6-cyano-7-nitroquinoxaline-2-3-dione and phenylalanyl-cyclo(cysteinyltyrosyl-tryptophyl-ornithyl-threonyl-penicillamine)threoninamide

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.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Anesthetics, Local; Animals; Animals, Newborn; Drug Interactions; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Fentanyl; gamma-Aminobutyric Acid; Glycine Agents; Heart; In Vitro Techniques; Medulla Oblongata; Membrane Potentials; Narcotics; Neural Inhibition; Neurons; Patch-Clamp Techniques; Rats; Rats, Sprague-Dawley; Somatostatin; Strychnine; Synaptic Transmission; Tetrodotoxin; Vagus Nerve; Valine

The role of enkephalin and the opioid receptors in modulating GABA release within the rat globus pallidus (GP) was investigated using whole-cell patch recordings made from visually identified neurons. Two major GP neuronal subtypes were classified on the basis of intrinsic membrane properties, action potential characteristics, the presence of the anomalous inward rectifier (Ih), and anode break depolarizations. The mu opioid receptor agonist [D-Ala2-N-Me-Phe4-Glycol5]-enkephalin (DAMGO) (1 microM) reduced GABAA receptor-mediated IPSCs evoked by stimulation within the striatum. DAMGO also increased paired-pulse facilitation, indicative of presynaptic mu opioid receptor modulation of striatopallidal input. In contrast, the delta opioid agonist D-Pen-[D-Pen2, 5]-enkephalin (DPDPE) (1 microM) was without effect. IPSCs evoked by stimulation within the GP were depressed by application of [methionine 5']-enkephalin (met-enkephalin) (30 microM). Met-enkephalin also reduced the frequency, but not the amplitude, of miniature IPSCs (mIPSCs) and increased paired-pulse facilitation of evoked IPSCs, indicative of a presynaptic action. Both DAMGO and DPDPE reduced evoked IPSCs and the frequency, but not amplitude, of mIPSCs. However, spontaneous action potential-driven IPSCs were reduced in frequency by met-enkephalin and DAMGO, whereas DPDPE was without effect. Overall, these results indicate that presynaptic mu opioid receptors are located on striatopallidal terminals and pallidopallidal terminals of spontaneously firing GP neurons, whereas presynaptic delta opioid receptors are preferentially located on terminals of quiescent GP cells. Enkephalin, acting at both of these receptor subtypes, serves to reduce GABA release in the GP and may therefore act as an adaptive mechanism, maintaining the inhibitory function of the GP in basal ganglia circuitry.

Topics: 2-Amino-5-phosphonovalerate; 6-Cyano-7-nitroquinoxaline-2,3-dione; Analgesics; Analgesics, Opioid; Animals; Bicuculline; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalin, D-Penicillamine (2,5)-; Enkephalin, Methionine; Enkephalins; Excitatory Amino Acid Antagonists; GABA Antagonists; Globus Pallidus; In Vitro Techniques; Male; Membrane Potentials; Neostriatum; Neurons; Patch-Clamp Techniques; Presynaptic Terminals; Rats; Rats, Wistar; Receptors, GABA-A; Receptors, Opioid, delta; Receptors, Opioid, mu; Somatostatin; Synaptic Transmission; Tetrodotoxin