Muscle IL1  Drives Ischemic Myalgia via ASIC3-Mediated Sensory Neuron Sensitization

Abstract

Musculoskeletal pain is a significantly common clinical complaint. Although it is known that muscles are quite sensitive to alterations in blood flow/oxygenation and a number of muscle pain disorders are based in problems of peripheral perfusion, the mechanisms by which ischemic-like conditions generate myalgia remain unclear. We found, using a multidisciplinary experimental approach, that ischemia and reperfusion injury (I/R) in male Swiss Webster mice altered ongoing and evoked pain-related behaviors in addition to activity levels through enhanced muscle interleukin-1 beta (IL1␤)/IL1 receptor signaling to group III/IV muscle afferents. Peripheral sensitization depended on acid-sensing ion channels (ASICs) because treatment of sensory afferents in vitro with IL1␤-upregulated ASIC3 in single cells, and nerve-specific knock-down of ASIC3 recapitulated the results of inhibiting the enhanced IL1␤/IL1r1 signaling after I/R, which was also found to regulate afferent sensitization and pain-related behaviors. This suggests that targeting muscle IL1␤ signaling may be a potential analgesic therapy for ischemic myalgia.

Growth hormone regulates the sensitization of developing peripheral nociceptors during cutaneous inflammation

“…Single cells were first expelled from the borosilicate electrodes into individual tubes containing lysis buffer from the Message Booster cDNA Synthesis Kit (Epicentre/Illumina) and prokaryotic spike RNAs (1000 copies of LYS transcripts) were used for internal and reverse transcription controls since internal controls such as GAPDH will consistently vary from single cell to cell [58]. Single cell RNAs were reverse transcribed with Superscript III (Invitrogen) primed by an Oligo (dT) containing a T7 RNA polymerase promoter.…”

A dual role for peripheral GDNF signaling in nociception and cardiovascular reflexes

“…A common method to study the involvement of peripheral sensory neurons in both nociception and sympathetic reflexes is to use a skeletal muscle ischemic injury model 13,14,15,16,17 . After ischemic injuries, group III and IV muscle afferents display peripheral sensitization, including increased responsiveness to mechanical and chemical stimuli.…”

“…Chemo-reception and mechanical responsiveness of primary muscle afferents have been attributed to expression of a combination of both acid sensing ion channels (ASICs) and purinergic, P2X receptors 7,19,20,21,22,23 . Each of these ion channels have also been associated with altered nociception and EPR modulation after ischemic injury 8,16,24,25 . P2X and ASIC channel activity has been linked to sensing of fatigue and ischemic pain 7,19 by disrupting the metabolite responses of DRG neurons 7,9,19 .…”

“…P2X5 has also been shown to modulate the pH sensitivity of ASIC3 19 , which may further shape afferent and behavioral responsiveness. The role of these channels in the normal mechanical responses of nociceptors is not as clear, but both ASIC3 and P2X receptors have been linked to mechanical hypersensitivity in different injury models 7,16,20,23,26 .…”

“…We previously reported an important role for the cytokine interleukin 1-beta (IL-1β) modulating the expression of ASIC3 in mechanically and chemically sensitive afferents in the DRGs to regulate peripheral sensitization after ischemia with reperfusion (I/R) injury 16 . This suggested that factors expressed in the injured muscles may have a substantial influence on afferent function and subsequent behaviors after I/R.…”