Cutaneous tactile allodynia associated with microvascular dysfunction in muscle

<p>Abstract</p> <p>Background</p> <p>Cutaneous tactile allodynia, or painful hypersensitivity to mechanical stimulation of the skin, is typically associated with neuropathic pain, although also present in chronic pain patients who do not have evidence of nerve injury. We examine whether deep tissue microvascular dysfunction, a feature common in chronic non-neuropathic pain, contributes to allodynia.</p> <p>Results</p> <p>Persistent cutaneous allodynia is produced in rats following a hind paw ischemia-reperfusion injury that induces microvascular dysfunction, including arterial vasospasms and capillary slow flow/no-reflow, in muscle. Microvascular dysfunction leads to persistent muscle ischemia, a reduction of intraepidermal nerve fibers, and allodynia correlated with muscle ischemia, but not with skin nerve loss. The affected hind paw muscle shows lipid peroxidation, an upregulation of nuclear factor kappa B, and enhanced pro-inflammatory cytokines, while allodynia is relieved by agents that inhibit these alterations. Allodynia is increased, along with hind paw muscle lactate, when these rats exercise, and is reduced by an acid sensing ion channel antagonist.</p> <p>Conclusion</p> <p>Our results demonstrate how microvascular dysfunction and ischemia in muscle can play a critical role in the development of cutaneous allodynia, and encourage the study of how these mechanisms contribute to chronic pain. We anticipate that focus on the pain mechanisms associated with microvascular dysfunction in muscle will provide new effective treatments for chronic pain patients with cutaneous tactile allodynia.</p

PKMζ is essential for spinal plasticity underlying the maintenance of persistent pain

<p>Abstract</p> <p>Background</p> <p>Chronic pain occurs when normally protective acute pain becomes pathologically persistent. We examined here whether an isoform of protein kinase C (PKC), PKMζ, that underlies long-term memory storage in various brain regions, also sustains nociceptive plasticity in spinal cord dorsal horn (SCDH) mediating persistent pain.</p> <p>Results</p> <p>Cutaneous injury or spinal stimulation produced persistent increases of PKMζ, but not other atypical PKCs in SCDH. Inhibiting spinal PKMζ, but not full-length PKCs, reversed plasticity-dependent persistent painful responses to hind paw formalin and secondary mechanical hypersensitivity and SCDH neuron sensitization after hind paw capsaicin, without affecting peripheral sensitization-dependent primary heat hypersensitivity after hind paw capsaicin. Inhibiting spinal PKMζ, but not full-length PKCs, also reversed mechanical hypersensitivity in the rat hind paw induced by spinal stimulation with intrathecal dihydroxyphenylglycine. Spinal PKMζ inhibition also alleviated allodynia 3 weeks after ischemic injury in rats with chronic post-ischemia pain (CPIP), at a point when allodynia depends on spinal changes. In contrast, spinal PKMζ inhibition did not affect allodynia in rats with chronic contriction injury (CCI) of the sciatic nerve, or CPIP rats early after ischemic injury, when allodynia depends on ongoing peripheral inputs.</p> <p>Conclusions</p> <p>These results suggest spinal PKMζ is essential for the maintenance of persistent pain by sustaining spinal nociceptive plasticity.</p

Regulation of peripheral blood flow in Complex Regional Pain Syndrome: clinical implication for symptomatic relief and pain management

Background. During the chronic stage of Complex Regional Pain Syndrome (CRPS), impaired microcirculation is related to increased vasoconstriction, tissue hypoxia, and metabolic tissue acidosis in the affected limb. Several mechanisms may be responsible for the ischemia and pain in chronic cold CPRS. Discussion. The diminished blood flow may be caused by either sympathetic dysfunction, hypersensitivity to circulating catecholamines, or endothelial dysfunction. The pain may be of neuropathic, inflammatory, nociceptive, or functional nature, or of mixed origin. Summary. The origin of the pain should be the basis of the symptomatic therapy. Since the difference in temperature between both hands fluctuates over time in cold CRPS, when in doubt, the clinician should prioritize the patient's report of a persistent cold extremity over clinical tests that show no difference. Future research should focus on developing easily applied methods for clinical use to differentiate between central and peripheral blood flow regulation disorders in individual patients

Contribution of microvascular dysfunction to chronic pain

There is growing evidence that microvascular dysfunction is a pathology accompanying various injuries and conditions that produce chronic pain and may represent a significant contributing factor. Dysfunction that occurs within each component of the microvasculature, including arterioles, capillaries and venules impacts the health of surrounding tissue and produces pathology that can both initiate pain and influence pain sensitivity. This mini review will discuss evidence for a critical role of microvascular dysfunction or injury in pathologies that contribute to chronic pain conditions such as complex regional pain syndrome (CRPS) and fibromyalgia.</jats:p

Peripheral and central mechanisms of pain and hyperalgesia : effects of adrenergic and sensory neuron blockade on autotomy and pain sensitivity following injury

The mechanisms of pain and hyperalgesia were examined in rats following cutaneous-heat and peripheral-nerve injury. Central mechanisms of hyperalgesia were indicated since a heat injury produced a decrease in foot-withdrawal latencies in the paw contralateral to the injury and an increase in autotomy of the injured paw following section of the sciatic and saphenous nerves. The reduced contralateral foot-withdrawal latencies were reversed by spinal anesthesia and subcutaneous guanethidine, but were unaffected by local anesthetics and capsaicin at the site of injury. The enhancement of autotomy produced by an injury was reduced by spinal anesthesia and a combination of intrathecal capsaicin and subcutaneous guanethidine. Both intrathecal substance P and systemic noradrenaline produced an increase in autotomy following nerve lesions; guanethidine, but neither capsaicin nor procaine, produced a decrease in autotomy. A reduction in inflammation and hyperalgesia within an injured paw was produced by local capsaicin, but not by guanethidine. The results suggest that central mechanisms, such as spinal hyperactivity, combined with peripheral neurogenic mechanisms are involved in the production of hyperalgesia following heat injury. Pain and hyperalgesia following nerve injury are proposed to be due to spinal cord plasticity resulting from deafferentation and abnormal sympathetic activity