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)

The human 7-transmembrane receptor GPR7 has sequence similarity to opioid and somatostatin receptors, and can be activated by the recently discovered neuropeptides NPB and NPW. This receptor is highly expressed in the nervous system, with suggested roles in neuroendocrine events and pain signaling. In this study, we investigated whether the GPR7 receptor is expressed in the peripheral nervous system under normal and pathological conditions. A low level of GPR7 receptor was observed in myelin-forming Schwann cells in both normal human and rat nerve, and in primary rat Schwann cell cultures. Peripheral nerve samples taken from patients exhibiting inflammatory/immune-mediated neuropathies showed a dramatic increase of GPR7 receptor expression restricted to myelin-forming Schwann cells. Complementary animal models of immune-inflammatory and ligation-induced nerve injury and neuropathic pain similarly exhibited an increased myelin-associated expression of GPR7 receptor. These results suggest a relationship between the pathogenesis of inflammatory/immune-mediated neuropathies, GPR7 receptor expression, and pain transmission.
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PMID:Schwann cell overexpression of the GPR7 receptor in inflammatory and painful neuropathies. 1560 41

Neuropeptide W-23 (NPW23) is an endogenous ligand of both GPR7 and GPR8, and neuropeptide B (NPB) is an endogenous ligand of GPR7. GPR7 mRNA has been detected in regions of the cortex, the hippocampus, the hypothalamus, and the spinal cord in the rat, but GPR8 has not been found in rodents. GPR7 and GPR8 receptors have structural features in common with both opioid and somatostatin receptors. The effects of intrathecal (i.t.) application of NPW23 and NPB were tested in two inflammatory pain models (plantar injection of formalin or carrageenan) and two thermal nociceptive tests (52.5 degrees C and 50.5 degrees C hot plates) and one mechanical nociceptive test in the rat. I.t. injection of either NPW23 or NPB decreased the number of agitation behaviors induced by paw formalin injection and attenuated the level of mechanical allodynia, but not the level of thermal hyperalgesia, induced by paw carrageenan injection in a dose-dependent manner at a dose between 0.1 and 10 microg, significantly. The effects of either 10 microg of NPW23 or 10 microg of NPB were not antagonized by 10 microg of naloxone. I.t. injection of either NPW23 or NPB had no effect in both the 52.5 degrees C hot plate test or in the 50.5 degrees C hot plate tests at a dose between 1 and 100 microg. I.t. injection of either 10 microg of NPW23 or 10 microg of NPB had no effect in the mechanical nociceptive test. I.t. injection of either 10 microg of NPW23 or 10 microg of NPB significantly suppressed the expression of Fos-like immunoreactivity of the L4-5 spinal dorsal horn induced by paw formalin injection. These data suggest that both spinally-applied NPW23 and NPB suppressed the input of nociceptive information to the spinal dorsal horn, produced an analgesic effect in the formalin test, and attenuated the level of mechanical allodynia in the carrageenan test, and that either spinally applied NPW23 or spinally applied NPB had no effect in the physiological condition.
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PMID:Anti-hyperalgesic effects of intrathecally administered neuropeptide W-23, and neuropeptide B, in tests of inflammatory pain in rats. 1591 Jul 67

Neuropeptide B (NPB) and neuropeptide W (NPW) have been recently identified as ligands for the G protein-coupled receptor (GPR) 7 and GPR8. The precise in vivo role of this neuropeptide-receptor pathway has not been fully demonstrated. In this paper, we report that NPB-deficient mice manifest a mild adult-onset obesity, similar to that reported in GPR7-null mice. NPB-deficient mice also exhibit hyperalgesia in response to inflammatory pain. Hyperalgesia was not observed in response to chemical pain, thermal pain, or electrical stimulation. NPB-deficient mice demonstrated intact behavioral responses to pain, and learning from the negative reinforcement of electrical stimulation was unaltered. Baseline anxiety was also unchanged as measured in both the elevated plus maze and time spent immobile in a novel environment. These data support the idea that NPB is a factor in the modulation of responses to inflammatory pain and body weight homeostasis.
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PMID:Neuropeptide B-deficient mice demonstrate hyperalgesia in response to inflammatory pain. 1598 70

