Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
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.
 ...
PMID:Fyn kinase-mediated phosphorylation of NMDA receptor NR2B subunit at Tyr1472 is essential for maintenance of neuropathic pain. 1619 Aug 98

Neuropathic pain, a chronic pain due to neuronal lesion, remains unaltered even after the injury-induced spinal afferent discharges have declined, suggesting an involvement of supraspinal dysfunction. The midbrain ventrolateral periaqueductal gray (vlPAG) is known to be a crucial supraspinal region for initiating descending pain inhibition, but its role in neuropathic pain remains unclear. Therefore, here we examined neuroplastic changes in the vlPAG of midbrain slices isolated from neuropathic rats induced by L5/L6 spinal nerve ligation (SNL) via electrophysiological and neurochemical approaches. Significant mechanical hypersensitivity was induced in rats 2 d after SNL and lasted for >14 d. Compared with the sham-operated group, vlPAG slices from neuropathic rats 3 and 10 days after SNL displayed smaller EPSCs with prolonged latency, less frequent and smaller miniature EPSCs, higher paired-pulse ratio of EPSCs, smaller AMPAR-mediated EPSCs, smaller AMPA currents, greater NMDAR-mediated EPSCs, greater NMDA currents, lower AMPAR-mediated/NMDAR-mediated ratios, and upregulation of the NR1 and NR2B subunits, but not the NR2A, GluR1, or GluR2 subunits, of glutamate receptors. There were no significant differences between day 3 and day 10 neuropathic groups. These results suggest that SNL leads to hypoglutamatergic neurotransmission in the vlPAG resulting from both presynaptic and postsynaptic mechanisms. Upregulation of NMDARs might contribute to hypofunction of AMPARs via subcellular redistribution. Long-term hypoglutamatergic function in the vlPAG may lead to persistent reduction of descending pain inhibition, resulting in chronic neuropathic pain.
 ...
PMID:Hypofunction of glutamatergic neurotransmission in the periaqueductal gray contributes to nerve-injury-induced neuropathic pain. 2363 74

Neuropathic pain (NP) is an intractable disease accompanying with allodynia, hyperalgesia and spontaneous pain. Accumulating evidence suggested that large volume of neurotransmitters, genes, and signaling pathways were implicated with the initiation and development of NP, while the underlying mechanism still remained poorly understood. Therefore, it was extremely important to further elucidate the potential regulatory networks for developing appropriate treatment options. Here, the RNA-Seq high-throughput sequencing was employed to determine the genes expression change in mice undergoing spinal nerve ligation (SNL). Meanwhile, the differentially expressed genes (DEGs) were analyzed by using integrated Differential Expression and Pathway analysis (iDEP) tools and String database. Then, quantitative real-time PCR (qRT-PCR) was employed to detect the expression of hub gens. The results showed that the DEGs mainly comprised 1712 upregulated and 1515 downregulated genes at 7 days, and consisted of 243 upregulated and 357 downregulated genes at 28 days after surgery, respectively. Additionally, 133 genes and two pathways including retrograde endocannabinoid signaling and cardiac muscle contraction collectively participated in biological reactions of 7th and 28th day after operation. Moreover, the results showed that the mRNA and protein expression of Ccl5, Cacna2d1, Cacna2d2, Cacnb2, Gabrb3, GluA1, and GluA2 were significantly upregulated in SNL-7/28d group than that of in Sham-7/28d group (SNL-7d vs. Sham-7d; SNL-28d vs. Sham-28d; P < 0.05). And the level of Glra2, Glra4, Glra3, Grik1, Grik2, NR1, NR2A, and NR2B was obviously increased in SNL-7d group compared to Sham-7d group (P < 0.05), but which was no statistical difference between SNL-28d group and Sham-28d group. Therefore, these results provided new perspectives and strategies for deeply illuminating the underlying mechanism, and identifying the key elements for treating NP.
 ...
PMID:Temporal Changes of Spinal Transcriptomic Profiles in Mice With Spinal Nerve Ligation. 3192 May 16