Hyperexcitability of muscle spindle afferents in jaw-closing muscles in experimental myalgia: Evidence for large primary afferents involvement in chronic pain

The goals of this review are to improve understanding of the aetiology of chronic muscle pain and identify new targets for treatments. Muscle pain is usually associated with trigger points in syndromes such as fibromyalgia and myofascial syndrome, and with small spots associated with spontaneous electrical activity that seems to emanate from fibers inside muscle spindles in EMG studies. These observations, added to the reports that large-diameter primary afferents, such as those innervating muscle spindles, become hyperexcitable and develop spontaneous ectopic firing in conditions leading to neuropathic pain, suggest that changes in excitability of these afferents might make an important contribution to the development of pathological pain. Here, we review evidence that the muscle spindle afferents (MSAs) of the jaw-closing muscles become hyperexcitable in a model of chronic orofacial myalgia. In these afferents, as in other large-diameter primary afferents in dorsal root ganglia, firing emerges from fast membrane potential oscillations that are supported by a persistent sodium current (INaP) mediated by Na+ channels containing the alpha-subunit NaV1.6. The current flowing through NaV1.6 channels increases when the extracellular Ca2+ concentration decreases, and studies have shown that INaP-driven firing is increased by S100 beta, an astrocytic protein that chelates Ca2+ when released in the extracellular space. We review evidence of how astrocytes, which are known to be activated in pain conditions, might, through their regulation of extracellular Ca2+, contribute to the generation of ectopic firing in MSAs. To explain how ectopic firing in MSAs might cause pain, we review evidence supporting the hypothesis that cross-talk between proprioceptive and nociceptive pathways might occur in the periphery, within the spindle capsule. What is the topic of this review?Firing in muscle spindle afferents (MSAs) is generated when their muscle is stretched, but sometimes generated elsewhere along the neuron (ectopic firing) in pathological pain. Appearance of ectopic firing coincides with appearance of pain. We examine mechanisms underlying emergence of ectopic firing in MSAs of the jaw-closing muscles.What advances does it highlight?Firing in MSAs emerges from oscillations supported by a persistent sodium current, which varies with extracellular Ca2+, which is, in turn, regulated by astrocytes. We emphasize the potential role of astrocytes in appearance of ectopic firing. We proposed an explanation for how activity in MSAs crosses to nociceptors in the periphery.

Automated summary

The topic of this review is the emergence of ectopic firing in muscle spindle afferents (MSAs) and its potential role in pathological pain. The review highlights the mechanisms underlying the generation of ectopic firing, such as oscillations supported by a persistent sodium current and regulation of extracellular Ca2+ by astrocytes. The review also discusses the possible cross-talk between MSAs and nociceptors in the periphery.