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)

Opioids are coupled through G proteins to both ion channels and adenylyl cyclase. This study describes opioid modulation of the voltage-dependent cation channel, Ih, in cultured guinea pig nodose ganglion neurons. Forskolin, PGE2, and cAMP analogs shifted the voltage dependence of activation of Ih to more depolarized potentials and increased the inward current at -60 mV. Opioids had no effect on Ih alone, but reversed the effect of forskolin on Ih. This action of opioids was blocked by naloxone. Opioids had no effect on Ih in the presence of cAMP analogs, suggesting that modulation occurs at the level of adenylyl cyclase. The shift in the voltage dependence of Ih by agents that induce inflammation (i.e., PGE2) is one potential mechanism to mediate an increased excitability. Opioid inhibition of adenylyl cyclase and subsequent inhibition of Ih may be a mechanism by which opioids inhibit primary afferent excitability and relieve pain.
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PMID:Opioid inhibition of Ih via adenylyl cyclase. 751 24

Opioid drugs exert a wide spectrum of physiological and behavioral effects, including effects on pain perception, mood, motor control and autonomic functions. The effects of opioids are mediated via a family of membrane-bound receptors, of which the most extensively characterized are the mu, delta and kappa receptors. We have now cloned the human homolog of the mu opioid receptor and, in the present study, we have examined its pharmacological profile. The human mu receptor has high affinities for several alkaloids of high abuse potential as well as a variety of peptide and nonpeptide drugs characterized previously as mu-selective, but not delta- or kappa-selective. Most importantly, the human mu receptor has higher affinity for morphine and methadone than does the rat mu receptor, despite the fact that these receptors are 95% identical at the amino acid level. The labeling of the receptor by agonist was decreased by nonhydrolyzable GTP analogs and by pertussis toxin treatment of cells expressing the human mu receptor, consistent with the coupling of the receptor to guanine nucleotide binding proteins. The human mu receptor functionally couples to the inhibition of adenylyl cyclase in a stereospecific and naloxone-reversible manner. We have also investigated the distribution of mRNAs encoding the mu receptor in human brain by Northern analysis, which demonstrates the existence of multiple transcripts of 13.5, 11, 4.3 and 2.8 kb, which were highly expressed in the hypothalamus, thalamus and subthalamic nucleus, more moderately expressed in the amygdala and caudate nucleus and which demonstrated lowest levels of expression in the hippocampus, substantia nigra and corpus callosum.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Characterization of the cloned human mu opioid receptor. 781 59

The mu opioid receptor mediates the pain-relieving effects of opioid narcotics. Cellular signalling of the mu receptor involves G-proteins, and the effectors include adenylyl cyclase and ion channels. Studies in which the cloned mu opioid receptor is used for cellular expression show that the receptor function is modulated by multiple protein kinases.
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PMID:Protein kinase modulation of mu opioid receptor signalling. 891 86

Opioids modulate numerous central and peripheral processes including pain perception neuroendocrine secretion and the immune response. The opioid signal is transduced from receptors through G proteins to various different effectors. Heterogeneity exists at all levels of the transduction process. There are numerous endogenous ligands with differing selectivities for at least three distinct opioid receptors (mu, delta, kappa). G proteins activated by opioid receptors are generally of the pertussis toxin-sensitive Gi/Go class, but there are also opioid actions that are thought to involve Gq and cholera toxin-sensitive G proteins. To further complicate the issue, the actions of opioid receptors may be mediated by G-protein alpha subunits and/or beta gamma subunits. Subsequent to G protein activation several effectors are known to orchestrate the opioid signal. For example activation of opioid receptors increases phosphatidyl inositol turnover, activates K+ channels and reduces adenylyl cyclase and Ca2+ channel activities. Each of these effectors shows considerable heterogeneity. In this review we examine the opioid signal transduction mechanism. Several important questions arise: Why do opioid ligands with similar binding affinities have different potencies in functional assays? To which Ca2+ channel subtypes do opioid receptors couple? Do opioid receptors couple to Ca2+ channels through direct G protein interactions? Does the opioid-induced inhibition of vesicular release occur through modulation of multiple effectors? We are attempting to answer these questions by expressing cloned opioid receptors in GH3 cells. Using this well characterized system we can study the entire opioid signal transduction process from ligand-receptor interaction to G protein-effector coupling and subsequent inhibition of vesicular release.
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PMID:Functional analysis of cloned opioid receptors in transfected cell lines. 894 17

