{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T14:00:12Z","timestamp":1792072812148,"version":"4.4.0"},"reference-count":36,"publisher":"Wiley","issue":"17","license":[{"start":{"date-parts":[[2024,5,7]],"date-time":"2024-05-07T00:00:00Z","timestamp":1715040000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"published-print":{"date-parts":[[2024,9]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background and Purpose<\/jats:title><jats:p>The voltage\u2010gated sodium channel isoform Na<jats:sub>V<\/jats:sub>1.7 is a high\u2010interest target for the development of non\u2010opioid analgesics due to its preferential expression in pain\u2010sensing neurons. Na<jats:sub>V<\/jats:sub>1.7 is also expressed in autonomic neurons, yet its contribution to involuntary visceral reflexes has received limited attention. The small molecule inhibitor ST\u20102560 was advanced into pain behaviour and cardiovascular models to understand the pharmacodynamic effects of selective inhibition of Na<jats:sub>V<\/jats:sub>1.7.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>Potency of ST\u20102560 at Na<jats:sub>V<\/jats:sub>1.7 and off\u2010target ion channels was evaluated by whole\u2010cell patch\u2010clamp electrophysiology. Effects on nocifensive reflexes were assessed in non\u2010human primate (NHP) behavioural models, employing the chemical capsaicin and mechanical stimuli. Cardiovascular parameters were monitored continuously in freely\u2010moving, telemetered NHPs following administration of vehicle and ST\u20102560.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>ST\u20102560 is a potent inhibitor (IC<jats:sub>50<\/jats:sub>\u2009=\u200939\u2009nM) of Na<jats:sub>V<\/jats:sub>1.7 in primates with \u22651000\u2010fold selectivity over other isoforms of the human Na<jats:sub>V<\/jats:sub>1.x family. Following systemic administration, ST\u20102560 (0.1\u20130.3\u2009mg\u00b7kg<jats:sup>\u22121<\/jats:sup>, s.c.) suppressed noxious mechanical\u2010 and chemical\u2010evoked reflexes at free plasma concentrations threefold to fivefold above Na<jats:sub>V<\/jats:sub>1.7 IC<jats:sub>50<\/jats:sub>. ST\u20102560 (0.1\u20131.0\u2009mg\u00b7kg<jats:sup>\u22121<\/jats:sup>, s.c.) also produced changes in haemodynamic parameters, most notably a 10\u2010 to 20\u2010mmHg reduction in systolic and diastolic arterial blood pressure, at similar exposures.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions and Implications<\/jats:title><jats:p>Acute pharmacological inhibition of Na<jats:sub>V<\/jats:sub>1.7 is antinociceptive, but also has the potential to impact the cardiovascular system. Further work is merited to understand the role of Na<jats:sub>V<\/jats:sub>1.7 in autonomic ganglia involved in the control of heart rate and blood pressure, and the effect of selective Na<jats:sub>V<\/jats:sub>1.7 inhibition on cardiovascular function.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.16398","type":"journal-article","created":{"date-parts":[[2024,5,8]],"date-time":"2024-05-08T06:05:18Z","timestamp":1715148318000},"page":"3160-3171","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["ST\u20102560, a selective inhibitor of the Na<sub>V<\/sub>1.7 sodium channel, affects nocifensive and cardiovascular reflexes in non\u2010human primates"],"prefix":"10.1111","volume":"181","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3997-6073","authenticated-orcid":false,"given":"John V.","family":"Mulcahy","sequence":"first","affiliation":[{"name":"SiteOne Therapeutics, Inc.  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