TY - JOUR
T1 - Pharmacological modulation of voltage-gated sodium (NaV) channels alters nociception arising from the female reproductive tract
AU - Castro, Joel
AU - Maddern, Jessica
AU - Erickson, Andelain
AU - Caldwell, Ashlee
AU - Grundy, Luke
AU - Harrington, Andrea M.
AU - Brierley, Stuart M.
PY - 2021/1/1
Y1 - 2021/1/1
N2 - 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.
AB - 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.
KW - Pharmacological modulation
KW - voltage-gated sodium channels
KW - NaV
KW - nociception
KW - female reproductive tract
UR - http://www.scopus.com/inward/record.url?scp=85093526440&partnerID=8YFLogxK
UR - http://purl.org/au-research/grants/NHMRC/1181448
UR - http://purl.org/au-research/grants/NHMRC/1126378
UR - http://purl.org/au-research/grants/NHMRC/1083480
UR - http://purl.org/au-research/grants/NHMRC/1139366
UR - http://purl.org/au-research/grants/NHMRC/1140297
UR - http://purl.org/au-research/grants/ARC/DE130100223
UR - http://purl.org/au-research/grants/ARC/DP180101395
U2 - 10.1097/j.pain.0000000000002036
DO - 10.1097/j.pain.0000000000002036
M3 - Article
C2 - 32826751
AN - SCOPUS:85093526440
SN - 0304-3959
VL - 162
SP - 227
EP - 242
JO - Pain
JF - Pain
IS - 1
ER -