Peripheral Mechanisms of Ischemic Myalgia

Abstract

Musculoskeletal pain due to ischemia is present in a variety of clinical conditions including peripheral vascular disease (PVD), sickle cell disease (SCD), complex regional pain syndrome (CRPS), and even fibromyalgia (FM). The clinical features associated with deep tissue ischemia are unique because although the subjective description of pain is common to other forms of myalgia, patients with ischemic muscle pain often respond poorly to conventional analgesic therapies. Moreover, these patients also display increased cardiovascular responses to muscle contraction, which often leads to exercise intolerance or exacerbation of underlying cardiovascular conditions. This suggests that the mechanisms of myalgia development and the role of altered cardiovascular function under conditions of ischemia may be distinct compared to other injuries/diseases of the muscles. It is widely accepted that group III and IV muscle afferents play an important role in the development of pain due to ischemia. These same muscle afferents also form the sensory component of the exercise pressor reflex (EPR), which is the increase in heart rate and blood pressure (BP) experienced after muscle contraction. Studies suggest that afferent sensitization after ischemia depends on interactions between purinergic (P2X and P2Y) receptors, transient receptor potential (TRP) channels, and acid sensing ion channels (ASICs) in individual populations of peripheral sensory neurons. Specific alterations in primary afferent function through these receptor mechanisms correlate with increased pain related behaviors and altered EPRs. Recent evidence suggests that factors within the muscles during ischemic conditions including upregulation of growth factors and cytokines, and microvascular changes may be linked to the overexpression of these different receptor molecules in the dorsal root ganglia (DRG) that in turn modulate pain and sympathetic reflexes. In this review article, we will discuss the peripheral mechanisms involved in the development of ischemic myalgia and the role that primary sensory neurons play in EPR modulation.

Nerve growth factor‐induced muscle hyperalgesia facilitates ischaemic contraction‐evoked pain

“…Pain conditions, and especially clinical chronic inflammatory pain, but also experimental ischaemic pain, often involve Nerve Growth Factor (NGF) driving peripheral sensitization (Mamet, Lazdunski, & Voilley, 2003;Queme, Ross, & Jankowski, 2017). In human experimental studies, single i.m.…”

Identification of a novel population of peripheral sensory neuron that regulates blood pressure

“…Accordingly, we observed a profound mechanical hypersensitivity upon local stimulation of TrkC + /Th + neurons that paralleled the reduction in vascularized area. Of note, alterations in neuronal control of vasculature have been associated with a number of painful conditions including diabetic neuropathy, migraine, Raynaud's disease and fibromyalgia (Albrecht et al, 2013;Burnstock, 2008;Cooke and Marshall, 2005;Edvinsson et al, 2019;Jacobs and Dussor, 2016;Pietrobon and Moskowitz, 2013;Queme et al, 2017;Schmidt, 2014). To date, the majority of studies have considered only the contribution of autonomic and peptidergic sensory neurons to these conditions.…”

Selective Prostacyclin Receptor Agonist Selexipag, in Contrast to Prostacyclin Analogs, Does Not Evoke Paradoxical Vasoconstriction of the Rat Femoral Artery

“…The femoral artery was chosen for investigation since its occlusion contributes to leg pain in patients with peripheral artery disease (Beard 2000). This artery is also predominantly used in preclinical models of leg ischemia (Krishna et al, 2016;Queme et al, 2017).…”

“…Leg ischemia is commonly associated with pain in the calf and thigh muscles while walking, due to restriction of blood flow through the femoral artery (Beard 2000). In addition, reduced blood flow and tissue oxygenation, as occur after exaggerated vasoconstriction, promote the production of metabolism-derived pain mediators (Queme et al, 2017). The high selectivity of selexipag and its metabolite for the prostacyclin IP receptor precludes EP 3 receptor-mediated vasoconstriction and sensitization of afferent neurons, which might translate into improved tolerability over PGI 2 analogs in patients with PAH.…”