The 5-HT₃Subtype of Serotonin Receptor Contributes to Nociceptive Processing via a Novel Subset of Myelinated and Unmyelinated Nociceptors

Abstract

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.

CC12, a high-affinity ligand for [3H]cimetidine binding, is an improgan antagonist

“…Table 1 is a large, but certainly not comprehensive list of antinociceptive targets. For example, 5HT 3 and other receptors in the spinal cord are capable of nociceptive modulation (Zeitz et al, 2002). However, mapping studies have shown that improgan acts in the brain stem, but not in the spinal cord (Nalwalk et al, 2004), making many of these receptors unlikely targets for CC12.…”

5-HT3A Receptor Subunit is Required for 5-HT3 Antagonist-Induced Reductions in Alcohol Drinking

“…It is not known, however, if the effects of 5-HT 3 antagonists on alcohol drinking are mediated by this subunit or other(s), which may coexpress with the 3A subunit (eg, Fletcher and Barnes, 1998). To address this question, we examined alcohol drinking by mutant mice lacking the 5-HT 3A receptor subunit (Zeitz et al, 2002a). One of the primary findings of this study is that 5-HT 3A -null mice did not differ from wildtype controls on measures of voluntary alcohol drinking either during or after a sucrose fading initiation procedure.…”

“…Mice 5-HT 3A receptor-null mice were derived by homologous recombination as previously reported (Zeitz et al, 2002a). F1 hybrid C57BL/6J Â 129vJ heterozygous progeny were backcrossed to C57BL/6J mice to produce F9 generation congenics.…”

“…Heterozygotes from the F9 generation were bred to generate male wild-type and 5-HT 3A -null mutants used in the present study. Genotyping was conducted in Dr David Julius' laboratory at the University of California San Francisco as described in Zeitz et al (2002a). All experiments were conducted in male mice.…”

“…To address this issue, we studied voluntary alcohol drinking both during and after a sucrose fading procedure in mice with a targeted deletion of the 5-HT 3A receptor subunit (Kelley et al, 2003;Zeitz et al, 2002b). Moreover, to determine if the 5-HT 3 antagonists reduce alcohol drinking by inhibiting 3A containing receptors, we tested the effects of the 5-HT 3 antagonist LY-278,584 on alcohol drinking by 5-HT 3A -null mice and controls.…”