Deorphanised G-protein-coupled receptors represent new and expanding targets for drug development. Neuropeptide B (NPB) and W (NPW) have recently been identified as the cognate endogenous ligands for the orphan receptor GPR7, now designated as NPBW(1). NPB and NPW also bound to a second related orphan receptor, GPR8, now designated as NPBW(2) that is present in humans but not rats or mice. In humans, high levels of NPW mRNA have been visualised in the substantia nigra, whereas moderate expression levels have been detected in the amygdala and hippocampus. In peripheral tissues, expression of NPW mRNA has been confirmed in the progenital system, comprising the kidney, testis, uterus, ovary and placenta, and also in stomach homogenates. Immunocytochemical, molecular biological and autoradiography techniques have revealed a discrete CNS distribution for NPBW(1) in human, mouse and rat. Highest expression of NPBW(1) mRNA and protein was identified in the amygdala and hypothalamic nuclei known to regulate feeding behaviour. [(125)I]-NPW bound with a single high affinity to rat amygdala, K(D)=0.44 nM and 150 fmol mg(-1) protein. Physiological studies demonstrate that intracerebroventricular infusion of NPBW(1) ligands modulates feeding behaviour, regulates the release of corticosterone, prolactin and growth hormone while also manipulating pain pathway. Mouse knockout models of the gene encoding either NPB or NPBW(1) have a gender-specific phenotype, with moderate obesity evident in males but not females. Further investigation is required to elucidate the precise physiological role of NPB and NPW as neurotransmitters.
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PMID:Neuropeptide B and W: neurotransmitters in an emerging G-protein-coupled receptor system. 1684 39

Neuropeptide W (NPW) is an endogenous ligand for GPR7, a member of the G-protein-coupled receptor family. NPW plays an important role in the regulation of both feeding and energy metabolism, and is also implicated in modulating responses to an acute inflammatory pain through activation of the hypothalamus-pituitary-adrenal axis. GPR7 mRNA has been shown to be expressed in the hypothalamus, pituitary gland and adrenal cortex. Similarly, NPW expression has been demonstrated in the brain and pituitary gland. However, the precise distribution of NPW-producing cells in the adrenal gland remains unknown. The aim of this study was to explore the distribution and localization of NPW immunoreactivity in the rat adrenal gland. Total RNA was prepared from the hypothalamus, pituitary gland and adrenal gland. RT-PCR revealed the expression of NPW mRNA in these tissues, while in situ hybridization demonstrated the presence of NPW mRNA in the adrenal medulla. When immunohistochemistry was performed on sections of adrenal gland, NPW-like immunoreactivity (NPW-LI) was observed in the medulla but not in the cortex. Moreover, NPW-LI was found to be co-localized in cells which expressed dopamine beta hydroxylase but not phenylethanolamine-N-methyltransferase. The finding that NPW is expressed in noradrenalin-containing cells in the adrenal medulla suggests that it may play an important role in endocrine function in the adrenal gland.
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PMID:Neuropeptide W is expressed in the noradrenalin-containing cells in the rat adrenal medulla. 1787 Jan 91

Neuropeptide B (NPB) and neuropeptide W (NPW) are neuropeptides that were recently identified as endogenous ligands for the previously orphan G-protein coupled receptors, GPR7 (NPBWR1) and GPR8 (NPBWR2). This neuropeptide system is thought to have a role in regulating feeding behavior, energy homeostasis, neuroendocrine function, and modulating inflammatory pain. Strong and discrete expression of their receptors in the extended amygdala suggests a potential role in regulating stress responses, emotion, anxiety and fear; however, there have been no functional studies to date to support this possibility. Future studies of NPB/NPW using both pharmacological and phenotypic analysis of genetically engineered mice will lead to further elucidation of the physiological role of this novel neuropeptide system.
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PMID:The NPB/NPW neuropeptide system and its role in regulating energy homeostasis, pain, and emotion. 1820 24

