Department of Physiological Genomics, Biomedical Center, Ludwig-Maximilians-University, Planegg-Martinsried, Germany.
Department of Neurology, LMU Klinikum, Friedrich-Baur-Institute, Ludwig-Maximilians-University, Munich, Germany.
Muscle Nerve. 2022 Jul;66(1):96-105. doi: 10.1002/mus.27546. Epub 2022 Apr 27.
INTRODUCTION/AIMS: The muscle relaxant methocarbamol and the antimyotonic drug mexiletine are widely used for the treatment of muscle spasms, myotonia, and pain syndromes. To determine whether these drugs affect muscle spindle function, we studied their effect on the resting discharge and on stretch-induced action potential frequencies of proprioceptive afferent neurons.
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-and-hold stretches. Maximal tetanic force of the same muscle after direct stimulation was determined. High-resolution confocal microscopy analysis was performed to determine the distribution of Na 1.4 channels, a potential target for both drugs.
Methocarbamol and mexiletine inhibited the muscle spindle resting discharge in a dose-dependent manner with IC values around 300 μM and 6 μM, 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-gated sodium channel Na 1.4 in intrafusal fibers.
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.
简介/目的：肌肉松弛剂美索巴莫和抗肌肉紧张药物美西律被广泛用于治疗肌肉痉挛、肌强直和疼痛综合征。为了确定这些药物是否影响肌梭功能，我们研究了它们对本体感受传入神经元静息放电和拉伸诱导动作电位频率的影响。
在成年 C57BL/6J 小鼠伸趾长肌的肌梭中，记录本体感受传入神经元的单个单位动作电位频率，在静息状态下和在斜坡和保持拉伸期间进行记录。直接刺激后测定同一肌肉的最大强直力。进行高分辨率共聚焦显微镜分析，以确定两种药物的潜在靶点 Na 1.4 通道的分布。
美索巴莫和美西律以剂量依赖性方式抑制肌梭静息放电，IC 值分别约为 300μM 和 6μM。随着两种药物浓度的增加，对拉伸的反应也受到影响，首先是静态敏感性，然后是动态敏感性。在高浓度下，两种药物均可完全阻断肌梭传入输出。两种药物还可逆地降低了伸趾长肌在强直刺激后的比力。最后，我们提供了电压门控钠离子通道 Na 1.4 存在于梭内纤维中的证据，并证明其具有特异性定位。
在这项研究中，我们证明了这两种肌肉松弛剂都影响肌梭功能，这表明两者都可能作为潜在的副作用导致本体感觉受损。此外，我们的结果提供了美索巴莫和美西律具有外周活性的额外证据。
