Abstract
Increasing evidence suggests that transmembrane protein 16A (TMEM16A) in nociceptive neurons is an important molecular component contributing to peripheral pain transduction. The present study aimed to evaluate the role and mechanism of TMEM16A in chronic nociceptive responses elicited by spared nerve injury (SNI). In this study, SNI was used to induce neuropathic pain. Drugs were administered intrathecally. The expression and cellular localization of TMEM16A, the ERK pathway, and NK-1 in the dorsal root ganglion (DRG) were detected by western blot and immunofluorescence. Behavioral tests were used to evaluate the role of TMEM16A and p-ERK in SNI-induced persistent pain and hypersensitivity. The role of TMEM16A in the hyperexcitability of primary nociceptor neurons was assessed by electrophysiological recording. The results show that TMEM16A, p-ERK, and NK-1 are predominantly expressed in small neurons associated with nociceptive sensation. TMEM16A is colocalized with p-ERK/NK-1 in DRG. TMEM16A, the MEK/ERK pathway, and NK-1 are activated in DRG after SNI. ERK inhibitor or TMEM16A antagonist prevents SNI-induced allodynia. ERK and NK-1 are downstream of TMEM16A activation. Electrophysiological recording showed that CaCC current increases and intrathecal application of T16Ainh-A01, a selective TMEM16A inhibitor, reverses the hyperexcitability of DRG neurons harvested from rats after SNI. We conclude that TMEM16A activation in DRG leads to a positive interaction of the ERK pathway with activation of NK-1 production and is involved in the development of neuropathic pain after SNI. Also, the blockade of TMEM16A or inhibition of the downstream ERK pathway or NK-1 upregulation may prevent the development of neuropathic pain.
Highlights
Neuropathic pain is a clinically common chronic refractory pain syndrome that affects approximately 7–10% of the global population [1, 2]
We investigated the respective roles of transmembrane protein 16A (TMEM16A) and ERK/neurokinin-1 receptors (NK-1) signaling on dorsal root ganglion (DRG) in neuropathic pain and the ways in which they participate in pain
To determine whether phosphorylation of ERK and upregulation of NK-1 are mediated by TMEM16A, we investigated the effect of TMEM16A antagonist T16AinhA01 on the induction of p-ERK and NK-1 in L4-L6 DRGs
Summary
Neuropathic pain is a clinically common chronic refractory pain syndrome that affects approximately 7–10% of the global population [1, 2]. Recent studies have shown that chloride ion concentrations are increased in dorsal root ganglion neurons following nerve injury [3]. The activated form of ERK1/2, p-ERK1/2, stimulates the production and release of inflammatory factors and amplifies pain signals, which can contribute to the development of neuropathic pain [17,18,19]. After TMEM16A knockdown, the phosphorylation levels of MEK and ERK1/2 were significantly decreased, indicating that TMEM16A regulates cardiac fibrosis through the MAPK signaling pathway [22] This result suggests that the MEK/ ERK pathway plays a role in TMEM16A-mediated tumor proliferation, migration, and myocardial infarction [23, 24]. We investigated the respective roles of TMEM16A and ERK/NK-1 signaling on DRG in neuropathic pain and the ways in which they participate in pain. These studies provide, to the best of our knowledge, the first mechanistic description of the role of TMEM16A in neuropathic pain and suggest that this protein may play an important role in facilitating the generation and development of neuropathic pain
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