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)

Neuropathic pain associated with abnormal tactile and thermal responses that are extraterritorial to the injured nerve is known to be difficult to diagnose and treat because of clinical observation of limited responsiveness to opioids and non-steroidal anti-inflammatory drugs. To reproduce the different pathological changes observed in neuropathic pain patients, several laboratory animal models have been proposed. Recent studies using such models suggest the involvement of neuronal plasticity in pain pathways through nociceptive neurons. Our new experimental model using specific pain-producing molecules that clearly distinguish three different nociceptive fibers from each other reproduces neuropathic pain-like hyperalgesia and less sensitivity to morphine. After nerve injury, the nociceptive responses through type I neurons, which are polymodal C-fibers and drive NK1-receptor mechanisms in spinal pain transmission, were completely lost, but without changes in type II ones, which are polymodal C-fibers and drive NMDA receptor-mechanisms, while type III ones, which are capsaicin-insensitive (possibly A-fibers) and drive NMDA-receptor mechanisms, were markedly enhanced. Such pain transmission switch mechanisms are clearly consistent with clinical effectiveness including less sensitivity to morphine and more sensitivity to NMDA-antagonists. This article also presents currently used methods for experimental neuropathic pain models.
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PMID:[Animal models and peripheral nociception tests for the study of neuropathic pain]. 1153 Jun 84

Neuropathic pain states and tolerance to opioids can result from system changes in the CNS, such as up-regulation of the NK1 receptor and substance P, lead to antiopioid effects in ascending or descending pain-signaling pathways. Bifunctional compounds, possessing both the NK1 antagonist pharmacophore and the opioid agonist pharmacophore with delta-selectivity, could counteract these system changes to have significant analgesic efficacy without undesirable side effects. As a result of the introduction of cyclic and topological constraints with penicillamines, 2 (Tyr-cyclo[d-Pen-Gly-Phe-Pen]-Pro-Leu-Trp-NH-[3',5'-(CF(3))(2)-Bzl]) was found as the best bifunctional compound with effective NK1 antagonist and potent opioid agonist activities, and 1400-fold delta-selectivity over the mu-receptor. The NMR structural analysis of 2 revealed that the relative positioning of the two connected pharmacophores as well as its cyclic and topological constraints might be responsible for its excellent bifunctional activities as well as its significant delta-opioid selectivity. Together with the observed high metabolic stability, 2 could be considered as a valuable research tool and possibly a promising candidate for a novel analgesic drug.
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PMID:Biological and conformational evaluation of bifunctional compounds for opioid receptor agonists and neurokinin 1 receptor antagonists possessing two penicillamines. 2061 91

Neuropathic pain is a debilitating condition resulting from damage to sensory transmission pathways in the peripheral and central nervous system. A potential new way of treating chronic neuropathic pain is to target specific pain-processing neurons based on their expression of particular receptor molecules. We hypothesized that a toxin-neuropeptide conjugate would alter pain by first being taken up by specific receptors for the neuropeptide expressed on the neuronal cells. Then, once inside the cell the toxin would inhibit the neurons' activity without killing the neurons, thereby providing pain relief without lesioning the nervous system. In an effort to inactivate the nociceptive neurons in the trigeminal nucleus caudalis in mice, we targeted the NK1 receptor (NK1R) using substance P (SP). The catalytically active light chain of botulinum neurotoxin type A (LC/A) was conjugated with SP. Our results indicate that the conjugate BoNT/A-LC:SP is internalized in cultured NK1R-expressing neurons and also cleaves the target of botulinum toxin, a component-docking motif necessary for release of neurotransmitters called SNAP-25. The conjugate was next tested in a murine model of Taxol-induced neuropathic pain. An intracisternal injection of BoNT/A-LC:SP decreased thermal hyperalgesia as measured by the operant orofacial nociception assay. These findings indicate that conjugates of the light chain of botulinum toxin are extremely promising agents for use in suppressing neuronal activity for extended time periods, and that BoNT/A-LC:SP may be a useful agent for treating chronic pain.
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PMID:Anti-nociceptive effect of a conjugate of substance P and light chain of botulinum neurotoxin type A. 2393 81