Using the mouse caudate-putamen, where delta-opioid receptor subtypes have been shown to regulate adenylyl cyclase activity, we show in this study that endogenous enkephalins inhibit enzyme activity through activation of delta 1- and delta 2-opioid receptors. Thus, naltriben or 7-benzylidenenaltrexone as well as the delta-selective antagonist naltrindole (mixed delta 1 and delta 2 antagonist) antagonized inhibition of adenylyl cyclase activity induced by methionine- or leucine-enkephalin, while the micro-antagonist D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP) was without effect. Furthermore, we have previously shown that activation of delta-opioid receptors increases cholecystokinin release in the central nervous system, resulting in a potentiation of micro-opioid antinociceptive responses, and the respective role of delta 1- and delta 2-opioid receptors in this facilitatory effect has now been evaluated. Activation of delta 2-opioid receptors, either by endogenous enkephalins protected from catabolism by the complete enkephalin-degrading enzyme inhibitor N-((R,S)-2-benzyl-3((S)(2-amino-4-methyl-thio) butyldithio)-1-oxopropyl)-L-phenyl-alanine benzyl ester (RB 101), or by the delta 2-selective agonist Tyr-D-Ser(O-tert-butyl)-Gly-Phe-Leu-Thr(O-tert-butyl) (BUBU), potentiated micro-opioid antinociceptive responses in the hot-plate test in mice. This effect was antagonized by a selective cholecystokinin-A antagonist. Activation of delta 1-opioid receptors by endogenous opioid peptides decreased the micro-opioid responses. These results suggest that stimulation of delta 2-opioid receptors potentiates micro-opioid analgesia in the hot-plate test in mice through an increase in endogenous cholecystokinin release, while activation of delta 1-opioid receptors could decrease it. Thus, the pre-existing physiological balance between opioid and cholecystokinin systems seems to be modulated in opposite directions depending on whether delta 1- or delta 2-opioid receptors are selectively activated. This is the first demonstration that endogenous enkephalins, methionine- and leucine-enkephalin, are the natural ligands of delta-opioid receptor subtypes, and that delta 2-opioid receptor activation may facilitate the endogenous cholecystokinin-related modulation of micro-opioid analgesia, while the delta 1-opioid receptors may have an inhibitory role. These results could have important applications for the characterization of opioid delta 1 and delta 2 as subtypes or subsites and in pain alleviation.
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PMID:Opposite role of delta 1- and delta 2-opioid receptors activated by endogenous or exogenous opioid agonists on the endogenous cholecystokinin system: further evidence for delta-opioid receptor heterogeneity. 895 84

