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)

In the arcuate nucleus of hypothalamus (ARC), galaninergic fibers form synaptic contacts with proopiomelanocortin neurons, which are involved in pain modulation. The present study assessed the role of exogenous and endogenous galanin in the modulation of nociception in the ARC of rats. The hindpaw withdrawal latency (HWL) to thermal and mechanical stimulation was assessed by the hot-plate test and the Randall Selitto Test. Intra-ARC injection of galanin dose-dependently increased the HWLs in intact rats, indicating an antinociceptive role of exogenous galanin in the ARC. The antinociceptive effect of galanin was blocked by following intra-ARC injection of galantide, a putative galanin receptor antagonist, suggesting that the antinociceptive effect of galanin is mediated by galanin receptors. Moreover, intra-ARC injection of galanin increased the HWL in rats with inflammation. Intra-ARC administration of galantide alone reduced the HWLs in rats with inflammation, while there were no influences of galantide on the HWL in intact rats. Taken together, the results show that galanin has an antinociceptive role in the ARC of intact rats and rats with inflammation.
Pain 2003 Nov
PMID:An antinociceptive role of galanin in the arcuate nucleus of hypothalamus in intact rats and rats with inflammation. 1458 Nov 21

The opioid peptide beta-endorphin (END) as well as mRNA for its precursor proopiomelanocortin (POMC) are found not only in the pituitary gland, but also within various types of immune cells infiltrating inflamed sc tissue. During stressful stimuli END is released and interacts with peripheral opioid receptors to inhibit pain. However, the subcellular pathways of POMC processing and END release have not yet been delineated in inflammatory cells. The aim of the present study was to examine the presence of POMC, carboxypeptidase E, the prohormone convertases 1 (PC1), and 2 (PC2), PC2-binding protein 7B2, and the release of END from inflammatory cells in rats. Using immunohistochemistry we detected END and POMC alone or colocalized with PC1, PC2, carboxypeptidase E, and 7B2 in macrophages/monocytes, granulocytes, and lymphocytes of the blood and within inflamed sc paw tissue. Immunoelectron microscopy revealed that END is localized within secretory granules packed in membranous structures in macrophages, monocytes, granulocytes, and lymphocytes. Finally, END is released by noradrenaline from immune cells in vitro. Taken together, our results indicate that immune cells express the entire machinery required for POMC processing into functionally active peptides such as END and are able to release these peptides from secretory granules.
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PMID:Subcellular pathways of beta-endorphin synthesis, processing, and release from immunocytes in inflammatory pain. 1463 Jul 14

Chronic pain is frequently associated with profound alterations of neuronal systems involved in pain processing and should be considered as a real disease state of the nervous system. Unfortunately, some forms of chronic pain remain difficult to be satisfactorily treated. In the search for new therapeutic strategies, the gene-based approaches are of potential interest as they offer the possibility to introduce a therapeutic protein into some relevant structures and to drive its continuous production in the near vicinity of targeted cells. Recently, these techniques have been experimented in several animal models of chronic pain, showing that transfer at the spinal level of some genes, in particular those of opioid precursors proopiomelanocortin or proenkephalin A, leading to the overproduction of products that they encode, attenuated persistent pain of both inflammatory and neuropathic origin. Thus, in polyarthritic rat, a model of chronic inflammatory pain, we demonstrated that herpes simplex virus vector mediated overexpression of proenkephalin A in primary sensory neurons at the lumbar level elicited both antihyperalgesic and anti-inflammatory activities. Apart from opioids, numerous other molecules involved in pain processing are of potential therapeutic interest for gene-based protocols. For instance, targeting some molecules involved in pain induction and perpetuation, such as proinflammatory cytokines, raises an interesting possibility to block the "development" of pain. The clinical application of these approaches remains to be established, and, presently, one of the main problems to be solved is the innocuity of virus-derived vectors. However, the experimental use of gene-based techniques might be particularly useful for the evaluation of the therapeutic interest of some recently identified molecules involved in pain processing and might finally lead to the development of new "classical" pharmacological tools.
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PMID:[From inflammation to pain: experimental gene therapy]. 1506 78

Corticotropin-releasing hormone (CRH) mainly regulates the synthesis and secretion of adrenocorticotropin (ACTH) in the anterior pituitary (AP). By using CRH-deficient mice (CRH KO), we investigated the role of CRH in the processing of proopiomelanocortin (POMC), a precursor of ACTH, beta-lipotropic hormone, and beta-endorphin (EP). In the basal condition, the plasma ACTH level was similar in CRH KO and wild-type mice (WT), while its response to pain stress in CRH KO was smaller than that in WT. Immunoreactive (ir) beta-EP contents in the AP of CRH KO were not significantly different from those of WT. In order to determine the different molecule profile of POMC-related peptides between WT and CRH KO, ir beta-EP contents extracted from AP of WT and CRH KO were assayed by gel filtration chromatography. The gel filtration analyses revealed that a higher molecular weight form of ir beta-EP, putative POMC, was increased in CRH KO, but the beta-EP peak level was small and similar between two groups. These results suggest that CRH has little influence on the basal release of ACTH and prohormone convertase-2 processing enzyme. On the other hand, it is essential for ACTH secretion under stress conditions, and CRH would affect on the prohormone convertase-1/3 processing enzyme in AP.
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PMID:Effects of corticotropin-releasing hormone (CRH) on the synthesis and secretion of proopiomelanocortin-related peptides in the anterior pituitary: a study using CRH-deficient mice. 1533 Nov 53

