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The Journal of Neuroscience, February 1, 2002, 22(3):1010-1019

The 5-HT₃ Subtype of Serotonin Receptor Contributes to Nociceptive Processing via a Novel Subset of Myelinated and Unmyelinated Nociceptors

Karla P. Zeitz^{1, *}, Nicolas Guy^{2, *}, Annika B. Malmberg^{1, *}, Sahera Dirajlal³, William J. Martin¹, Linda Sun², Douglas W. Bonhaus⁴, Cheryl L. Stucky³, David Julius², and Allan I. Basbaum¹

¹ Departments of Anatomy and Physiology and W. M. Keck Foundation Center for Integrative Neuroscience and ² Department of Cellular and Molecular Pharmacology and Silvio Conte Center for Neuroscience Research, University of California at San Francisco, San Francisco, California 94143, ³ Departments of Cell Biology, Neurobiology, and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, and ⁴ Roche Bioscience, Palo Alto, California 94304

Serotonin is a major component of the inflammatory chemical milieu and contributes to the pain of tissue injury via an action on multiple receptor subtypes. Here we studied mice after genetic or pharmacological disruption of the 5-HT₃ receptor, an excitatory serotonin-gated ion channel. We demonstrate that tissue injury-induced persistent, but not acute, nociception is significantly reduced after functional elimination of this receptor subtype. Specifically, in the setting of tissue injury, the 5-HT₃ receptor mediates activation of nociceptors but does not contribute to injury-associated edema. This result is explained by the localization of 5-HT₃ receptor transcripts to a previously uncharacterized subset of myelinated and unmyelinated afferents, few of which express the proinflammatory neuropeptide substance P. Finally, we provide evidence that central serotonergic circuits modulate nociceptive transmission via a facilitatory action at spinal 5-HT₃ receptors. We conclude that activation of both peripheral and central 5-HT₃ receptors is pronociceptive and that the contribution of peripheral 5-HT₃ receptors involves a novel complement of primary afferent nociceptors.

Key words: serotonin; 5-HT₃ receptor; inflammatory pain; primary afferent nociceptors; descending pain modulation; neurogenic inflammation

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^* K.P.Z., N.G., and A.B.M. contributed equally to this work.

Correspondence should be addressed to Allan Basbaum, Department of Anatomy, University of California at San Francisco, 513 Parnassus Avenue, Box 0452, San Francisco, CA 94143. E-mail: aib{at}phy.ucsf.edu.

N. Guy's present address: Centre National de la Recherche Scientifique, l'Institut de Pharmacologie Moléculaire et cellulaire, 06560 Valbonne, France.

A. B. Malmberg's present address: NeurogesX, 969C Industrial Road, San Carlos, CA 94070.

W. J. Martin's present address: Merck and Co., P.O. Box 2000, RY80Y-145, Rahway, NJ 07065.

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Copyright © 2002 Society for Neuroscience  0270-6474/02/2231010-10$05.00/0

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