The voltage-gated sodium channel NaV1.7 underlies endometriosis-associated chronic pelvic pain

Joel Castro, Jessica Maddern, Chun Yuen Chow, Poanna Tran, Irina Vetter, Glenn F. King, Stuart M. Brierley

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)

Abstract

Chronic pelvic pain (CPP) is the primary symptom of endometriosis patients, but adequate treatments are lacking. Modulation of ion channels expressed by sensory nerves innervating the viscera has shown promise for the treatment of irritable bowel syndrome and overactive bladder. However, similar approaches for endometriosis-associated CPP remain underdeveloped. Here, we examined the role of the voltage-gated sodium (NaV) channel NaV1.7 in (i) the sensitivity of vagina-innervating sensory afferents and investigated whether (ii) NaV1.7 inhibition reduces nociceptive signals from the vagina and (iii) ameliorates endometriosis-associated CPP. The mechanical responsiveness of vagina-innervating sensory afferents was assessed with ex vivo single-unit recording preparations. Pain evoked by vaginal distension (VD) was quantified by the visceromotor response (VMR) in vivo. In control mice, pharmacological activation of NaV1.7 with OD1 sensitised vagina-innervating pelvic afferents to mechanical stimuli. Using a syngeneic mouse model of endometriosis, we established that endometriosis sensitised vagina-innervating pelvic afferents to mechanical stimuli. The highly selective NaV1.7 inhibitor Tsp1a revealed that this afferent hypersensitivity occurred in a NaV1.7-dependent manner. Moreover, in vivo intra-vaginal treatment with Tsp1a reduced the exaggerated VMRs to VD which is characteristic of mice with endometriosis. Conversely, Tsp1a did not alter ex vivo afferent mechanosensitivity nor in vivo VMRs to VD in Sham control mice. Collectively, these findings suggest that NaV1.7 plays a crucial role in endometriosis-induced vaginal hyperalgesia. Importantly, NaV1.7 inhibition selectively alleviated endometriosis-associated CPP without the loss of normal sensation, suggesting that selective targeting of NaV1.7 could improve the quality of life of women with endometriosis. (Figure presented.)

Original languageEnglish
JournalJournal of Neurochemistry
Early online date24 Feb 2023
DOIs
Publication statusE-pub ahead of print - 24 Feb 2023

Keywords

  • chronic pelvic pain
  • endometriosis
  • mechanosensitivity
  • vagina-innervating afferents
  • visceromotor response
  • voltage-gated sodium channels

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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