BACKGROUND AND PURPOSEA growing number of studies have demonstrated that oxytocin (OT) plays an analgesic role in modulation of nociception and pain. Most work to date has focused on the central mechanisms of OT analgesia, but little is known about whether peripheral mechanisms are also involved. Acid-sensing ion channels (ASICs) are distributed in peripheral sensory neurons and participate in nociception. Here, we investigated the effects of OT on the activity of ASICs in dorsal root ganglion (DRG) neurons. EXPERIMENTAL APPROACHElectrophysiological experiments were performed on neurons from rat DRG. Nociceptive behaviour was induced by acetic acid in rats and mice lacking vasopressin, V1A receptors. KEY RESULTSOT inhibited the functional activity of native ASICs. Firstly, OT dose-dependently decreased the amplitude of ASIC currents in DRG neurons. Secondly, OT inhibition of ASIC currents was mimicked by arginine vasopressin (AVP) and completely blocked by the V1A receptor antagonist SR49059, but not by the OT receptor antagonist L-368899. Thirdly, OT altered acidosis-evoked membrane excitability of DRG neurons and significantly decreased the amplitude of the depolarization and number of action potentials induced by acid stimuli. Finally, peripherally administered OT or AVP inhibited nociceptive responses to intraplantar injection of acetic acid in rats. Both OT and AVP also induced an analgesic effect on acidosis-evoked pain in wild-type mice, but not in V1A receptor knockout mice. CONCLUSIONS AND IMPLICATIONSThese results reveal a novel peripheral mechanism for the analgesic effect of OT involving the modulation of native ASICs in primary sensory neurons mediated by V1A receptors. AbbreviationsASIC, acid-sensing ion channels; AVP, arginine vasopressin; DRG, dorsal root ganglion; IpH, proton-gated current; OT, oxytocin; TRPV1, transient receptor potential vanilloid channel type 1; TTX, tetrodotoxin; V1A receptor, vasopressin type 1A receptor; V1A-/-mice, V1A receptor knockout mice; WT, wild-type IntroductionAcid-sensing ion channels (ASICs) are members of protongated cation channels and are expressed in both central and peripheral nervous systems (Waldmann et al., 1997b). In peripheral sensory neurons, ASICs have been found on cell bodies and sensory terminals, where they have been suggested to be important for nociception (Alvarez de la Rosa et al., 2002;Benson et al., 2002;Wemmie et al., 2013). As pH sensors, ASICs are activated by a decrease in extracellular pH and depolarize the terminals of nociceptive primary sensory neurons to trigger pain sensation. Direct perfusion of acidic solutions into the skin causes pain in humans (Steen et al., 1995;Ugawa et al., 2002;Jones et al., 2004). Protons, canonical ligands for ASICs, are released and cause tissue acidosis under multiple pathological conditions such as inflammation, tissue injury, ischaemic stroke and cancer (Deval et al., 2010). It is well known that the local extracellular pH levels drop to 5.4 in acute inflammation and 6.3 or lower in severe ischaemi...

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Sex differences have been reported in a number of pain conditions. Women are more sensitive to most types of painful stimuli than men, and estrogen plays a key role in the sex differences in pain perception. However, it is unclear whether there is a sex difference in acidosis-evoked pain. We report here that both male and female rats exhibit nociceptive behaviors in response to acetic acid, with females being more sensitive than males. Local application of exogenous 17β-estradiol (E2) exacerbated acidosis-evoked nociceptive response in male rats. E2 and estrogen receptor (ER)-α agonist 1,3,5-Tris(4-hydroxyphenyl)-4-propyl-1H-pyrazole, but not ERβ agonist 2,3-bis(4-hydroxyphenyl)-propionitrile, replacement also reversed attenuation of the acetic acid-induced nociceptive response in ovariectomized females. Moreover, E2 can exert a rapid potentiating effect on the functional activity of acid-sensing ion channels (ASICs), which mediated the acidosis-induced events. E2 dose dependently increased the amplitude of ASIC currents with a 42.8 ± 1.6 nM of EC50. E2 shifted the concentration-response curve for proton upward with a 50.1% ± 6.2% increase of the maximal current response to proton. E2 potentiated ASIC currents via an ERα and ERK1/2 signaling pathway. E2 also altered acidosis-evoked membrane excitability of dorsal root ganglia neurons and caused a significant increase in the amplitude of the depolarization and the number of spikes induced by acidic stimuli. E2 potentiation of the functional activity of ASICs revealed a peripheral mechanism underlying this sex difference in acetic acid-induced nociception.