Castro Joel, Maddern Jessica, Erickson Andelain, Caldwell Ashlee, Grundy Luke, Harrington Andrea M, Brierley Stuart M
Visceral Pain Research Group, College of Medicine and Public Health, Flinders Health and Medical Research Institute (FHMRI), Flinders University, Bedford Park, Australia.
Hopwood Centre for Neurobiology, Lifelong Health Theme, South Australian Health and Medical Research Institute (SAHMRI), North Terrace, Adelaide, Australia.
Pain. 2021 Jan;162(1):227-242. doi: 10.1097/j.pain.0000000000002036.
Dyspareunia, also known as vaginal hyperalgesia, is a prevalent and debilitating symptom of gynaecological disorders such as endometriosis and vulvodynia. Despite this, the sensory pathways transmitting nociceptive information from female reproductive organs remain poorly characterised. As such, the development of specific treatments for pain associated with dyspareunia is currently lacking. Here, we examined, for the first time, (1) the mechanosensory properties of pelvic afferent nerves innervating the mouse vagina; (2) the expression profile of voltage-gated sodium (NaV) channels within these afferents; and (3) how pharmacological modulation of these channels alters vaginal nociceptive signalling ex vivo, in vitro, and in vivo. We developed a novel afferent recording preparation and characterised responses of pelvic afferents innervating the mouse vagina to different mechanical stimuli. Single-cell reverse transcription-polymerase chain reaction determined mRNA expression of NaV channels within vagina-innervating dorsal root ganglia neurons. Vagina-innervating dorsal root ganglia neuroexcitability was measured using whole-cell patch-clamp electrophysiology. Nociception evoked by vaginal distension was assessed by dorsal horn neuron activation within the spinal cord and quantification of visceromotor responses. We found that pelvic afferents innervating the vagina are tuned to detect various mechanical stimuli, with NaV channels abundantly expressed within these neurons. Pharmacological modulation of NaV channels (with veratridine or tetrodotoxin) correspondingly alters the excitability and mechanosensitivity of vagina-innervating afferents, as well as dorsal horn neuron activation and visceromotor responses evoked by vaginal distension. This study identifies potential molecular targets that can be used to modulate vaginal nociceptive signalling and aid in the development of approaches to manage endometriosis and vulvodynia-related dyspareunia.
性交疼痛，也称为阴道痛觉过敏，是子宫内膜异位症和外阴痛等妇科疾病中普遍存在且使人衰弱的症状。尽管如此，从女性生殖器官传递伤害性信息的感觉通路仍未得到充分表征。因此，目前缺乏针对与性交疼痛相关疼痛的特异性治疗方法。在此，我们首次研究了：（1）支配小鼠阴道的盆腔传入神经的机械感觉特性；（2）这些传入神经内电压门控钠（NaV）通道的表达谱；以及（3）这些通道的药理学调节如何在体外、体内改变阴道伤害性信号传导。我们开发了一种新型的传入神经记录制剂，并表征了支配小鼠阴道的盆腔传入神经对不同机械刺激的反应。单细胞逆转录-聚合酶链反应确定了支配阴道的背根神经节神经元内NaV通道的mRNA表达。使用全细胞膜片钳电生理学测量支配阴道的背根神经节神经兴奋性。通过脊髓内背角神经元激活和内脏运动反应的量化来评估阴道扩张诱发的伤害感受。我们发现支配阴道的盆腔传入神经能够检测各种机械刺激，并且这些神经元中大量表达NaV通道。NaV通道的药理学调节（用藜芦碱或河豚毒素）相应地改变了支配阴道的传入神经的兴奋性和机械敏感性，以及阴道扩张诱发的背角神经元激活和内脏运动反应。这项研究确定了可用于调节阴道伤害性信号传导并有助于开发治疗子宫内膜异位症和外阴痛相关性交疼痛方法的潜在分子靶点。
