Postganglionic sympathetic nerve terminals innervate cardiac muscle and express opioid receptor-like 1 (ORL1) receptors, the most recently described member of the opioid receptor subclass. ORL1 receptors are stimulated by the endogenous heptadecapeptide nociceptin (Noc). To better understand how the signaling events by Noc regulate sympathetic neuron excitability, the goal of the present study was to determine whether sympathetic stellate ganglion (SG) neurons, innervating the heart, natively express ORL1 opioid receptors and couple to Ca 2ϩ channels. SG neurons in adult male rats were retrograde-labeled with a fluorescent tracer via injection of the ventricular muscle employing ultrasound imaging. Thereafter, N-type Ca 2ϩ channel modulation was investigated using the whole-cell variant of the patch-clamp technique. Exposure of labeled SG neurons to Noc resulted in a concentration-dependent inhibition of Ca 2ϩ currents (with an estimated EC 50 of 193 Ϯ 14 nM). Pre-exposure of SG neurons to the ORL1 receptor blocker, [Nphe 1 ,Arg 14 ,Lys 15 ]N/OFQ-NH 2 (UFP-101), significantly decreased the Noc-mediated Ca 2ϩ current inhibition. The Ca 2ϩ current inhibition was also blocked by pertussis toxin pretreatment, indicating that signaling occurs via G␣ i/o G proteins. Finally, the full-length ORL1 receptor cDNA in SG neurons was cloned and sequenced. Of the two known alternatively spliced variants in rats, sequencing analysis showed that the ORL1 receptor expressed in SG neurons is the short form. Overall, these results suggest that stimulation of postsynaptic ORL1 receptors by Noc in SG neurons regulate cardiac sympathetic activity.The opioid receptor-like 1 (ORL1) receptor and the three "classic" opioid receptor subtypes (, , and ␦) are members of the G protein-coupled receptor superfamily. The heptadecapeptide nociceptin, (Noc, also known as orphanin/FQ) is the endogenous ORL1 receptor ligand. ORL1 receptors are coupled to members of the pertussis toxin (PTX)-sensitive

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