Neuropeptides B (NPB) and W (NPW) have been identified as endogenous ligands of two G-protein-coupled receptors, neuropeptides B/W receptor 1 (NPBWR1, formerly known as GPR7) and neuropeptides B/W receptor 2 (NPBWR2, formerly known as GPR8). In rodents where NPBWR2 is absent, its counterpart is named the similar to neuropeptides B/W receptor 2 (similar to NPBWR2, formerly GPR8-like). Both NPB and NPW play a role in the control of feeding, neuroendocrine axis functions, memory and learning processes as well as in pain regulation. The present study aimed to investigate the expression of NPB, NPW, NPBWR1 and the similar to NPBWR2 genes in cultured rat calvarial osteoblast-like (ROB) cells and the effects of both peptides on proliferative activity and osteocalcin secretion by ROB cells. Classic RT-PCR technique revealed the presence of ppNPB mRNA, ppNPW mRNA, and NPBWR1 mRNA, but not similar to NPBWR2 mRNA in ROB cells. QPCR revealed gradual (days 7, 14 and 21 of culture) increase of the ppNPB gene expression, while expression of ppNPW gene was the highest at day 14 and was comparable to that seen in freshly isolated cells. In ROB cells, expression of NPBWR1 gene was notable at day 7 of culture, lower at day 21, and negligible at day 14. Neither NPB nor NPW changed osteocalcin secretion by cultured osteoblast-like cells while both neuropeptides inhibited their proliferative activity. Results of the present study suggest that the systems of NPW, NPB and NPBWR1 directly regulate proliferative activity of cultured rat calvaria osteoblast-like cells. The physiological significance of this osteoblastic system remains unclear, and requires further investigation.
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PMID:Neuropeptide B (NPB) and neuropeptide W (NPW) system in cultured rat calvarial osteoblast-like (ROB) cells: NPW and NPB inhibit proliferative activity of ROB cells. 1988 18

Novel small molecule antagonists of NPBWR1 (GPR7) are herein reported. A high-throughput screening (HTS) of the Molecular Libraries-Small Molecule Repository library identified 5-chloro-4-(4-methoxyphenoxy)-2-(p-tolyl)pyridazin-3(2H)-one as a NPBWR1 hit antagonist with micromolar activity. Design, synthesis and structure-activity relationships study of the HTS-derived hit led to the identification of 5-chloro-2-(3,5-dimethylphenyl)-4-(4-methoxyphenoxy)pyridazin-3(2H)-one lead molecule with submicromolar antagonist activity at the target receptor and high selectivity against a panel of therapeutically relevant off-target proteins. This lead molecule may provide a pharmacological tool to clarify the molecular basis of the in vivo physiological function and therapeutic utility of NPBWR1 in diverse disease areas including inflammatory pain and eating disorders.
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PMID:Design, synthesis and SAR analysis of novel potent and selective small molecule antagonists of NPBWR1 (GPR7). 2307 22

In this Letter we report on the advances in our NPBWR1 antagonist program aimed at optimizing the 5-chloro-2-(3,5-dimethylphenyl)-4-(4-methoxyphenoxy)pyridazin-3(2H)-one lead molecule previously obtained from a high-throughput screening (HTS)-derived hit. Synthesis and structure-activity relationships (SAR) studies around the 3,5-dimethylphenyl and 4-methoxyphenyl regions resulted in the identification of a novel series of non-peptidic submicromolar NPBWR1 antagonists based on a 5-chloro-4-(4-alkoxyphenoxy)-2-(benzyl)pyridazin-3(2H)-one chemotype. Amongst them, 5-chloro-2-(9H-fluoren-9-yl)-4-(4-methoxyphenoxy)pyridazin-3(2H)-one 9h (CYM50769) inhibited NPW activation of NPBWR1 with a submicromolar IC(50), and displayed high selectivity against a broad array of off-targets with pharmaceutical relevance. Our medicinal chemistry study provides innovative non-peptidic selective NPBWR1 antagonists that may enable to clarify the biological role and therapeutic utility of the target receptor in the regulation of feeding behavior, pain, stress, and neuroendocrine function.
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PMID:SAR analysis of novel non-peptidic NPBWR1 (GPR7) antagonists. 2328 38

Neuropeptide B/W receptor-1 (NPBWR1) and NPBWR2 had been known as orphan receptors GPR7 and 8, respectively. Endogenous peptide ligands of these receptors, neuropeptide B (NPB) and neuropeptide W (NPW), were identified in 2002 and 2003 (Fujii et al., 2002; Brezillon et al., 2003; Tanaka et al., 2003). These peptides have been implicated in regulation of feeding behavior, energy homeostasis, neuroendocrine function, and modulating inflammatory pain. In addition, strong and discrete expression of their receptors in the extended amygdala and bed nucleus of the stria terminalis suggests a potential role in regulating stress responses, emotion, anxiety, and fear. Recent studies of NPB/NPW using both pharmacological and phenotypic analyses of genetically engineered mice as well as a human study support this hypothesis.
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PMID:NPBWR1 and NPBWR2: Implications in Energy Homeostasis, Pain, and Emotion. 2351 89


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