Oxytocin Modulates Nociception as an Agonist of Pain-Sensing TRPV1

Abstract

SUMMARY Oxytocin is a hormone with various actions. Oxytocin-containing parvocellular neurons project to the brainstem and spinal cord. Oxytocin release from these neurons suppresses nociception of inflammatory pain, the molecular mechanism of which remains unclear. Here, we report that the noxious stimulus receptor, TRPV1, is an ionotropic oxytocin receptor. Oxytocin elicits TRPV1 activity in native and heterologous expression systems, irrespective of the presence of the classical oxytocin receptor. In TRPV1 knockout mice, DRG neurons exhibit reduced oxytocin sensitivity relative to controls, and oxytocin injections significantly attenuate capsaicin-induced nociception in in vivo experiments. Furthermore, oxytocin potentiates TRPV1 in planar lipid bilayers, supporting a direct agonistic action. Molecular modeling and simulation experiments provide insight into oxytocin-TRPV1 interactions, which resemble RTX/DkTx. Together our findings suggest the existence of endogenous regulatory pathways that modulate nociception via direct action of oxytocin on TRPV1, implying its analgesic effect via channel desensitization.

Role of oxytocin in the control of stress and food intake

“…Oxytocin has also been reported to act not only on the oxytocin receptor, but also on vasopressin receptors, on δ subunit-containing GABA A receptors 276 and on transient receptor potential vanilloid (TRPV1). 277 Although pharmacological studies have shown the importance of vasopressin receptors in the actions of oxytocin, 278 molecular and genetic evidence directly showing the roles of vasopressin receptors is not sufficient. 279,280 The physiological roles of these receptors in the actions of oxytocin remain to be clarified.…”

Linking Cigarette Smoking/Tobacco Exposure and Cluster Headache: A Pathogenesis Theory

“…It appears oxytocin may have anti-nociceptive capabilities via TRPV1 receptors, thus alterations in oxytocin levels induced by cadmium exposure may also change the nociceptive properties in tobacco exposed CH patients, making them more susceptible to headaches at certain times of the year when hypothalamic dysfunction occurs. 46 Modulator of Pituitary Hormones Linked to CH. Recent studies in rat models demonstrate that low concentrations of cadmium via its xenoestrogenic activity can stimulate PRL secretion and cell growth from the anterior pituitary.…”

“…36 In most instances testosterone levels are low in CH patients both in and out of cycle. 46 Modulator of Pituitary Hormones Linked to CH. 37 In female rodents, estrogen tonically inhibits the expression of orexin, and estrogen replacement will normalize very elevated orexin levels in postmenopausal women.…”

A single TRPV1 amino acid controls species sensitivity to capsaicin

“…Frog and rabbit TRPV1 channels are less sensitivite to capsaicin, (Gavva et al, 2004; Ohkita et al, 2012) and the chicken TRPV1 shows the least sensitivity (Jordt and Julius, 2002). The pharmacological characteristics of TRPV1 provides the understanding to efficiently target, activate and inhibit the channel, which may be one of the strategies to design analgesic drugs (Brito et al, 2014; Nersesyan et al, 2017; Szallasi et al, 2007).…”