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Abstract
The peripheral serotonergic system has been implicated in the modulation of an array
of pain states, from migraine to fibromyalgia; however, the mechanism by which serotonin
(5HT) induces pain is unclear. Peripherally released 5HT induces thermal hyperalgesia,
possibly via modulation of the transient receptor potential V1 (TRPV1) channel, which
is gated by various noxious stimuli, including capsaicin. We previously reported in
vitro that 5HT increases calcium accumulation in the capsaicin-sensitive population
of sensory neurons with a corresponding increase in proinflammatory neuropeptide release,
and both are antagonized by pretreatment with 5HT(2A) and 5HT(3) antagonists, as well
as the anti-migraine drug sumatriptan. In the current study, we extended these findings
in vivo using the rat hind paw thermal assay to test the hypothesis that peripheral
5HT enhances TRPV1-evoked thermal hyperalgesia that can be attenuated with 5HT(2A)
and 5HT(3) receptor antagonists, as well as sumatriptan. Thermal hyperalgesia and
edema were established by 5HT injection (0.1-10 nmol/100 μl) into the rat hind paw,
and the latency to paw withdrawal (PWL) from noxious heat was determined. Rats were
then pretreated with either 5HT before capsaicin (3 nmol/10 μl), the 5HT(2A) receptor
antagonist ketanserin or the 5HT(3) receptor antagonist granisetron (0.0001-0.1 nmol/100
μl) before 5HT and/or capsaicin, or the 5HT(1B/1D) receptor agonist sumatriptan (0.01-1
nmol/100 μl) before capsaicin, and PWL was determined. We report that 5HT pretreatment
enhances TRPV1-evoked thermal hyperalgesia, which is attenuated with local pretreatment
with ketanserin, granisetron, or sumatriptan. We also report that peripheral 5HT induced
a similar magnitude of thermal hyperalgesia in male and female rats. Overall, our
results provide in vivo evidence supporting an enhancing role of 5HT on TRPV1-evoked
thermal hyperalgesia, which can be attenuated by peripheral serotonergic intervention.