Oxytocin inhibits the activity of acid‐sensing ion channels through the vasopressin, V_1A receptor in primary sensory neurons

Abstract

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...

Enhancement of acid-sensing ion channel activity by metabotropic P2Y UTP receptors in primary sensory neurons

“…Our previous and current studies show that these characterized currents could be completely blocked by broad-spectrum ASIC channel blocker amiloride, also by ASIC3 channels blocker APETx2 (Fig. 1a) [28]. These currents were thus considered to be ASIC3-like currents and were mainly investigated in this study.…”

“…Most of these acid currents can be characterized by a large transient current followed by fast inactivation and then a small sustained current with no or very slow inactivation [27]. Our previous and current studies have identified that the characterized acidosis-evoked currents are mainly mediated by ASIC3, since they could be completely blocked by ASIC3 channels blocker APETx2 [28]. We thus considered them to be ASIC3-like currents, although precise ASIC subunits need to be identified.…”

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“…Acting through a pathway involving nitrous oxide, oxytocin leads to a reduction in excitability of capsaicin sensitive nociceptors (Gong et al, 2015). There is evidence that oxytocin also acts through the vasopressin, V1A receptor in primary sensory neurons (Qiu et al, 2014). Interestingly activation of parvocellular PVN oxytocin secreting neurons, in addition to acting by a descending spinal pathway, also results its systemic release from the posterior pituitary by virtue of its parallel projection to the SON (Eliava et al, 2016).…”

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“…Yang et al further demonstrated a dose-dependent, enhanced analgesic effect of DN with stimulation of the supraoptic nucleus and a minimal analgesic effect when the nucleus was ablated [160]. According to Qiu et al the activation of vasopressin (V1A) receptors by oxytocin released form the posterior pituitary is thought to trigger calcineurindependent phosphorylation of ASIC channels, decreasing the amplitude of ASIC currents, acid-evoked membrane excitability, and the depolarization amplitude secondary to acid stimuli [161]. In addition, oxytocin has been shown to inhibit pain directly by binding to oxytocin receptors (OXTR) on first order sensory afferents, second order neurons and GABAergic interneurons in the spinal cord, inhibiting the transmission of pain [162].…”