Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0423716 (Neuropathic pain)
 1,417 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Despite abundant evidence implicating the importance of N-methyl-D-aspartate (NMDA) receptors in the spinal cord for pain transmission, the signal transduction coupled to NMDA receptor activation is largely unknown for the neuropathic pain state that lasts over periods of weeks. To address this, we prepared mice with neuropathic pain by transection of spinal nerve L5. Wild-type, NR2A-deficient, and NR2D-deficient mice developed neuropathic pain; in addition, phosphorylation of NR2B subunits of NMDA receptors at Tyr1472 was observed in the superficial dorsal horn of the spinal cord 1 week after nerve injury. Neuropathic pain and NR2B phosphorylation at Tyr1472 were attenuated by the NR2B-selective antagonist CP-101,606 and disappeared in mice lacking Fyn kinase, a Src-family tyrosine kinase. Concomitant with the NR2B phosphorylation, an increase in neuronal nitric oxide synthase activity was visualized in the superficial dorsal horn of neuropathic pain mice by NADPH diaphorase histochemistry. Electron microscopy showed that the phosphorylated NR2B was localized at the postsynaptic density in the spinal cord of mice with neuropathic pain. Indomethacin, an inhibitor of prostaglandin (PG) synthesis, and PGE receptor subtype EP1-selective antagonist reduced the NR2B phosphorylation in these mice. Conversely, EP1-selective agonist stimulated Fyn kinase-dependent nitric oxide formation in the spinal cord. The present study demonstrates that Tyr1472 phosphorylation of NR2B subunits by Fyn kinase may have dual roles in the retention of NMDA receptors in the postsynaptic density and in activation of nitric oxide synthase, and suggests that PGE2 is involved in the maintenance of neuropathic pain via the EP1 subtype.
Eur J Neurosci 2005 Sep
PMID:Fyn kinase-mediated phosphorylation of NMDA receptor NR2B subunit at Tyr1472 is essential for maintenance of neuropathic pain. 1619 Aug 98

Neuropathic pain may be primarily driven by immune responses in peripheral nerves. Peripherally released catecholamines may exacerbate neuropathic pain and also modulate immune responses in a complex and sometimes opposing manner by actions on multiple adrenoceptor subtypes. We showed previously that injection of the alpha2-adrenoceptor agonist clonidine at the site of peripheral nerve injury reduces pain behavior and local tissue pro-inflammatory cytokine content in rats. The current study used a model of acute inflammatory neuritis to test the efficacy and mechanisms of action of alpha2-adrenoceptor stimulation to reduce pain. Zymosan, injected on the sciatic nerve, caused hypersensitivity to mechanical stimuli ipsilateral to injection and contralaterally, so-called mirror image pain. Ipsilateral hypersensitivity was inhibited dose-dependently by perineural injection of clonidine. Zymosan increased leukocyte number at the site of injection 3 d later as well as their content of interleukin 1alpha (IL-1alpha), IL-1beta, and IL-6. Perineural clonidine prevented both the increase in leukocyte number and cytokine expression induced by zymosan. Additionally, clonidine reduced the capacity of leukocytes to express pro-inflammatory cytokines as assessed by treatment of cells ex vivo with lipopolysaccharide, whereas no repression of IL-10 production occurred. Clonidine reduced the number of macrophages and lymphocytes as well as their expression of tumor necrosis factor alpha. All of the effects of clonidine were prevented by coadministration of an alpha2A-adrenoceptor-preferring antagonist. These results suggest that alpha2-adrenoceptor stimulation transforms cytokine gene expression, especially in macrophages and lymphocytes from a pro- to an anti-inflammatory profile in the setting of neuritis, likely relieving neuritis-induced pain by this mechanism.
J Neurosci 2005 Sep 28
PMID:Alpha2-adrenoceptor stimulation transforms immune responses in neuritis and blocks neuritis-induced pain. 1619 89

Pain may be the most common reason patients seek treatment from physicians. When persistent and unrelieved, pain can frustrate both the person suffering with this condition and the physician trying to alleviate it. Relief from chronic pain may be particularly difficult to achieve and fraught with misconceptions. Treatment usually requires trials of physical, pharmacologic, and surgical interventions to achieve resolution. In cases that remain insoluble, patients must accept partial relief and seek adaptive strategies. The source of persistent pain may be nociceptive or neuropathic. Both utilize the same nervous system pathways for transmission, but significant physiologic differences exist in the mechanism through which the body processes and resolves these painful stimuli. Nociceptive pain that results from a known or obvious source (eg, trauma, cancer metastasis, ischemia, arthritis) is often easy to identify. Neuropathic pain, however, may occur in the absence of an identifiable precipitating cause. Physicians must remain alert to differences in presentation and course of neuropathic pain syndromes, some of which may be subtle or unusual.
J Am Osteopath Assoc 2005 Sep
PMID:Management of neuropathic pain. 1627 20

