Glycinergic inputs to cardiac vagal neurons in the nucleus ambiguus are inhibited by nociceptin and mu-selective opioids.

Most parasympathetic regulation of heart rate originates from preganglionic cardiac vagal neurons within the nucleus ambiguus. Little is known regarding the modulation of glycinergic transmission to these neurons. However, the presence of mu-opioid receptors and opioid-receptor-like (ORL1) receptors within the ambiguus, together with the presence of endogenous ligands for both receptor types in the same area, suggests opioids may modulate synaptic transmission to cardiac vagal neurons. This study therefore examined the effects of endomorphin-1 and endomorphin-2 (the mu-selective endogenous peptides), DAMGO (a synthetic, mu-selective agonist), and nociceptin (the ORL1-selective endogenous peptide) on spontaneous glycinergic inhibitory postsynaptic currents (IPSCs) in rat cardiac parasympathetic neurons. All four of the opioids used in this study decreased spontaneous IPSCs. At concentrations of 100 microM, the amplitude of the IPSCs was reduced significantly by nociceptin (-56.6%), DAMGO (-46.5%), endomorphin-1 (-45.1%), and endomorphin-2 (-26%). IPSC frequency was also significantly reduced by nociceptin (-61.1%), DAMGO (-69.9%), and endomorphin-1 (-40.8%) but not endomorphin-2. Lower concentrations of nociceptin and DAMGO (10-30 microM) also effectively decreased IPSC amplitude and frequency. The inhibitory effects of DAMGO were blocked by d-Phe-Cys-Tyr-d-Trp-Orn-Thr-Pen-Thr-NH2 (C-TOP; 10 microM), a selective mu-receptor antagonist. Neither nociceptin nor DAMGO inhibited the postsynaptic responses evoked by exogenous application of glycine or affected TTX-insensitive glycinergic mini-IPSCs. These results indicate that mu-selective opioids and nociceptin act on preceding neurons to decrease glycinergic inputs to cardiac vagal neurons in the nucleus ambiguus. The resulting decrease in glycinergic transmission would increase parasympathetic activity to the heart and may be a mechanism by which opioids induce bradycardia.