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

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

Neuronal Plasticity Associated with Burn Injury and Its Relevance for Perception and Management of Pain in Burn Patients

Through the introduction of the gate control theory and various subsequent works, Ronald Melzack has inspired many investigators worldwide to realize two important facts about pain. First, incoming pain messages are subject to both negative and positive modulation, which significantly affect its perception. Second, the progression of knowledge about the basic mechanisms underlying persistent and chronic pain is critically dependent on the increased understanding of the complexity of the symptoms experienced by pain patients. The present paper examines these two very important issues in an effort to understand better the mechanisms that underlie the pain suffered by burn patients. The physiological responses to burn injury involve many different mediators and mechanisms, all of which contribute to pain perception and development of neuronal plasticity underlying short and long term changes in pain sensitivity. While experimental burn injuries in humans and animals are typically well controlled and mild, in burn victims, the severity is much more variable, and clinical care involves repeated traumas and manipulations of the injured sites. Recurrent inputs from damaged and redamaged tissue impinge on a nervous system that becomes an active participant in the initiation of changes in sensory perception and maintenance of long term sensory disturbances. Recently acquired experimental evidence on postburn hyperalgesia, central hyperexcitability and changes in opioid sensitivity provides strong support that burn patients need an analgesic approach aimed at preventing or reducing the 'neural' memory of pain, including the use of more than one treatment modality. Burn injuries offer a unique opportunity to combine experimental and clinical research to understand pain mechanisms better. Over the years, Ronald Melzack has insisted that one of the most laudable enterprises in research is to span the gap between these two often separate worlds

Spinal NGF Restores Opioid Sensitivity in Neuropathic Rats: Possible Role of NGF as a Regulator of CCK-Induced Anti-Opioid Effects

The breadth of peripheral effects produced by nerve growth factor (NGF) in nociceptive processing has been well documented. However, less is known about the functional significance of central NGF in nociceptive transmission. The effect of NGF on the nervous system is dependent on the developmental stage. During the prenatal developmental period, NGF is critical for survival of nociceptors; in the postnatal period it regulates the expression of nociceptor phenotype, and in the adult it contributes to pain following an inflammatory insult. The implications for central NGF in the expression and regulation of spinal neuropeptides that are involved in pain mechanisms are reviewed. Knowledge has been gained by studies using peripheral nerve injury models that cause a deprivation of central NGF. These models also give rise to the development of pain syndromes, which encompass spontaneous pain, hyperalgesia and allodynia, routinely referred to as neuropathic pain. These models provide an approach for examining the contribution of central NGF to nociceptive transmission. Chronic pain emanating from a nerve injury is typically refractory to traditional analgesics such as opioids. Recent evidence suggests that supplementation of spinal NGF restores morphine-induced antinociception in an animal model of neuropathic pain. This effect appears to be mediated by alterations in spinal levels of cholecystokinin. The authors hypothesize that NGF is critical in maintaining neurochemical homeostasis in the spinal cord of nociceptive neurons, and that supplementation may be beneficial in restoring and/or maintaining opioid analgesia in chronic pain conditions resulting from traumatic nerve injury

Attenuation of hyperalgesia in a rat model of neuropathic pain after intrathecal pre- or post-treatment with a neurokinin-1 antagonist.

Although many studies have demonstrated a role for substance P in pain, there have been conflicting reports implicating the involvement of substance P in neuropathic pain models. In this study, the non-peptide neurokinin-1 (NK-1) receptor antagonist, L-732,138 was chronically administered by intrathecal (i.t.) injection to rats with mono-neuropathy produced by sciatic nerve constriction. Rats exhibited tactile allodynia and cold hyperalgesia over a 16-day testing period. L-732,138 (5-200 nmol) administered i.t. prior to and for 3 consecutive days post-surgery attenuated the mechanical allodynia and cold hyperalgesia on days 4 and 8 post-surgery. The effects of i.t. L-732,138 were also determined in rats with established nerve injury-induced neuropathy. The NK-1 receptor antagonist was injected for 4 consecutive days starting on day 8 post-sciatic nerve injury. Administration of L-732,138 (5-200 nmol) i.t. produced both anti-allodynic and anti-hyperalgesic effects on day 12, but the effect was not permanent, as nociceptive thresholds were similar to controls by day 16. These results demonstrate that substance P is involved both in the induction and the maintenance of neuropathic pain and provides justification for the development and administration of substance P antagonists for the management of clinical neuropathic pain