The 5-HT3 subtype of serotonin receptor contributes to nociceptive processing via a novel subset of myelinated and unmyelinated nociceptors.
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-HT(3) 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-HT(3) receptor mediates activation of nociceptors but does not contribute to injury-associated edema. This result is explained by the localization of 5-HT(3) 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-HT(3) receptors. We conclude that activation of both peripheral and central 5-HT(3) receptors is pronociceptive and that the contribution of peripheral 5-HT(3) receptors involves a novel complement of primary afferent nociceptors.
Zeitz
Karla P
KP
Department of Anatomy, W. M. Keck Foundation Center for Integrative Neuroscience, University of California at San Francisco, San Francisco, California 94143, USA. aib@phy.ucsf.edu
Guy
Nicolas
N
Malmberg
Annika B
AB
Dirajlal
Sahera
S
Martin
William J
WJ
Sun
Linda
L
Bonhaus
Douglas W
DW
Stucky
Cheryl L
CL
Julius
David
D
Basbaum
Allan I
AI
D000818:Animals; D001345:Autoradiography; D001522:Behavior, Animal / Q000502:physiology; D002478:Cells, Cultured; D051379:Mice; D008815:Mice, Inbred Strains; D008817:Mice, Mutant Strains; D009412:Nerve Fibers / Q000378:metabolism; D009413:Nerve Fibers, Myelinated / Q000378:metabolism*; D009619:Nociceptors / Q000166:cytology / Q000378:metabolism*; D010146:Pain / Q000235:genetics / Q000378:metabolism*; D010147:Pain Measurement; D021122:Protein Subunits; D011869:Radioligand Assay; D011985:Receptors, Serotonin / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D044406:Receptors, Serotonin, 5-HT3; D012701:Serotonin / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism; D014162:Transfection
D021122:Protein Subunits; D011985:Receptors, Serotonin; D044406:Receptors, Serotonin, 5-HT3; D012701:Serotonin