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

Abstract

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 (I_NaP ) mediated by Na⁺ channels containing the α-subunit Na_V 1.6. The current flowing through Na_V 1.6 channels increases when the extracellular Ca²⁺ concentration decreases, and studies have shown that I_NaP -driven firing is increased by S100β, 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.

Keywords: astrocytes; chronic muscle pain; ectopic firing; muscle spindle afferent; trigeminal system.

FIGURE 1

Schematic representation synthesizing the proposed mechanisms underlying the appearance of ectopic firing in large‐diameter PAs of NVmes and DRG neurons. Left: In physiological conditions, higher levels of extracellular Ca²⁺ limit activity in the cells by occluding the Na⁺ channels (Na_V1.6) mediating I _NaP that supports membrane potential oscillations from which firing normally emerges. Right: In pathological states, reactive astrocytes (perhaps activated initially by firing of large‐diameter PAs sensing acidosis) release S100β, which chelates extracellular Ca²⁺ and enhances I _NaP, causing an increase in the amplitude of the fast membrane oscillations and emergence of ectopic firing. Abbreviations: DRG, dorsal root ganglion; I _NaP, persistent sodium current; NVmes, trigeminal mesencephalic nucleus; PA, primary afferent.

FIGURE 2

Effect of S100β and BAPTA on oscillations and firing properties of NVmes cells. (a) S100β locally applied on an NVmes cell increases the amplitude of the oscillations and induces firing (left), which is abolished by riluzole (right). (b) Both BAPTA and S100β decrease the threshold for firing (red arrows) and for oscillations (black arrows) in NVmes neurons subjected to a ramp protocol. Insets: Schematic representation of the experimental set‐up. Abbreviation: NVmes, trigeminal mesencephalic nucleus.

FIGURE 3

Proximity of astrocytic processes to NVmes axons and their activation in the acidic saline masseteric myalgia model. (a) S100β‐immunoreactive (pink) astrocytes have processes closely apposed (*) to NVmes somata and axons that are immunoreactive to Na_V1.6 (green). (b) Expression of GFAP (green) in the NVmes area of rats from the control and pain groups at 7 days after the second neutral (left) or acidic (right) saline injection. Somata of NVmes neurons (red) are retrogradely labelled by intramuscular injections of fluorescent cholera toxin β‐subunit. Abbreviations: GFAP, glial fibrillary acidic protein; NVmes, trigeminal mesencephalic nucleus.

FIGURE 4

Schematic summary of mechanisms thought to underlie peripheral sensitization within spindle capsules, with indications of all locations where therapeutic interventions have been shown to have analgesic effects in humans. Top: Blockade of I _NaP with riluzole (left) prevents ectopic firing in NVmes or the DRG (see Figure 1 for mechanisms underlying the appearance of the ectopic firing) and produces analgesia. Bottom left: Unless prevented, the ectopic firing travels antidromically to the peripheral endings of large‐diameter VGluT1‐positive PAs and induces glutamate release within the spindle capsule (using vesicular release), thereby activating nociceptors (which normally express VGluT2) through ionotropic and metabotropic glutamate receptors and contributing to the observed allodynia. Intramuscular injections of ionotropic and metabotropic glutamate receptor antagonists prevent activation of nociceptors and induction of allodynia. Bottom right: Chronic activation of nociceptors (having their soma in the TG or the DRG) and/or central endings of large‐diameter PAs leads to chronic activation of second‐order neurons and central sensitization. Abbreviations: DRG, dorsal root ganglion; I _NaP, persistent sodium current; NVmes, trigeminal mesencephalic nucleus; PA, primary afferent; TG, trigeminal ganglion.