Sensitization of group III and IV muscle afferents in the mouse after ischemia and reperfusion injury

J Pain. 2014 Dec;15(12):1257-70. doi: 10.1016/j.jpain.2014.09.003.


Ischemic myalgia is a unique type of muscle pain in the patient population. The role that discrete muscle afferent subpopulations play in the generation of pain during ischemic events, however, has yet to be determined. Using 2 brachial artery occlusion models to compare prolonged ischemia or transient ischemia with reperfusion of the muscles, we found that both injuries caused behavioral decrements in grip strength, as well as increased spontaneous pain behaviors. Using our ex vivo forepaw muscles, median and ulnar nerves, dorsal root ganglion, and spinal cord recording preparation, we found after both prolonged and transient ischemia that there was a significant increase in the number of afferents that responded to both noxious and non-noxious chemical (lactate, adenosine triphosphate, varying pH) stimulation of the muscles compared to uninjured controls. However, we found an increase in firing to heat stimuli specifically in muscle afferents during prolonged ischemia, but a distinct increase in afferent firing to non-noxious chemicals and decreased mechanical thresholds after transient ischemia. The unique changes in afferent function observed also corresponded with distinct patterns of gene expression in the dorsal root ganglia. Thus, the development of ischemic myalgia may be generated by unique afferent-based mechanisms during prolonged and transient ischemia.

Perspective: This study analyzed the response properties of thinly myelinated group III and unmyelinated group IV muscle afferents during prolonged and transient ischemia in addition to pain behaviors and alterations in DRG gene expression in the mouse. Results suggest that mechanisms of pain generation during prolonged ischemia may be different from ischemia/reperfusion.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials
  • Adenosine Triphosphate
  • Animals
  • Disease Models, Animal
  • Forelimb / physiopathology
  • Ganglia, Spinal / physiopathology
  • Hot Temperature
  • Hydrogen-Ion Concentration
  • Ischemia / physiopathology*
  • Lactic Acid
  • Median Nerve / physiopathology
  • Mice
  • Muscle Strength / physiology
  • Muscle, Skeletal / physiopathology*
  • Myalgia / physiopathology*
  • Neurons, Afferent / physiology*
  • Reperfusion Injury / physiopathology*
  • Spinal Cord / physiopathology
  • Time Factors
  • Ulnar Nerve / physiopathology


  • Lactic Acid
  • Adenosine Triphosphate