M3-receptor activation counteracts opioid-mediated apneusis, but the apneusis per se is not necessarily related to an impaired M3 mechanism in rats

Abstract

Aims 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. Main methods The efferent discharge was recorded from the phrenic nerve in artificially ventilated and anesthetized rats with vagotomy. All drugs were injected intravenously. Key findings The phrenic nerve displayed an augmenting discharge during inspiration and arrest of discharge during expiration in normal condition. Administration of morphine (0.3–10.0 mg/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 (0.1 mg/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 (3.0 mg/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 10.0 mg/kg) but not by an antagonist of M1 cholinergic receptors, pirenzepine (1.0 and 10.0 mg/kg). Significance These results demonstrate that the activation of endogenous M3 cholinergic mechanisms counteracts the morphine-induced apneusis.