ABSTRACT
Group III/IV muscle afferents transduce nociceptive signals and modulate exercise pressor reflexes (EPRs). However, the mechanisms governing afferent responsiveness to dually modulate these processes are not well characterized. We and others have shown that ischemic injury can induce both nociception-related behaviors and exacerbated EPRs in the same mice. This correlated with primary muscle afferent sensitization and increased expression of glial cell line-derived neurotrophic factor (GDNF) in injured muscle and increased expression of GDNF family receptor α1 (GFRα1) in dorsal root ganglia (DRG). Here, we report that increased GDNF/GFRα1 signaling to sensory neurons from ischemia/reperfusion-affected muscle directly modulated nociceptive-like behaviors and increased exercise-mediated reflexes and group III/IV muscle afferent sensitization. This appeared to have taken effect through increased cyclic adenosine monophosphate (cAMP) response element binding (CREB)/CREB binding protein-mediated expression of the purinergic receptor P2X5 in the DRGs. Muscle GDNF signaling to neurons may, therefore, play an important dual role in nociception and sympathetic reflexes and could provide a therapeutic target for treating complications from ischemic injuries.
Subject(s)
Glial Cell Line-Derived Neurotrophic Factor/metabolism , Myalgia/etiology , Nociception/physiology , Reflex/physiology , Reperfusion Injury/pathology , Animals , CREB-Binding Protein/metabolism , Cardiovascular System/innervation , Cyclic AMP/metabolism , Cyclic AMP Response Element-Binding Protein/metabolism , Disease Models, Animal , Exercise/physiology , Ganglia, Spinal/metabolism , Glial Cell Line-Derived Neurotrophic Factor Receptors/metabolism , Heart Rate/physiology , Humans , Male , Mice , Muscle, Skeletal/blood supply , Muscle, Skeletal/innervation , Muscle, Skeletal/metabolism , Myalgia/pathology , Neurons, Afferent/physiology , Receptors, Purinergic P2X5/metabolism , Reperfusion Injury/complications , Signal Transduction/physiologyABSTRACT
UNLABELLED: 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 (IL1ß)/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 IL1ß-upregulated ASIC3 in single cells, and nerve-specific knock-down of ASIC3 recapitulated the results of inhibiting the enhanced IL1ß/IL1r1 signaling after I/R, which was also found to regulate afferent sensitization and pain-related behaviors. This suggests that targeting muscle IL1ß signaling may be a potential analgesic therapy for ischemic myalgia. SIGNIFICANCE STATEMENT: Here, we have described a novel pathway whereby increased inflammation within the muscle tissue during ischemia/reperfusion injury sensitizes group III and IV muscle afferents via upregulation of acid-sensing ion channel 3 (ASIC3), leading not only to alterations in mechanical and chemical responsiveness in individual afferents, but also to pain-related behavioral changes. Furthermore, these I/R-induced changes can be prevented using an afferent-specific siRNA knock-down strategy targeting either ASIC3 or the upstream mediator of its expression, interleukin 1 receptor 1. Therefore, this knowledge may contribute to the development of alternative therapeutics for muscle pain and may be especially relevant to pain caused by issues of peripheral circulation, which is commonly observed in disorders such as complex regional pain syndrome, sickle cell anemia, or fibromyalgia.
