Methocarbamol blocks muscular Na_v1.4 channels and decreases isometric force of mouse muscles

Abstract

Background: The muscle relaxant methocarbamol is widely used for the treatment of muscle spasms and pain syndromes. To elucidate molecular mechanisms of its action, we studied its influence on neuromuscular transmission, on isometric muscle force, and on voltage-gated Na + channels. Methods: Neuromuscular transmission was investigated in murine diaphragm-phrenic nerve preparations and muscle force studied on mouse soleus muscles. Na v 1.4 channels and Na v 1.7 channels were functionally expressed in eukaryotic cell lines. Results: Methocarbamol, at 2 mM, decreased the decay of endplate currents, slowed the decay of endplate potentials and reduced tetanic force of soleus muscles. The drug reversibly inhibited current flow through muscular Na v 1.4 channels, while neuronal Na v 1.7 channels were unaffected. Conclusions: The study provides evidence for peripheral actions of methocarbamol on skeletal muscle. Muscular Na + channels are a molecular target of methocarbamol. Since Na v 1.7 currents were unaffected, methocarbamol is unlikely to exert its analgesic effect by directly blocking Na v 1.7 channels.

The effect of methocarbamol and mexiletine on murine muscle spindle function

“…Mexiletine and methocarbamol both bind to several voltagegated sodium channels, including Na v 1.4, and both drugs preferentially affect the inactivated state. 23,33 Several sodium channels have been localized in muscle spindles by immunocytochemistry. 49 50 It remains to be solved, however, which of these sodium channels is the target of mexiletine and/or methocarbamol in muscle spindles.…”

“…In this study we have shown that methocarbamol and mexiletine inhibit generation of action potentials in muscle spindle afferents at rest as well as in response to stretch, but they do not affect muscle tension. Mexiletine and methocarbamol both bind to several voltage‐gated sodium channels, including Na v 1.4, and both drugs preferentially affect the inactivated state 23,33 . Several sodium channels have been localized in muscle spindles by immunocytochemistry 49 .…”

“…12,13,[17][18][19][20] For many years, methocarbamol was considered a centrally acting relaxant 4,21,22 ; however, recently the specific inhibition of the voltage-gated sodium channel 1.4 (Na v 1.4), but not of Na v 1.7, was reported. 23 Because Na v 1.4 is the primary voltage-gated sodium channel responsible for the initiation of action potentials in skeletal muscle fibers, a peripheral action of methocarbamol is likely to contribute to its muscle-relaxing activity. Accordingly, Crankshaw and Raper reported that methocarbamol caused a prolongation of the refractory period of cat tibialis muscle and a suppression of polysynaptic reflex contractions without an effect on spinal interneurons.…”

“…Methocarbamol is used for the treatment of lower back pain, as an adjunct to physical therapy for the relief of acute musculoskeletal pain, such as after acute traumatic injury, 4,12‐15 treatment of stiff‐man syndrome, 16 and painful muscle spasm 12,13,17‐20 . For many years, methocarbamol was considered a centrally acting relaxant 4,21,22 ; however, recently the specific inhibition of the voltage‐gated sodium channel 1.4 (Na v 1.4), but not of Na v 1.7, was reported 23 . Because Na v 1.4 is the primary voltage‐gated sodium channel responsible for the initiation of action potentials in skeletal muscle fibers, a peripheral action of methocarbamol is likely to contribute to its muscle‐relaxing activity.…”

Focus on the role of Na(v)1.7 channel as molecular target of methocarbamol and its analgesic effects

“…Heo and Kim for their interest in our recent study of the elastographic and sonographic assessment of the common extensor tendon (CET) in patents with carpal tunnel syndrome. 1 We agree that comparison of ultrasound elastography studies is affected by differences in the technique used.…”