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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Background Tumor necrosis factor-α (TNF-α) is a pro-inflammatory cytokine involved in pain processing and hypersensitivity. It regulates not only the expression of a variety of inflammatory mediators but also the functional activity of some ion channels. Acid-sensing ion channels (ASICs), as key sensors for extracellular protons, are expressed in nociceptive sensory neurons and contribute to pain signaling caused by tissue acidosis. It is still unclear whether TNF-α has an effect on functional activity of ASICs. Herein, we reported that a brief exposure of TNF-α acutely sensitized ASICs in rat dorsal root ganglion (DRG) neurons. Methods Electrophysiological experiments on rat DRG neurons were performed in vitro and acetic acid induced nociceptive behavior quantified in vitro. Results A brief (5min) application of TNF-α rapidly enhanced ASIC-mediated currents in rat DRG neurons. TNF-α (0.1-10 ng/ml) dose-dependently increased the proton-evoked ASIC currents with an EC50 value of 0.12 ± 0.01 nM. TNF-α shifted the concentration-response curve of proton upwards with a maximal current response increase of 42.34 ± 7.89%. In current-clamp recording, an acute application of TNF-α also significantly increased acid-evoked firing in rat DRG neurons. The rapid enhancement of ASIC-mediated electrophysiological activity by TNF-α was prevented by p38 mitogen-activated protein kinase (MAPK) inhibitor SB202190, but not by non-selective cyclooxygenase inhibitor indomethacin, suggesting that p38 MAPK is necessary for this enhancement. Behaviorally, TNF-α exacerbated acid-induced nociceptive behaviors in rats via activation of local p38 MAPK pathway. Conclusions These results suggest that TNF-α rapidly enhanced ASIC-mediated functional activity via a p38 MAPK pathway, which revealed a novel peripheral mechanism underlying TNF-α involvement in rapid hyperalgesia by sensitizing ASICs in primary sensory neurons.

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