Neuropathic pain is caused by functional abnormalities of structural lesions in the peripheral or central nervous system, and occurs without peripheral nociceptor stimulation. Many common diseases, such as postherpetic neuralgia, trigeminal neuralgia, diabetic neuropathy, spinal cord injury, cancer, stroke, and degenerative neurological diseases may produce neuropathic pain. Recently, theories have been proposed that state there are specific cellular and molecular changes that affect membrane excitability and induce new gene expression after nerve injury, thereby allowing for enhanced responses to future stimulation. In addition, the ectopic impulses of neuroma, changes of sodium and calcium channels in injured nerves, sympathetic activation, and deficient central inhibitory pathway contribute to the mechanisms of neuropathic pain. Currently, treatment of neuropathic pain is still a challenge. Pharmacotherapies (antidepressants, antiepileptics) remain the basis of Dr. Long-Sun Ro neuropathic pain management. However, patient satisfaction in the results of the treatment of neuropathic pain is still disappointing. Since it has been established that intense noxious stimulation produces a sensitization of central nervous neurons, it may be possible to direct treatments not only at the site of peripheral nerve injury, but also at the target of central changes. In order to provide better pain control, the mechanism-based approach in treating neuropathic pain should be familiar to physicians. In the future, it is hoped that a combination of new pharmacotherapeutic developments, careful clinical trials, and an increased understanding of the contribution and mechanisms of neuroplasticity will lead to an improvement in the results of clinical treatments and prevention of neuropathic pain.
Chang Gung Med J 2005 Sep
PMID:Neuropathic pain: mechanisms and treatments. 1632 50

Neuropathic pain that occurs after peripheral nerve injury is poorly controlled by current therapies. Increasing evidence shows that mitogen-activated protein kinase (MAPK) play an important role in the induction and maintenance of neuropathic pain. Here we show that activation of extracellular signal-regulated protein kinases 5 (ERK5), also known as big MAPK1, participates in pain hypersensitivity caused by nerve injury. Nerve injury increased ERK5 phosphorylation in spinal microglia and in both damaged and undamaged dorsal root ganglion (DRG) neurons. Antisense knockdown of ERK5 suppressed nerve injury-induced neuropathic pain and decreased microglial activation. Furthermore, inhibition of ERK5 blocked the induction of transient receptor potential channels and brain-derived neurotrophic factor expression in DRG neurons. Our results show that ERK5 activated in spinal microglia and DRG neurons contributes to the development of neuropathic pain. Thus, blocking ERK5 signaling in the spinal cord and primary afferents has potential for preventing pain after nerve damage.
J Neurochem 2007 Sep
PMID:Roles of extracellular signal-regulated protein kinases 5 in spinal microglia and primary sensory neurons for neuropathic pain. 1750 87

Neuropathic pain after periphery nerve injury is frequently accompanied by the regeneration of the injured nerve fibers. We tested in this study whether local administration of Nogo-66, a well-studied axon growth inhibiting peptide in the central nerve system, could reduce the pain related behavior after sciatic nerve transection in rat. Nogo-66 peptide was purified as a GST fusion protein. Its inhibitory function was testified by neurite outgrowth assay of primary cultured neurons, and then it was given directly at the lesion site by a minipump for 2 weeks. Mechanical nociceptive withdrawal responses and heat hyperalgesia responses were assessed during a 4-week period, and autotomy was evaluated during a 6-week period. The results showed that the mechanical allodynia and heat hyperalgesia scores of the rats treated with GST-Nogo-66 were significantly higher than the controls between 7 and 14 days after sciatic nerve transection. The autotomy scores in the GST-Nogo-66 group were significantly lower than the controls from 28 days after surgery. Taken together, the results of our present study suggest that Nogo-66 may be utilized to decrease the neuropathic pain after periphery nerve injury.
Neurosci Lett 2007 Sep 13
PMID:Local Nogo-66 administration reduces neuropathic pain after sciatic nerve transection in rat. 1772 Mar 11

Neuropathic pain resulting from nerve injury or from diseases such as diabetes, HIV AIDS or cancer, that damage the peripheral nerves, can be agonizing, persistent over long periods, and, unfortunately, is often resistant to known pain-killers. The P2X receptors, of which seven subtypes (P2X1-P2X7) have been cloned, are a family of ligand-gated cation channels activated by extracellular ATP and have important roles in regulating neuronal and glial functions in the nervous system. Recent advances in our understanding of the mechanisms underlying neuropathic pain have been made by defining important roles of P2X4 receptors and spinal microglia in the pathogenesis of neuropathic pain. Within the spinal dorsal horn, peripheral nerve injury leads to a progressive series of changes in microglia including morphological hypertrophy of the cell body and proliferation that are considered indicative of activation. Furthermore, P2X4 receptors that which are upregulated in activated microglia, have been found to be essential molecular mediators. The activation of P2X4 receptors releases brain-derived neurotrophic factor from microglia; this mediates the signaling from microglia to neurons, which in turn leads to pain hypersensitivity. We expect that understanding the key roles of these molecules in spinal microglia may lead to new strategies for the management of neuropathic pain.
Brain Nerve 2007 Sep
PMID:[Neuropathic pain and ATP receptors in spinal microglia]. 1788 77

