Peripheral Mechanisms of Ischemic Myalgia, 2017, Querne et al

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https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5743676/

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.

 

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In the management of persistent muscle pain, first-line therapies often consist of opioids, non-steroidal anti-inflammatory drugs (NSAIDs), and physical activity regimens (Light et al., 2009; Ambrose and Golightly, 2015; Clauw, 2015; Bacurau et al., 2016); however, these types of interventions may be ineffective or even detrimental in some patient populations (Kindler et al., 2011; Murphy et al., 2011; Clauw, 2015). Thus, understanding how muscle pain arises across various diseases and injury types is paramount for increasing the availability and efficacy of specific pain management strategies.

Numerous basic and clinical reports have shown that ischemic conditions are able to generate muscle pain (Alam and Smirk, 1937; Sinoway et al., 1989; Coderre et al., 2004; Laferrière et al., 2008; Ross et al., 2014). Decreased blood flow to the skeletal muscle that impairs oxygen supply sufficient to inadequately meet the metabolic demands of the tissue is a feature of multiple clinical conditions in which patients often report deep tissue pain (Dennis and Keating, 1991; Norris et al., 1993; Kasikcioglu et al., 2006; Katz et al., 2007; Nishida et al., 2009; Coderre and Bennett, 2010; McDermott, 2015). In this context, age is an important epidemiological variable. In pediatric patients, ischemic pain is often the result of pathologies like sickle cell disease (SCD), juvenile fibromyalgia (JFM) and complex regional pain syndrome (CRPS; Groeneweg et al., 2009; Zemel and Blier, 2016; Bou-Maroun et al., 2018). In adults, peripheral vascular disease (PVD) is a more prevalent cause of ischemic myalgia (McDermott et al., 2004; Norgren et al., 2007; Muir, 2009).

The origin of the muscle pain is evident in cases like PVD, where there is a mechanical obstruction of the vasculature due to atherosclerosis for example, or in SCD, in which the sickling crises induce both mechanical obstructions and hemolytic anemia (Hands et al., 1990; Beard, 2000; Meru et al., 2006; Davies, 2012; Garrison et al., 2012; Brandow et al., 2013). In other cases, anomalies in peripheral perfusion have also been hypothesized to be major contributors to the painful symptoms of conditions like CRPS and fibromyalgia (FM; Elvin et al., 2006; Coderre and Bennett, 2010; Chalaye et al., 2014).

In the case of type 1 CRPS, it has been proposed that the perfusion anomalies are the consequence of a hyperactive sympathetic outflow (Bonica, 1990; Iolascon et al., 2015), usually in response to a deep tissue injury in which inflammation causes a compartment-like syndrome that impairs perfusion to the affected tissues (Coderre and Bennett, 2010).

In FM, the driving factors that lead to the development of deep tissue pain are less clear, yet, studies in patients have shown impaired perfusion within the painful areas of the body (Jeschonneck et al., 2000; Morf et al., 2005; Elvin et al., 2006; McIver et al., 2006). Evidence of this deficit has been detected using enhanced ultrasound imaging of muscular blood flow during static and dynamic contractions. These studies have reported lower muscle vascularity that was accompanied by a shorter flow response to muscle activity in FM patients (Elvin et al., 2006). Furthermore, the microcirculation, measured by laser Doppler flowmetry, above sensitive points in FM patients is reported to be decreased compared to healthy controls (Jeschonneck et al., 2000).

Severe muscle ischemia is most often not permanent. Blood flow is at least partially reestablished and this causes a complex ischemia-reperfusion (I/R) injury that is characterized by the generation of free radicals (Debold, 2015) and reactive oxygen species like hydrogen peroxide (Paradis et al., 2016) that impair mitochondrial function, damage muscle fibers and promote apoptosis (Pipinos et al., 2008a,b; McDermott, 2015; Ryan et al., 2015). In addition, during the reperfusion phase, the muscle microvasculature experiences increased permeability and injury that facilitates the sequestration of activated lymphocytes in the injured tissue. These cells, mostly macrophages and neutrophils, release pro-algesic cytokines like interleukin-1 (IL-1), tumor necrosis factor and many others (Figure (Figure1).1). Intracellular granules containing radical forming enzymes can further increase cell damage and in turn enhance the immune response to injury (Blaisdell, 2002; Eisenhardt et al., 2012; Gillani et al., 2012).

The duration of the insult is also relevant, as the underlying mechanisms of muscle pain generation in disorders of peripheral perfusion seem to depend on the length of ischemia and/or reperfusion; partially due to enhanced muscle atrophy and microvascular changes observed following a prolonged occlusion over those detected following a transient I/R injury (Blaisdell, 2002; Eisenhardt et al., 2012; Ross et al., 2014).