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cAMP-dependent reversal of opioid- and prostaglandin-mediated depression of the isolated respiratory network in newborn rats

Authors


  • This manuscript was accepted as a Short Paper for rapid publication.

  • Author's permanent address
    B. Hoch: Medizinisches Zentrum für Kinderheilkunde, Philipps Universität Marburg, Germany.

  • Author's email address
    P. M. Lalley: pmlalley@facstaff.wisc.edu

Abstract

  • 1Membrane 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 Et (PGE1).
  • 2PGE1 (0.1–3 μm) and fentanyl or Ala-Leu-Enk (1–50 μm) 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.
  • 3The selective μ- and δ-receptor blockers naloxonazine (10–20 μm) and naltrindole (50–100 μM) antagonized the effects of 5 μm fentanyl and 50 μM Ala-Leu-Enk, respectively.
  • 4Opioid- and PGE1-evoked respiratory depression was reversed upon elevation of endogenous cAMP levels by stimulating adenylyl cyclase with 100 μM forskolin, activating dopamine D1 receptors with 50–100 μm 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 μm isobutylmethylxanthine.
  • 5The 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.
  • 6We suggest that elevation of cAMP levels is an effective antidote in neonates against such forms of respiratory depression.

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