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Pain research and treatment typically focus on nerve and inflammatory injury, and more recently neuron-glia interactions, but little attention is paid to dysfunction in the microvasculature. This is surprising given that the microvascular is critical for endoneurial health and multiple inflammatory processes. Interruptions in normal microvasculature function can induce nerve damage and exaggerate inflammatory processes such as plasma extravasation, immune cell attraction, platelet adhesion, and processes affecting coagulation, thrombosis, and the proliferation of blood and lymphatic vessels [1-3]. Over the years there has been accumulating clinical evidence that microvascular dysfunction contributes to chronic pain in CRPS, fibromyalgia, and various other syndromes.

CRPS is a chronic pain condition that often follows deep tissue injuries such as fractures, crush injuries, or sprains and includes symptoms of spontaneous burning pain, mechanical and cold allodynia, and sometimes heat hyperalgesia [4,5]. CRPS-I includes pain that is disproportionate to the trauma but does not include signs of major nerve injury, while patients with CRPS-II have concomitant nerve injury. In addition to pain, CRPS patients exhibit vascular abnormalities affecting blood flow, skin temperature (hot or cold), and sudomotor function, which can cause edema or cyanosis, exaggerated sweating, trophic changes in skin, nails, and bone, and muscle dystonia [5-11].

In many CRPS patients, there is evidence that pain, vascular, and trophic changes are associated with ischemia in deep tissues and sometimes skin. Ischemia in these cases is often associated with oxidative stress, lipid peroxidation, collapsed or thickened capillary lumens, and increased arterial-venous shunting. Additional signs include high lactate flux, mitochondrial oxygen deficiency, and reduced capillary hemoglobin oxygen saturation, suggestive of poor oxygenation of various tissues [6,10,12-21]. These findings indicate that microvascular dysfunction and deep tissue ischemia play a role in CRPS, suggesting that nutritive blood flow disruptions may be more important for CRPS symptoms than alterations in thermoregulatory flow [21].

Distinguishing features of fibromyalgia are numerous trigger points and chronic widespread pain, that are associated with both peripheral and central sensitization, and dysfunction of descending inhibitory pain control systems. Fibromyalgia pain is often accompanied by fatigue, sleep disturbance, irritable bowel, mood disorders, and headache [22-26]. The pain of fibromyalgia is described as deep, gnawing, or burning and can be associated with stiffness, tenderness, pain post-exercise, paresthesia, restless legs, and Raynaud’s phenomenon [27].

Muscle pathology has been reported in fibromyalgia but is often subtle and can include capillary dysfunction and mitochondrial abnormalities indicative of poor oxygenation [28-34]. Painful areas in fibromyalgia patients exhibit signs of oxidative stress, including increases in oxygen free radicals, and decreases in endogenous antioxidants, and patients experience pain relief in response to antioxidant treatments [35-40]. Fibromyalgia patients have reduced capillary or nutritive flow, increased lactate in various tissues, and additional signs of poor oxygenation of muscle tissue [41-48].

Other than CRPS and fibromyalgia, there is considerable evidence for a role of microvascular dysfunction in syndromes such as angina, frostbite, peripheral vascular, and sickle cell disease [49,50]. A dysfunction of microvascular flow has also been demonstrated in the endoneurial tissue of patients with painful diabetic neuropathy and experimental animals with neuropathic pain [51-53]. Patients with migraine have also been observed to have microvascular dysfunction in various sites, such as the cerebral cortex and dura matter, as well as in the retina and coronary tissue [54-57].

It is hoped that clinicians and researchers will begin to appreciate the critical importance of microvascular dysfunction to local pathology in various chronic pain syndromes and to further develop treatments aimed at alleviating reduced capillary flow and tissue oxygenation, the major pathologic consequences of microvascular dysfunction.

T.J.C. has received grant support from CIHR, NSERC, FRQSQPRN, and the Louise and Alan Edwards Foundation.

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