Abstract
Serotonin (5-HT) and seritonergic receptors are strategic participants in nociception. Traumatic injury to peripheral tissues which results in arachadonic acid, bradykinin and prostaglandin release, initiates vasodilation and extravisation of serotonin which then binds with 5-HT3 receptors on pain afferents. This sequence has been shown to mediate inflammatory pain both peripherally and centrally and is exclusively excitatory. More recently, Wetzel has shown that gonadal steroids bind to 5-HT3 receptors non-competitively, blocking 5-HT3 receptor sites. This action interrupts propagation of painful stimuli potentially resulting in peripheral inflammatory analgesia. A review of the available literature was performed with the purpose of establishing the location and actions of 5-HT3 receptors in inflammatory pain, discussing the antagonism of 5-HT3 by gonadal steroids and outlining how early estrus might influence inflammatory pain. Of particular interest are the possible effects of elevated serum estrogen levels on 5-HT3 functionality in human pain and the potential for employing 5-HT3 selective drugs as a method of therapy. 5-HT3 receptors are non-competitively bound by circulating gonadal steroids and conduction of peripheral inflammatory pain is reduced or interrupted. Circulating gonadal steroids may affect the potential for conduction of inflammatory pain, enhancing the opportunity for near typical menses.
Highlights
Serotonin (5-hydroxytryptamine, 5-HT) is an abundant neurotransmitter found predominantly in enteric gastrointestinal enterochromaffin cells and platelets and in the central and peripheral nervous system neurons [1]
Several studies conclude that pain processing is estrus cycle stage dependant in rats [23,28]. 5-HT3 receptors have been shown to mediate inflammatory pain both [1] peripherally, by depolarizing C-fibers which terminate in the dorsal horn and [2] in the spinal cord dorsal horn hyperpolarizing GABA and opoidergic interneurons which terminate
5-HT3 receptors are non-competitively antagonized by gonadal steroids [27,29]
Summary
Serotonin (5-hydroxytryptamine, 5-HT) is an abundant neurotransmitter found predominantly in enteric gastrointestinal enterochromaffin cells and platelets and in the central and peripheral nervous system neurons [1]. Delineation of the role of peripheral 5-HT3 receptors was provided by peripheral intraplantar injections of 5-HT3 antagonists ICS 205-930 and MDL 72222 which produced dose-dependent anti-nociceptive effects against inflammatory pain [12]. 5-HT3 receptors have been identified in the superficial laminae of the spinal dorsal horn [9,4] Activation of these descending 5-HT pathways causes the release of serotonin at synaptic connections with both nociceptive afferents and interneurons within the cord to produce analgesia [12,14]. Published data supports that 5-HT, released from descending dorsolateral funicular pathways binds to spinal gray dorsal horn interneuronal 5-HT3 receptors, depolarizing them [18]. Ovarian hormones play a role in regulating 5-HT3 receptor expression in stressinduced bowel disfunction [23] Both the 5-HT3 receptor channel and the voltage-gated sodium channel are steroid targets. This is compatible with a common mechanistic principle in steroid-induced inhibition of the two channels [19]
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