Activation of cholinergic mechanisms in the medulla oblongata reverse intravenous opioid-induced respiratory depression.
The role of cholinergic mechanisms in opioid-induced respiratory depression was investigated in isoflurane-anesthetized rats. In these animals, the i.v. administration of fentanyl, a clinically useful potent opioid analgesic/anesthetic, induced a prolonged period of apnea and subsequent rise in the end-tidal CO2, hypotension and bradycardia. The centrally acting anticholinesterase, physostigmine, significantly decreased fentanyl-induced respiratory and circulatory depression. The beneficial respiratory and circulatory effects of physostigmine could be abolished by the administration of muscarinic antagonists, e.g., scopolamine hydrobromide or atropine sulfate. Inhibition of inspiratory phrenic nerve activity by fentanyl and restoration of this activity by the subsequent i.v. administration of physostigmine indicates that the origin of this opioid-cholinergic interaction is the central nervous system. Similar effects on phrenic nerve discharge were observed when the systemic administration of fentanyl was followed by microinjection of physostigmine or carbachol in the rostral ventrolateral medulla. In conclusion, opioid-induced respiratory depression after systemic administration is obtunded greatly by facilitation of muscarinic mechanisms in the ventrolateral medulla. Inhibition of a cholinergic link in the central chemosensor may underlie opioid-induced respiratory depression. Manipulation of this cholinergic link could lead to the use and development of analgesics devoid of respiratory depression.
D000698:Analgesia; D000818:Animals; D001285:Atropine / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D002799:Cholinergic Fibers / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D005283:Fentanyl / Q000494:pharmacology*; D006339:Heart Rate / Q000187:drug effects; D007530:Isoflurane; D008297:Male; D008526:Medulla Oblongata / Q000502:physiology*; D009270:Naloxone / Q000494:pharmacology; D010830:Physostigmine / Q000494:pharmacology; D011224:Prazosin / Q000494:pharmacology; D051381:Rats; D012119:Respiration / Q000187:drug effects*; D012601:Scopolamine / Q000494:pharmacology
D009270:Naloxone; D001285:Atropine; D010830:Physostigmine; D007530:Isoflurane; D012601:Scopolamine; D005283:Fentanyl; D011224:Prazosin