Opiates are potent analgesics used clinically in the treatment of pain. A significant drawback to the chronic use and clinical effectiveness of opiates is the development of tolerance. To investigate the cellular mechanisms of tolerance, the cloned human kappa-opioid receptor was stably expressed in human embryonic kidney (HEK 293) cells, and the effects of opioid agonist treatment were examined. The receptor-expressing cells showed specific high-affinity membrane binding for a kappa-selective opioid, 3H-labeled (+)-(5alpha,7alpha,8beta)-N-methyl-N-[7-(1-pyrrolidiny l)-1-oxaspiro [4,5] dec-8-yl] benzeneacetamide ([3H]U69,593), and a nonselective opioid antagonist, [3H]diprenorphine. Pretreatment with pertussis toxin or guanosine 5'-O-(3-thiotriphosphate) reduced [3H]69,593 binding, indicating that the human K receptor coupled to G proteins of the Gi or Go families in HEK 293 cells. The receptor-mediated inhibition of adenylyl cyclase was abolished by pertussis toxin pretreatment and was blocked by a kappa-selective antagonist, norbinaltorphimine. A 3-h pretreatment with a kappa-selective agonist, (+/-)-trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl] benzeneacetamide (U50,488), caused receptor down-regulation, whereas no receptor down-regulation was found after levorphanol pretreatment. U50,488 or dynorphin A(1-17) pretreatments (3 h) desensitized the ability of U50,488 or dynorphin A(1-17) to inhibit cyclic AMP accumulation, as evidenced by a decrease in functional potency. Also, U50,488 pretreatment desensitized the ability of levorphanol to inhibit forskolin-stimulated cyclic AMP accumulation. In contrast, pretreatment of cells with either levorphanol or a potent nonselective opioid, etorphine, resulted in no apparent receptor desensitization. Taken together, these results demonstrate that the human kappa receptor is differentially regulated by selective and nonselective opioid agonists, with selective agonists able to desensitize the receptor.
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PMID:Differential agonist regulation of the human kappa-opioid receptor. 910 9

Galanin, a neuroendocrine peptide with a multitude of functions, binds to and acts on specific G-protein coupled receptors. Only one galanin receptor subtype, GalRI, has been cloned so far, although pharmacological evidence suggests the presence of more than one galanin receptor subtype. These receptors mediate via different Gi/Go-proteins the inhibition of adenylyl cyclase, opening of K+-channels and closure of Ca2+-channels. Galanin inhibits secretion of insulin, acetylcholine, serotonin and noradrenaline, while it stimulates prolactin and growth hormone release. Determination of structural components of galanin receptors required for binding of the peptide ligand as carried out recently will facilitate the screening and design of molecules specifically acting on galaninergic systems with therapeutic potential in Alzheimer's disease, feeding disorders, pain and depression.
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PMID:Galanin receptors: involvement in feeding, pain, depression and Alzheimer's disease. 912 74

Opioid analgesics are used extensively in the management of pain. Although the clinically effective opioids bind with high affinity to the mu-opioid receptor, studies have suggested that the delta-opioid agonists might represent more ideal analgesic agents, with fewer side effects. A limitation to opiate effectiveness is the development of tolerance, an event that has been linked to opioid receptor desensitization. To gain a better understanding of delta-receptor agonist regulation, the cloned mouse delta receptor was stably expressed in human embryonic kidney 293 cells, and the functional effects of agonist pretreatment were examined. With a 3-hr pretreatment protocol, the delta-selective agonists [D-Pen2,D-Pen5]enkephalin, [D-Ala2,D-Leu5]enkephalin, and [D-Ser2,Leu5]enkephalin-Thr and the nonselective opioids levorphanol, etorphine, and ethylketocyclazocine were found to desensitize delta receptors. [D-Pen2,D-Pen5]enkephalin, [D-Ser2,Leu5]enkephalin-Thr, [D-Ala2,D-Leu5]enkephalin, and etorphine treatments also caused a pronounced internalization of the epitope-tagged delta receptor, suggesting that the desensitization and internalization may be related. In contrast, levorphanol pretreatment did not internalize the receptor but still resulted in a 400-fold reduction in potency, suggesting that prolonged treatment with levorphanol only uncoupled the delta receptor from adenylyl cyclase. In contrast to the desensitization induced by peptide-selective delta agonists, pretreatment with the delta-selective nonpeptide agonist 7-spiroindanyloxymorphone and morphine sensitized the opioid inhibition of forskolin-stimulated cAMP accumulation. This differential regulation of the delta receptor may be due to variations in the ability of agonists to bind to the receptor. This hypothesis was supported by the finding that a point mutation that converted Asp128 to Asn128 (D128N) diminished the ability of delta-selective agonists to inhibit cAMP accumulation while increasing the potency of morphine to reduce cAMP accumulation. In particular, a lack of desensitization of the delta receptor by morphine may contribute to our understanding of the molecular basis of development of morphine-induced tolerance and dependence.
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PMID:Opioid regulation of the mouse delta-opioid receptor expressed in human embryonic kidney 293 cells. 927 50

