Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0344307 (analgesia)
 28,200 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The nervous system represents a key area for development of novel therapeutic agents for the treatment of neurological and neurodegenerative diseases. Recent research has demonstrated the critical importance of neuroproteases for the production of specific peptide neurotransmitters and for the production of toxic peptides in major neurodegenerative diseases that include Alzheimer, Huntington, and Parkinson diseases. This review illustrates the successful criteria that have allowed identification of proteases responsible for converting protein precursors into active peptide neurotransmitters, consisting of dual cysteine protease and subtilisin-like protease pathways in neuroendocrine cells. These peptide neurotransmitters are critical regulators of neurologic conditions, including analgesia and cognition, and numerous behaviors. Importantly, protease pathways also represent prominent mechanisms in neurodegenerative diseases, especially Alzheimer, Huntington, and Parkinson diseases. Recent studies have identified secretory vesicle cathepsin B as a novel beta-secretase for production of the neurotoxic beta-amyloid (Abeta) peptide of Alzheimer disease. Moreover, inhibition of cathepsin B reduces Abeta peptide levels in brain. These neuroproteases potentially represent new drug targets that should be explored in future pharmaceutical research endeavors for drug discovery.
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PMID:Neuroproteases in peptide neurotransmission and neurodegenerative diseases: applications to drug discovery research. 1662 68

Dynorphin opioid neuropeptides mediate neurotransmission for analgesia and behavioral functions. Dynorphin A, dynorphin B, and alpha-neoendorphin are generated from prodynorphin by proteolytic processing. This study demonstrates the significant role of the cysteine protease cathepsin L for producing dynorphins. Cathepsin L knockout mouse brains showed extensive decreases in dynorphin A, dynorphin B, and alpha-neoendorphin that were reduced by 75%, 83%, and 90%, respectively, compared to controls. Moreover, cathepsin L in brain cortical neurons was colocalized with dynorphins in secretory vesicles, the primary site of neuropeptide production. Cellular coexpression of cathepsin L with prodynorphin in PC12 cells resulted in increased production of dynorphins A and B. Comparative studies of PC1/3 and PC2 convertases showed that PC1/3 knockout mouse brains had a modest decrease in dynorphin A, and PC2 knockout mice showed a minor decrease in alpha-neoendorphin. Overall, these results demonstrate a prominent role for cathepsin L, jointly with PC1/3 and PC2, for production of dynorphins in brain.
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PMID:Cathepsin L participates in dynorphin production in brain cortex, illustrated by protease gene knockout and expression. 1983 64

Microglia-derived lysosomal cysteine protease cathepsin S (CatS) is increasingly recognized as important mediators to exaggerate nociceptive signaling. However, the patterns and functional roles of CatS in morphine tolerance have never been investigated. Here, we showed that mature form of CatS was exclusively upregulated in the spinal microglia following chronic morphine treatment. Pharmacological blockade of CatS before each morphine treatment prolonged the efficacy of morphine analgesia. Correspondingly, inhibition of CatS suppressed activation of spinal microglia and phosphorylated p38 MAPK. Finally, intrathecal injection of selective microglia inhibitor minocycline reduced upregulation of mature CatS induced by chronic morphine treatment. Our data provide novel insight into the cellular mechanisms underlying morphine antinociceptive tolerance and highlight CatS as a therapeutic target for preventing morphine tolerance.
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PMID:Cathepsin S in the spinal microglia facilitates morphine-induced antinociceptive tolerance in rats. 3036 14