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A significant decrease in the expression of spinal microRNA‑29c (miR‑29c), which is responsible for the regulation of oxytocin receptor (OXTR) expression, was observed in nerve injury pain during childbirth. The present study investigates whether spinal miR‑29c could be a potential target for the treatment of pain, via the oxytocin (OT)‑γ‑aminobutyric acid (GABA) pathway. A spared nerve injury (SNI) rat model was established to induce neuropathic pain, simulating hyperalgesia. Spinal neurons were treated with OT to mimic the hormonal changes in the central nervous system after delivery. A change in the neuronal miniature inhibitory postsynaptic currents (mIPSCs) was observed in neurons, following the silencing of miR‑29c or OT treatment with or without OXTR antagonist. The Von‑Frey apparatus was used to measure the animal behaviors. Molecular biological experiments and electrophysical recordings in vivo and in vitro were performed to reveal the potential analgesic mechanisms. miR‑29c was significantly downregulated (more than 8‑fold) in the spinal dorsal horn of delivery+SNI rats compared with the SNI rats. The silencing of miR‑29c resulted in increased pain threshold in SNI rats. Bioinformatics analysis indicated that OXTR was a potential target gene of miR‑29c. The delivery+SNI rats presented with higher levels of OT in the cerebrospinal fluid compared with SNI rats, which indicated that the OT signaling pathway may participate in pain relief response. The increased expression of OXTR and GABA in delivery+SNI rats were observed in the miR‑29c‑silenced SNI rat model, suggesting that the silencing of miR‑29c can mediate pain relief by enhancing the OT‑GABA pathway. In addition, an electrophysiology assay was performed to assess the mIPSCs in neurons. The silencing of miR‑29c in neurons increased the frequency and amplitude of mIPSCs but there was no influence on the decay time, which suggested that the spinal inhibitory neurons became more active, subsequently reducing the feeling of pain. The inhibition of OXTR reversed the enhanced inhibitory postsynaptic currents, indicating a crucial role for OXTR in the miR‑29c‑associated pain regulation. Taken together, the results of the present study suggested that spinal oxytocinergic inhibitory control plays an important role in pain relief in the neuropathic pain rat model undergoing vaginal delivery. Silencing spinal miR‑29c may be a potential target for pain relief through the OT‑GABA pathway.

Neuropathic pain, often caused by nerve injury, is a major clinical challenge. Mechanisms that underlie neuropathic pain remain elusive and effective medications are limited. Numerous investigations of pain mechanisms have focused on alterations and phenotypic switches of the nociceptive transmitters and modulators, as well as on their receptors and downstream signaling pathways that have already exerted roles in the pain processes of mature nervous systems. We have demonstrated recently that nerve injury may elicit neuronal alterations that recapitulate events occurring during development. Signaling of the representative activated molecule Wnt thus becomes a trigger for the development of neuropathic pain and is a potential therapeutic target. We report that the transcriptional regulators YAP and TAZ, which orchestrate Wnt response via incorporation in the β-catenin destruction complex, are key in the pathogenesis of neuropathic pain and may serve as an “ON–OFF” switch for neuropathic pain status in rats. Peripheral nerve injury causes rapid-onset and long-lasting nuclear accumulation of YAP/TAZ/β-catenin in the spinal dorsal horn. Spinal inhibition or knock-down of either YAP or TAZ suppresses mechanical allodynia induced by nerve injury or the pain initiators lysophosphatidic acid and Wnt3a. Promoting the nuclear accumulation of YAP/TAZ leads to mechanical hypersensitivity in naive animals. Further, we discovered a new small molecule, dCTB, which targets YAP/TAZ/β-catenin and can greatly suppress neuropathic pain and the associated neurochemical alterations. Our study reveals that YAP and TAZ are core mechanisms underlying the pathogenesis of neuropathic pain and are targets in the screening for potent analgesics for the treatment of neuropathic pain.SIGNIFICANCE STATEMENTMechanisms that underlie neuropathic pain remain elusive. We have demonstrated recently that nerve injury can activate Wnt signaling, which becomes a trigger for the development of neuropathic pain. We report that the transcriptional regulators YAP and TAZ, which orchestrate Wnt response via incorporation in the β-catenin destruction complex, are key in the pathogenesis of neuropathic pain and may serve as an “ON–OFF” switch for neuropathic pain status. Further, we discovered a new small molecule, dCTB, which targets YAP/TAZ/β-catenin and can greatly suppress neuropathic pain. Our study reveals that YAP and TAZ are core mechanisms underlying the pathogenesis of neuropathic pain and are targets in the screening of potent analgesics for the treatment of neuropathic pain.