Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030193 (pain)
 261,466 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Neuropeptides are the largest class of intercellular signaling molecules, contributing to a wide variety of physiological processes. Neuropeptide receptors are therapeutic targets for a broad range of drugs, including medications to treat pain, addiction, sleep disorders, and nausea. In addition to >100 peptides with known functions, many peptides have been identified in mammalian brain for which the cognate receptors have not been identified. Similarly, dozens of "orphan" G protein-coupled receptors have been identified in the mammalian genome. While it would seem straightforward to match the orphan peptides and receptors, this is not always easily accomplished. In this review we focus on peptides named PEN and big LEN, which are among the most abundant neuropeptides in mouse brain, and their recently identified receptors: GPR83 and GPR171. These receptors are co-expressed in some brain regions and are able to interact. Because PEN and big LEN are produced from the same precursor protein and co-secreted, the interaction of GPR83 and GPR171 is physiologically relevant. In addition to interactions of these two peptides/receptors, PEN and LEN are co-localized with neuropeptide Y and Agouti-related peptide in neurons that regulate feeding. In this review, using these peptide receptors as an example, we highlight the multiple modes of regulation of receptors and present the emerging view that neuropeptides function combinatorially to generate a network of signaling messages. The complexity of neuropeptides, receptors, and their signaling pathways is important to consider both in the initial deorphanization of peptides and receptors, and in the subsequent development of therapeutic applications.
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PMID:Orphan neuropeptides and receptors: Novel therapeutic targets. 2917 50

ProSAAS is one of the most widely expressed proteins throughout the brain and was recently found to be upregulated in chronic fibromyalgia patients. BigLEN is a neuropeptide that is derived from ProSAAS and was recently discovered to be the endogenous ligand for the orphan G protein-coupled receptor GPR171. Although BigLEN-GPR171 has been found to play a role in feeding and anxiety behaviors, it has not yet been explored in pain and opioid modulation. The purpose of this study was to evaluate this novel neuropeptide-receptor system in opioid-induced antinociception. We found that GPR171 is expressed in GABAergic neurons within the periaqueductal gray, which is a key brain area involved in pain modulation and opioid functions. We also found that, although the GPR171 agonist and antagonist do not have nociceptive effects on their own, they oppositely regulate morphine-induced antinociception with the agonist enhancing and antagonist reducing antinociception. Lastly, we showed that the GPR171 antagonist or receptor knockdown decreases signaling by the mu-opioid receptor, but not the delta-opioid receptor. Taken together, these results suggest that antagonism of the GPR171 receptor reduces mu opioid receptor signaling and morphine-induced antinociception, whereas the GPR171 agonist enhances morphine antinociception, suggesting that GPR171 may be a novel target toward the development of pain therapeutics. SIGNIFICANCE STATEMENT: GPR171 is a recently deorphanized receptor that is expressed within the periaqueductal gray and can regulate mu opioid receptor signaling and antinociception. This research may contribute to the development of new therapeutics to treat pain.
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PMID:Opioid-Induced Signaling and Antinociception Are Modulated by the Recently Deorphanized Receptor, GPR171. 3130 96