title: Fentanyl inhibits GABAergic neurotransmission to cardiac vagal neurons in the nucleus ambiguus.
abstract: Fentanyl citrate is a synthetic opiate analgesic often used clinically for neonatal anesthesia. Although fentanyl significantly depresses heart rate, the mechanism of inducing bradycardia remains unclear. One possible site of action is the cardioinhibitory parasympathetic vagal neurons in the nucleus ambiguus (NA), from which originates control of heart rate and cardiac function. Inhibitory synaptic activity to cardiac vagal neurons is a major determinant of their activity. Therefore, the effect of fentanyl on GABAergic neurotransmission to parasympathetic cardiac vagal neurons was studied using whole-cell patch clamp electrophysiology. Application of fentanyl induced a reduction in both the frequency and amplitude of GABAergic IPSCs in cardiac vagal neurons. This inhibition was mediated at both pre- and postsynaptic sites as evidenced by a dual decrease in the frequency and amplitude of spontaneous miniature IPSCs. Application of the selective micro-antagonist CTOP abolished the fentanyl-mediated inhibition of GABAergic IPSCs. These results demonstrate that fentanyl acts on micro-opioid receptors on cardiac vagal neurons and neurons preceding them to reduce GABAergic neurotransmission and increase parasympathetic activity. The inhibition of GABAergic effects may be one mechanism by which fentanyl induces bradycardia.
authors.affiliation: Department of Pharmacology and Physiology, George Washington University, 2300 Eye Street N.W., Washington, DC 20037, USA. kgriff@gwu.edu
authors.forename: Kathleen J S
authors.initials: KJ
authors.lastname: Griffioen
authors.forename: Priya
authors.initials: P
authors.lastname: Venkatesan
authors.forename: Zheng-Gui
authors.initials: ZG
authors.lastname: Huang
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.forename: Evguenia
authors.initials: E
authors.lastname: Bouairi
authors.forename: Cory
authors.initials: C
authors.lastname: Evans
authors.forename: Allison
authors.initials: A
authors.lastname: Gold
authors.forename: David
authors.initials: D
authors.lastname: Mendelowitz
mesh_terms: D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D000779:Anesthetics, Local / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D004347:Drug Interactions; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005283:Fentanyl / Q000494:pharmacology*; D018684:Glycine Agents / Q000494:pharmacology; D006321:Heart / Q000187:drug effects; D066298:In Vitro Techniques; D008526:Medulla Oblongata / Q000166:cytology*; D008564:Membrane Potentials / Q000187:drug effects; D009294:Narcotics / Q000494:pharmacology*; D009433:Neural Inhibition / Q000187:drug effects; D009474:Neurons / Q000187:drug effects*; D018408:Patch-Clamp Techniques / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley; D013004:Somatostatin / Q000031:analogs & derivatives* / Q000494:pharmacology; D013331:Strychnine / Q000494:pharmacology; D009435:Synaptic Transmission / Q000187:drug effects*; D013779:Tetrodotoxin / Q000494:pharmacology; D014630:Vagus Nerve / Q000187:drug effects; D014633:Valine / Q000031:analogs & derivatives* / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D000779:Anesthetics, Local; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D018684:Glycine Agents; D009294:Narcotics; C049352:phenylalanyl-cyclo(cysteinyltyrosyl-tryptophyl-ornithyl-threonyl-penicillamine)threoninamide; D013779:Tetrodotoxin; D013004:Somatostatin; D005680:gamma-Aminobutyric Acid; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; C056639:2-amino-5-phosphopentanoic acid; D013331:Strychnine; D014633:Valine; D005283:Fentanyl