title: M3-receptor activation counteracts opioid-mediated apneusis, but the apneusis per se is not necessarily related to an impaired M3 mechanism in rats.
abstract: OBJECTIVE
  Morphine slows the respiratory cycle due to a predominant prolongation of inspiration (apneusis) by postponing the spontaneous termination of inspiration (inspiratory off-switching). The present study investigates whether the morphine-induced apneusis results from impairment of cholinergic mechanisms in the central respiratory network.
  
  
  METHODS
  The efferent discharge was recorded from the phrenic nerve in artificially ventilated and anesthetized rats with vagotomy. All drugs were injected intravenously.
  
  
  RESULTS
  The phrenic nerve displayed an augmenting discharge during inspiration and arrest of discharge during expiration in normal condition. Administration of morphine (0.3-10.0mg/kg) dose-dependently provoked apneusis characterized by a long-lasting, plateau inspiratory discharge of the phrenic nerve. It shortened the expiratory duration. Subsequent administration of physostigmine (0.1mg/kg) restored the morphine-induced apneusis to eupnea with a partial recovery of the augmenting inspiratory discharge. This modification of physostigmine was blocked by a non-specific muscarinic antagonist scopolamine (3.0mg/kg), leading to re-prolongation of inspiration. A similar antagonism was affected by an antagonist of M3 cholinergic receptors, 4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP, 1.0 and 10.0mg/kg) but not by an antagonist of M1 cholinergic receptors, pirenzepine (1.0 and 10.0mg/kg).
  
  
  CONCLUSIONS
  These results demonstrate that the activation of endogenous M3 cholinergic mechanisms counteracts the morphine-induced apneusis.
authors: Laboratory of Neuropharmacology, School of Pharmacy, Aichi Gakuin University, 1-100 Kusumoto, Chikusa, Nagoya 464-8650, Japan.
authors: Yuka
authors: Y
authors: Niwa
authors: Akira
authors: A
authors: Haji
mesh_terms: D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000633:toxicity*; D000818:Animals; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D001239:Inhalation / Q000187:drug effects*; D008297:Male; D009020:Morphine / Q000008:administration & dosage / Q000633:toxicity*; D018727:Muscarinic Antagonists / Q000008:administration & dosage / Q000494:pharmacology; D010791:Phrenic Nerve / Q000378:metabolism; D010830:Physostigmine / Q000494:pharmacology; D010890:Pirenzepine / Q000008:administration & dosage / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D043587:Receptor, Muscarinic M3 / Q000187:drug effects* / Q000378:metabolism; D012119:Respiration / Q000187:drug effects; D012601:Scopolamine / Q000494:pharmacology
chemical_list: D000701:Analgesics, Opioid; D002800:Cholinesterase Inhibitors; D018727:Muscarinic Antagonists; D043587:Receptor, Muscarinic M3; D010890:Pirenzepine; D009020:Morphine; D010830:Physostigmine; D012601:Scopolamine