cAMP-dependent reversal of opioid- and prostaglandin-mediated depression of the isolated respiratory network in newborn rats.
1. Membrane potential (Vm) and resistance (Rm) of ventral respiratory group (VRG) neurons were measured in the isolated brainstem-spinal cord from newborn rats during bath application of the opioid receptor agonists fentanyl or [D-Ala2, D-Leu5]-enkephalin (Ala-Leu-Enk) and of the prostaglandin E1 (PGE1). 2. PGE1 (0.1-3 microM) and fentanyl or Ala-Leu-Enk (1-50 microM) produced depression and, at higher doses, block of inspiratory nerve activity and respiration-related postsynaptic potentials. This apnoea was associated with hyperpolarization and Rm fall in 25% of thirty-two VRG neurons tested, whereas resting Vm and Rm were not changed in the other cells. 3. The selective mu- and delta-receptor blockers naloxonazine (10-20 microM) and naltrindole (50-100 microM) antagonized the effects of 5 microM fentanyl and 50 microM Ala-Leu-Enk, respectively. 4. Opioid- and PGE1-evoked respiratory depression was reversed upon elevation of endogenous cAMP levels by stimulating adenylyl cyclase with 100 microM forskolin, activating dopamine D1 receptors with 50-100 microM 6-chloro-7,8-dihydroxy-3-allyl-1-phenyl-2, 3,4,5-tetrahydro-1H-3-benzazepine (6-chloro-APB) or preventing cAMP breakdown with 50-100 microM isobutylmethylxanthine. 5. The results indicate that opioid- or prostaglandin-induced respiratory depression is due to a fall in cAMP levels in cells responsible for generation of rhythm or providing a tonic drive to the respiratory network. 6. We suggest that elevation of cAMP levels is an effective antidote in neonates against such forms of respiratory depression.
Ballanyi
K
K
II. Physiologisches Institut, Universität Göttingen, Germany.
Lalley
P M
PM
Hoch
B
B
Richter
D W
DW
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000527:Alprostadil / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn / Q000502:physiology*; D001049:Apnea / Q000503:physiopathology; D000242:Cyclic AMP / Q000502:physiology*; D019204:GTP-Binding Proteins / Q000378:metabolism; D009415:Nerve Net / Q000187:drug effects / Q000502:physiology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D011453:Prostaglandins / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D011957:Receptors, Opioid / Q000187:drug effects*; D017465:Receptors, Opioid, delta / Q000819:agonists; D017450:Receptors, Opioid, mu / Q000819:agonists; D012131:Respiratory Insufficiency / Q000139:chemically induced / Q000188:drug therapy*; D015656:Respiratory Mechanics / Q000502:physiology*; D012137:Respiratory System / Q000294:innervation*
D010726:Phosphodiesterase Inhibitors; D011453:Prostaglandins; D011957:Receptors, Opioid; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; D000242:Cyclic AMP; D019204:GTP-Binding Proteins; D000527:Alprostadil; D015056:1-Methyl-3-isobutylxanthine