The melanocortins, which are derived from proopiomelanocortin, have a variety of physiological functions mediated membrane surface receptors. To date, five subtypes have been cloned. With the cloning of melanocortin receptors, studies with genetic models, and development of selective compounds, the physiological roles of the five melanocortin receptors have begun to be understood. The melanocortin-4 receptor (MC4R), which is predominantly expressed in the central nervous system, has in particular become the focus of much attention in recent years because of the critical roles it plays in a wide range of functions, including feeding, sexual behavior, and stress. Recent development of selective antagonists for the MC4R has provided pharmacological evidence that blockade of MC4R could be a useful way of alleviating numerous conditions such as anxiety/depression, pain, and addiction to drugs of abuse.
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PMID:Involvement of melanocortin-4 receptor in anxiety and depression. 1597 4

We have shown that supplementation of proinflammatory agent with a high dose of morphine not only abolishes inflammation-related pain symptoms but also inhibits influx of leukocytes to the inflamed peritoneal cavity. Present investigations focused on effects of morphine on proopiomelanocortin and prodynorphin systems during zymosan-induced peritonitis. Males of SWISS mice were ip injected with zymosan (Z, 40 mg/kg) or zymosan with morphine (ZM, 20 mg/kg). At time 0 (controls) and 4 and 24h after stimulation, peritoneal leukocytes (PTLs) were counted, PTL levels of opioid peptides (beta-endorphin and dynorphin) measured by radioimmunoassays, while mRNAs coding their respective precursors (POMC and PDYN) and receptors (MOR and KOR) determined by QRT-PCR. Influx of inflammatory PTLs, mainly PMNs, was significantly delayed by morphine co-injection. Total levels of beta-endorphin and dynorphin corresponded with PTL numbers, while levels per cell were similar in all groups except of beta-endorphin, decreased in ZM at 4h. Levels of both peptides in peritoneal fluid were increased in Z and ZM groups at 4h, while at 24h only in case of beta-endorphin in Z group. POMC was increased only in ZM group at 4h of peritonitis, while PDYN in both Z and ZM groups at the same time. MOR mRNA was increased 24h after injection in Z and ZM groups, while KOR mRNA was similar in all groups except of decrease in Z at 24h. In conclusion, endogenous opioids and their receptors are involved in zymosan-induced peritonitis and affected in various ways by morphine co-injection.
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PMID:Morphine-induced changes in the activity of proopiomelanocortin and prodynorphin systems in zymosan-induced peritonitis in mice. 1597 27

Levels of beta-endorphin immunoreactive material (IRM) in cerebrospinal fluid (CSF) have been reported to correlate inversely with postoperative morphine requirement. Considering proopiomelanocortin (POMC) derivatives as predictors for sensitivity to postoperative pain, we determined authentic beta-endorphin (beta-endorphin(1-31)), beta-lipotropin IRM, N-acetyl-beta-endorphin IRM and ACTH in CSF of 17 patients undergoing hip or knee arthroplasty, before surgery (t(A)), immediately after termination of propofol infusion and still under spinal anesthesia (t(B)), under postoperative pain (t(C)) and one day after surgery (t(D)); patients rated their severity of pain on a visual analogue scale (VAS) at those four times. In all patients CSF concentrations of N-acetyl-beta-endorphin IRM and beta-lipotropin IRM were found to be increased after terminating the propofol infusion with spinal anesthesia still effective at t(B). Patients did not feel pain at times t(A), t(B) or t(D); however, they reported moderate to considerable pain at t(C). There were no correlations of postoperative pain severity at t(C) with ACTH, beta-endorphin(1-31) or N-acetyl-beta-endorphin IRM concentrations in CSF. In contrast, we observed significant inverse correlations (Spearman's rank correlation coefficients between -0.83 and -0.85, p<0.01) for postoperative pain severity with beta-lipotropin IRM concentrations in CSF at t(C), and, in addition, at t(A), t(B) and t(D); thus, postoperative pain severity appeared to be dependent on a central system controlling sensitivity to pain, linked to a POMC system releasing beta-lipotropin IRM into CSF and already active at times t(A) and t(B). We conclude that beta-lipotropin IRM in CSF might be considered to serve as a predictor of sensitivity to postoperative pain.
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PMID:Preoperative concentration of beta-lipotropin immunoreactive material in cerebrospinal fluid: a predictor of postoperative pain? 1628 30