The G protein Go is highly expressed in neurons and mediates effects of a group of rhodopsin-like receptors that includes the opioid, alpha2-adrenergic, M2 muscarinic, and somatostatin receptors. In vitro, Go is also activated by growth cone-associated protein of Mr 43,000 (GAP43) and the Alzheimer amyloid precursor protein, but it is not known whether this occurs in intact cells. To learn about the roles that Go may play in intact cells and whole body homeostasis, we disrupted the gene encoding the alpha subunits of Go in embryonic stem cells and derived Go-deficient mice. Mice with a disrupted alphao gene (alphao-/- mice) lived but had an average half-life of only about 7 weeks. No Goalpha was detectable in homogenates of alphao-/- mice by ADP-ribosylation with pertussis toxin. At the cellular level, inhibition of cardiac adenylyl cyclase by carbachol (50-55% at saturation) was unaffected, but inhibition of Ca2+ channel currents by opioid receptor agonist in dorsal root ganglion cells was decreased by 30%, and in 25% of the alphao-/- cells examined, the Ca2+ channel was activated at voltages that were 13.3 +/- 1.7 mV lower than in their counterparts. Loss of alphao was not accompanied by appearance of significant amounts of active free betagamma dimers (prepulse test). At the level of the living animal, Go-deficient mice are hyperalgesic (hot-plate test) and display a severe motor control impairment (falling from rotarods and 1-inch wide beams). In spite of this deficiency, alphao-/- mice are hyperactive and exhibit a turning behavior that has them running in circles for hours on end, both in cages and in open-field tests. Except for one, all alphao-/- mice turned only counterclockwise. These findings indicate that Go plays a major role in motor control, in motor behavior, and in pain perception and also predict involvement of Go in Ca2+ channel regulation by an unknown mechanism.
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PMID:Multiple neurological abnormalities in mice deficient in the G protein Go. 950 Dec 52

Fentanyl, and its structural analogs lofentanil and sufentanil, are potent analgesics used clinically in the management of pain. However, the high analgesic potency of these compounds is limited by the development of tolerance after chronic use. To investigate whether their tolerance development may be related to mu receptor desensitization, the cloned mouse mu receptor as well as mutant forms of the receptor were stably expressed in HEK 293 cells and tested for their response to continuous opioid treatment. Fentanyl and its analogs potently bound to the mu receptor and effectively inhibited cAMP accumulation. Three-hour pretreatment of mu receptors with fentanyl and its analogs desensitized the mu receptor by uncoupling it from adenylyl cyclase. The fentanyl analogs caused a slight internalization of the mu receptor as accessed by antibody binding to the epitope-tagged mu receptor. Truncation of the mu receptor by removal of its carboxyl terminus at Glu341 did not affect the ability of the fentanyl analogs to bind to and activate the mu receptor nor did it prevent the fentanyl analogs from desensitizing the receptor. In a previous study we showed that morphine did not desensitize the cloned mu receptor even though it is a potent and effective agonist at the mu receptor. Mutagenesis studies revealed that morphine interacts differently with the mu receptor to activate it than do the fentanyl analogs which may explain its lack of desensitization of the mu receptor. These results indicate that desensitization of the mu receptor may be a molecular basis for the development of tolerance to fentanyl and its analogs.
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PMID:Fentanyl and its analogs desensitize the cloned mu opioid receptor. 961 24


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