Neuropathic pain that typically develops when peripheral nerves are damaged through surgery, bone compression in cancer, diabetes, or infection is a major factor causing impaired quality of life in millions of people worldwide. Recently, there has been a rapidly growing body of evidence indicating that spinal glia play a critical role in the pathogenesis of neuropathic pain. Accumulating findings also indicate that nucleotides play an important role in neuron-glia communication through P2 purinoceptors. Damaged neurons release or leak nucleotides including ATP and UTP to stimulate microglia through P2 purinoceptors expressing on microglia. It was shown in an animal model of neuropathic pain that microglial P2X(4) and P2X(7) receptors are crucial in pain signaling after peripheral nerve lesion. In this review, we describe the modification of neuropathic pain sensation through microglial P2X(4) and P2X(7), with the possibility of P2Y(6) and P2Y(12) involvement.
Purinergic Signal 2007 Sep
PMID:Modification of neuropathic pain sensation through microglial ATP receptors. 1840 44

Chronic ischemic pain is a leading cause of pain in the lower extremities. A neuropathic component in ischemic pain has been shown. Neuropathic pain questionnaires are established as a common tool in pain research. The aim of this study was to analyze the clinical nature and the character of chronic ischemic pain in peripheral arterial disease (PAD). One hundred and two patients suffering from symptomatic PAD (Fontaine stages II-IV) were surveyed using validated pain questionnaires (VAS, NPSI, S-LANSS, PDI, SF-MPQ). Pain related disability was 22.7+/-1.7 (mean+/-SEM) in patients with intermittent claudication (CI) and 34.0+/-2.3 in patients with critical limb ischemia (CLI). Neuropathic pain questionnaires revealed distinctly higher scores for CLI than for CI: The S-LANSS indicated pain of predominantly neuropathic origin in patients with CLI (17.2+/-0.8) compared to CI (6.7+/-0.8; p<0.001). Global NPSI scores were 34.1+/-3.1 for CLI and 6.6+/-1.1 for CI (p<0.001). S-LANSS and NPSI correlated well (Spearman's rho=0.779; p<0.001). The SF-MPQ revealed that patients with CLI scored significantly higher for pain descriptors stabbing, hot-burning, tender and cruel-punishing compared to those with CI. The results suggest that the character of ischemic pain changes from nociceptive pain in patients with CI to predominantly neuropathic pain in patients with CLI. A neuropathic pain component seems to be a serious aspect in CLI, while it is not in CI. Questionnaires might be a helpful tool to investigate and diagnose ischemic pain.
Pain 2008 Sep 30
PMID:Characteristics of chronic ischemic pain in patients with peripheral arterial disease. 1847 16

Neuropathic pain remains a prevalent clinical problem because it is often poorly responsive to the currently used analgesics, thus it is crucial the identification of new potential targets and drugs. Recent evidence indicated that microglial cells in the spinal cord are critically involved in the development and maintenance of neuropathic pain, with a pivotal role of toll-like receptor 4 (TLR4). Binding of an endogenous ligand to TLR4 might be considered an important step in the regulation of microglia activity in pain facilitation, suggesting that a mechanism aimed to inhibit such a binding could be effective against neuropathic pain. We have synthesized new ligands to TLR4 with antagonistic activity. In the present work we evaluated the efficacy of the most potent TLR4 antagonist synthesized by us (FP-1), administered in mice with painful neuropathy. The repeated treatment of neuropathic mice with FP-1 (5-10 mg/kg, i.p.) evoked a relief of both thermal hyperalgesia and mechanical allodynia, whereas the administration of the highest dose to TLR4 knockout neuropathic mice revealed that in the absence of TLR4 receptor, the compound lost its efficacy. As consequence of TLR4 binding, the repeated treatment with FP-1 prevented the activation of the transcription factor NF-kB and the TNFalpha overproduction in the spinal cord. Together, our findings support the previous evidence indicative for a contribution of glial TLR4 to the initiation of neuropathic pain, suggest it as potential innovative target to treat this debilitating disease, and propose FP-1 as lead compound for the development of new effective drugs.
Glia 2008 Sep
PMID:Glial TLR4 receptor as new target to treat neuropathic pain: efficacy of a new receptor antagonist in a model of peripheral nerve injury in mice. 1861 68


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