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To determine whether these drugs affect muscle spindle function, we studied their effect on the resting discharge and on stretch\u2010induced action potential frequencies of proprioceptive afferent neurons.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Single unit action potential frequencies of proprioceptive afferents from muscle spindles in the murine extensor digitorum longus muscle of adult C57BL\/6J mice were recorded under resting conditions and during ramp\u2010and\u2010hold stretches. Maximal tetanic force of the same muscle after direct stimulation was determined. High\u2010resolution confocal microscopy analysis was performed to determine the distribution of Na<jats:sub>v<\/jats:sub>1.4 channels, a potential target for both drugs.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Methocarbamol and mexiletine inhibited the muscle spindle resting discharge in a dose\u2010dependent manner with IC<jats:sub>50<\/jats:sub> values around 300\u2009\u03bcM and 6\u00a0\u03bcM, respectively. With increasing concentrations of both drugs, the response to stretch was also affected, with the static sensitivity first followed by the dynamic sensitivity. At high concentrations, both drugs completely blocked muscle spindle afferent output. Both drugs also reversibly reduced the specific force of the extensor digitorum longus muscle after tetanic stimulation. Finally, we present evidence for the presence and specific localization of the voltage\u2010gated sodium channel Na<jats:sub>v<\/jats:sub>1.4 in intrafusal fibers.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>In this study we demonstrate that both muscle relaxants affect muscle spindle function, suggesting impaired proprioception as a potential side effect of both drugs. Moreover, our results provide additional evidence of a peripheral activity of methocarbamol and mexiletine.<\/jats:p><\/jats:sec>","DOI":"10.1002\/mus.27546","type":"journal-article","created":{"date-parts":[[2022,4,4]],"date-time":"2022-04-04T04:12:17Z","timestamp":1649045537000},"page":"96-105","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["The effect of methocarbamol and mexiletine on murine muscle spindle function"],"prefix":"10.1002","volume":"66","author":[{"given":"Bridgette","family":"Watkins","sequence":"first","affiliation":[{"name":"Department of Physiological Genomics, Biomedical Center Ludwig\u2010Maximilians\u2010University  Planegg\u2010Martinsried Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hedwig M.","family":"Schuster","sequence":"additional","affiliation":[{"name":"Department of Physiological Genomics, Biomedical Center Ludwig\u2010Maximilians\u2010University  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