondly, similar studies were performed utilizing medullary slice preparations consisting of respiratory rhythm-generating regions (pre-Bötzinger complex). Thirdly, whole-body plethysmographic recordings were obtained from unanaesthetized neonatal (P0-18) rats before and after I.P. administration of opioid-receptor agonists and antagonists. 2. The mu-receptor agonists morphiceptin and DAGO (Tyr-D-Ala-Gly-[NMePhe]-Gly-ol), when added either to the solutions bathing the brainstems of neonatal rat brainstem-spinal cord preparations or bathing the medullary slice preparations, resulted in a naloxone-reversible, dose-dependent decrease in the frequency of respiratory rhythmic discharge. 3. The respiratory burst frequency and amplitude in vitro were unaffected by the addition of the delta-opioid receptor agonist DPDPE ([D-pen2,5]-enkephalin) and the kappa-opioid receptor agonist U50488 (trans-[+]-3,4-dichloro-N-methyl-N-(2-[1- pyrrolidinyl]cyclohexyl) benzene-acetamide) or the opioid receptor antagonist naloxone. 4. Intraperitoneal administration of the mu-opioid receptor agonist fentanyl resulted in a naloxone-reversible, dose-dependent decrease in the frequency and amplitude of breathing of unanaesthetized neonatal rats (P0-P10). I.P. administration of the delta-opioid receptor agonist DPDPE did not affect breathing of neonatal rats until the second week postnatally. 5. We conclude that opioids suppress the frequency of neonatal rat respiration by acting via mu-opioid receptors located within regions of the ventral medulla containing respiratory rhythm-generating centres (the pre-Bötzinger complex). delta-Opioid receptor activation does not affect breathing in neonatal rats until approximately the second week postnatally.