Tetrodotoxin-resistant voltage-dependent sodium channels in identified muscle afferent neurons

Baker Laboratory of Pharmacology, Dept. of Pharmacology, Kirksville College of Osteopathic Medicine, AT Still Univ. of Health Sciences, Kirksville, MO 63501. .
Journal of Neurophysiology (Impact Factor: 2.89). 08/2012; 108(8):2230-41. DOI: 10.1152/jn.00219.2012
Source: PubMed


Muscle afferents are critical regulators of motor function (Group I and II) and cardiovascular responses to exercise (Group III and IV). However, little is known regarding the expressed voltage-dependent ion channels. We identified muscle afferent neurons in dorsal root ganglia (DRGs), using retrograde labeling to examine voltage-dependent sodium (Na(V)) channels. In patch-clamp recordings, we found that the dominant Na(V) current in the majority of identified neurons was insensitive to tetrodotoxin (TTX-R), with Na(V) current in only a few (14%) neurons showing substantial (>50%) TTX sensitivity (TTX-S). The TTX-R current was sensitive to a Na(V)1.8 channel blocker, A803467. Immunocytochemistry demonstrated labeling of muscle afferent neurons by a Na(V)1.8 antibody, which further supported expression of these channels. A portion of the TTX-R Na(V) current appeared to be noninactivating during our 25-ms voltage steps, which suggested activity of Na(V)1.9 channels. The majority of the noninactivating current was insensitive to A803467 but sensitive to extracellular sodium. Immunocytochemistry showed labeling of muscle afferent neurons by a Na(V)1.9 channel antibody, which supports expression of these channels. Further examination of the muscle afferent neurons showed that functional TTX-S channels were expressed, but were largely inactivated at physiological membrane potentials. Immunocytochemistry showed expression of the TTX-S channels Na(V)1.6 and Na(V)1.7 but not Na(V)1.1. Na(V)1.8 and Na(V)1.9 appear to be the dominant functional sodium channels in small- to medium-diameter muscle afferent neurons. The expression of these channels is consistent with the identification of these neurons as Group III and IV, which mediate the exercise pressor reflex.

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    • "The NaV1.8 channel has also been found in the soma of small diameter sensory C and Aδ neurons [24] which have been shown to be involved in nociception in models of neuropathic and inflammatory pain [25]. One study reported that the NaV1.8 channel is present in 86% of the muscle sensory afferent fibers, which makes it a useful marker of putative muscle nociceptors [26], and recently it has been found in trigeminal ganglion neurons innervating the rat masseter muscle [27]. Taken together, this evidence suggests that NaV1.8 channel mainly found in the peripheral sensory neurons and their expression on nerve fibers provides a method to identify putatively nociceptive afferent fibers [24,28]. "
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