In the present study the effects of intravenously administered corticotropin-releasing hormone (CRH) on the release of proopiomelanocortin (POMC) derivatives such as adrenocorticotropic hormone (ACTH), beta-lipotropin (beta-LPH) and beta-endorphin (beta-END) as well as direct effects of CRH on pain sensitivity were examined. In 16 healthy volunteers we studied the effects of 100 microg intravenously administered CRH in absence or presence of 12 mg naloxone on heat or pressure pain sensitivity, using a double-blind, cross-over and placebo-controlled design. To evaluate analgesic effects of CRH via release of POMC derivatives, we determined plasma concentrations of beta-END-immunoreactive material (IRM), authentic beta-END (beta-END(1-31)) and beta-LPH IRM, in parallel with heat and pressure pain tolerance thresholds before and 15 and 30 min after treatment with CRH (or placebo), and 5 min after naloxone (or placebo) administration which was administered 40 min after CRH (or placebo) injection. CRH increased levels of beta-END IRM, beta-END(1-31) and beta-LPH IRM. As compared to beta-END IRM levels measured by a commercial RIA kit, the beta-END(1-31) levels determined by a highly specific two-site RIA, proved to be remarkably small. Furthermore, CRH did not induce increases of heat pain tolerance thresholds, but of pressure pain tolerance thresholds, which, however, were not reversible by naloxone. Neither beta-END nor beta-LPH IRM nor beta-END(1-31) levels correlated with heat or pressure pain tolerance thresholds. We conclude that CRH does not modulate heat, but pressure pain; POMC derivatives like beta-END IRM, beta-END(1-31) or beta-LPH do not mediate this effect.
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PMID:Corticotropin-releasing hormone reduces pressure pain sensitivity in humans without involvement of beta-endorphin(1-31), but does not reduce heat pain sensitivity. 1653 40

Phosphorylation of specific sites in the second intracellular loop and in the C-terminal domain have previously been suggested to cause desensitization and internalization of the mu-opioid receptor (MOP-R). To assess sites of MOP-R phosphorylation in vivo, affinity-purified, phosphoselective antibodies were raised against either phosphothreonine-180 in the second intracellular loop (MOR-P1) or the C-terminal domain of MOP-R containing phosphothreonine-370 and phosphoserine-375 (MOR-P2). We found that MOR-P2-immunoreactivity (IR) was significantly increased within the striatum of wild-type C57BL/6 mice after injection of the agonist fentanyl. Pretreatment with the antagonist naloxone blocked the fentanyl-induced increase. Furthermore, mutant mice lacking MOP-R showed only non-specific nuclear MOR-P2-IR before or after fentanyl treatment, confirming the specificity of the MOR-P2 antibodies. To assess whether MOP-R phosphorylation occurs following endogenous opioid release, we induced chronic neuropathic pain by partial sciatic nerve ligation (pSNL), which caused a significant increase in MOR-P2-IR in the striatum. pSNL also induced signs of mu opioid receptor tolerance demonstrated by a rightward shift in the morphine dose response in the tail withdrawal assay and by a reduction in morphine conditioned place preference (CPP). Mutant mice selectively lacking all forms of the beta-endorphin peptides derived from the proopiomelanocortin (Pomc) gene did not show increased MOR-P2-IR, decreased morphine antinociception, or reduced morphine CPP following pSNL. In contrast gene deletion of either proenkephalin or prodynorphin opioids did not block the effects of pSNL. These results suggest that neuropathic pain caused by pSNL in wild-type mice activates the release of the endogenous opioid beta-endorphin, which subsequently induces MOP-R phosphorylation and opiate tolerance.
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PMID:The absence of endogenous beta-endorphin selectively blocks phosphorylation and desensitization of mu opioid receptors following partial sciatic nerve ligation. 1746 16

The processed products of the proopiomelanocortin gene (ACTH, alpha-MSH, beta-MSH, gamma-MSH, etc.) interact with five melanocortin receptors, the MC1R, MC2R, MC3R, MC4R, and MC5R to modulate and control many important biological functions crucial for good health both peripherally (as hormones) and centrally (as neurotransmitters). Pivotal biological functions include pigmentation, adrenal function, response to stress, fear/flight, energy homeostasis, feeding behavior, sexual function and motivation, pain, immune response, and many others, and are believed to be involved in many disease states including pigmentary disorders, adrenal disorders, obesity, anorexia, prolonged and neuropathic pain, inflammatory response, etc. The melanocortin-3 receptor (MC3R) is found primarily in the brain and spinal cord and also in the periphery, and its biological functions are still not well understood. Here we review some of the biological functions attributed to the MC3R, and then examine in more detail efforts to design and synthesize ligands that are potent and selective for the MC3R, which might help resolve the many questions still remaining about its function. Though some progress has been made, there is still much to be done in this critical area.
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PMID:Design, synthesis and biological evaluation of ligands selective for the melanocortin-3 receptor. 1758 28


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