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The Journal of Neuroscience, September 1, 2002, 22(17):7788-7796

Local Injection of a Selective Endothelin-B Receptor Agonist Inhibits Endothelin-1-Induced Pain-Like Behavior and Excitation of Nociceptors in a Naloxone-Sensitive Manner

Alla Khodorova^{1, 2, *}, Moin U. Fareed^{1, *}, Alexander Gokin^{1, 2, *}, Gary R. Strichartz^{1, 2, 3}, and Gudarz Davar¹

¹ Molecular Neurobiology of Pain, ² Sensory Neurophysiology Laboratories of the Pain Research Center, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, and ³ Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115

We showed previously that subcutaneous injection of the injury-associated peptide mediator endothelin-1 (ET-1) into the rat plantar hindpaw produces pain behavior and selective excitation of nociceptors, both through activation of ET_A receptors likely on nociceptive terminals. The potential role of ET_B receptor activation in these actions of ET-1-has not been examined. Therefore, in these experiments, we studied the effect of blocking or activating ET_B receptors on ET-1-induced hindpaw flinching and excitation of nociceptors in rats. An ET_B receptor-selective antagonist, BQ-788 (3 mM), coinjected with ET-1 (200 µM) reduced the time-to-peak of flinching and significantly enhanced the average maximal flinch frequency (MFF). In contrast, coinjection of an ET_B receptor selective agonist, IRL-1620 (100 or 200 µM), with ET-1 reduced the average MFF and the average total number of flinches. Interestingly, this unexpected inhibitory effect of IRL-1620 was prevented by the nonselective opioid receptor antagonist naloxone (2.75 mM). To confirm these inhibitory actions, we studied the effects of IRL-1620 on ET-1-induced spike responses in single, physiologically characterized nociceptive C-fibers. IRL-1620 suppressed spike responses to ET-1 in all (n = 12) C-units, with mean and maximum response frequencies of 0.08 ± 0.02 and 1.5 ± 0.4 impulses/sec versus 0.32 ± 0.07 and 4.17 ± 0.17 impulses/sec for ET-1 alone. In additional support of the behavioral results, coinjection of naloxone (2.75 mM) completely prevented this inhibitory action of IRL-1620. These results establish that ET_B receptor activation inhibits ET-1-induced pain behavior and nociception in a naloxone-sensitive manner and point to a previously unrecognized dual modulation of acute nociceptive signaling by ET_A and ET_B receptors in cutaneous tissues.

Key words: nociception; analgesia; G-protein; endothelin-1; opioid; potassium channel

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^* A.K., M.U.F., and A.G. contributed equally to this work.

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Copyright © 2002 Society for Neuroscience  0270-6474/02/22177788-09$05.00/0

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