Characterization of the ORL1 receptor on adrenergic nerves in the rat anococcygeus muscle

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Abstract
Nociceptin, the endogenous ORL1 receptor agonist inhibited the motor response to electrical‐field stimulation in the rat anococcygeus muscle. This effect was characterized using the peptide ligands acetyl‐Arg‐Tyr‐Tyr‐Arg‐Trp‐Lys‐NH2 (Ac‐RYYRWK‐NH2), acetyl‐Arg‐Tyr‐Tyr‐Arg‐Ile‐Lys‐NH2 (Ac‐RYYRIK‐NH2) and [Phe1ψ(CH2‐NH)Gly2]nociceptin(1‐13)NH2 ([F/G]NC(1‐13)NH2), and the non‐selective opioid antagonist naloxone benzoylhydrazone (NalBzOH). Nociceptin produced a concentration‐dependent inhibition of the adrenergic motor response to electrical‐field stimulation (EC50 19 nM, pEC50 7.7±0.1, n=8), but the response to exogenous noradrenaline (0.2–1 μM) was unaffected. The inhibitory nerve response was not affected by up to 1 μM nociceptin. After inhibition of nitric oxide synthase (Nω‐nitro‐L‐arginine 100 μM), and in the presence of peptidase inhibitors, nociceptin produced full inhibition of the pure adrenergic motor response (EC50 4 nM; pEC50 8.4±0.1, Emax 98.3±1.2%, n=12). Ac‐RYYRWK‐NH2 was a potent partial‐agonist (pEC50 9.0±0.1, Emax 66.4±5.2; n=11) but the efficacy of Ac‐RYYRIK‐NH2 (pEC50 8.0±0.2, Emax 36.7±3.5; n=12) was lower and the peptide could be tested as an antagonist (pA2 9.01). [F/G]NC(1‐13)NH2 and NalBzOH had little or no efficacy and were competitive antagonists with pKB values of 7.4 (95% c.l. 7.1, 7.7) and 6.9 (95% c.l. 6.7, 7.1) respectively. Both increased the response to field stimulation at high concentrations, suggesting the release of an endogenous agonist for the ORL1 receptor during stimulation. Rat nocistatin did not affect the response to electrical‐field stimulation, nor did it modify the inhibitory action of nociceptin. Our findings suggest there is a significant endowment of ORL1 receptors on sympathetic terminals of the rat anococcygeus, where nociceptin mediates a powerful inhibitory effect on adrenergic neuromuscular transmission. British Journal of Pharmacology (2000) 131, 349–355; doi:10.1038/sj.bjp.0703583