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 periaqueductal gray (PAG) is the main target site of the opioid-induced analgesia. The present study was designed to examine the roles of protein kinase A (PKA) and C (PKC) in the opioid-induced modulation of the currents activated by an inhibitory neurotransmitter, gamma-aminobutyric acid (GABA). The PAG neurons were acutely isolated and voltage-clamped under the nystatin-perforated patch-clamp mode. The GABA-activated current was sensitively blocked by a GABA(A) receptor antagonist, bicuculline, and selectively carried by chloride ions. The GABA(A) receptor-activated Cl(-) current was potentiated by a mu-opioid receptor agonist, [D-Ala(2),N-MePhe(4),Gly(5)-ol]-enkephalin acetate (DAMGO). The GABA response was also potentiated by phorbol-12-myristate-13-acetate (PMA). Pretreatment with PMA occluded the DAMGO potentiation. However, both chelerythrine and 2-[1-(3-dimethylaminopropyl)indol-3-yl]-3-(indol-3-yl) maleimide (GF109203X) also potentiated the GABA response. Pretreatment with chelerythrine or GF109203X also occluded the DAMGO potentiation. Meanwhile, the GABA response was potentiated by N-(2-[p-bromocinnamylamino]-ethyl)-5-isoquinolinesulfonamide (H-89), while not altered by forskolin. Pretreatment with H-89 occluded the potentiation effect of DAMGO on the GABA response. In addition, the DAMGO effect was completely blocked by pretreatment with forskolin. From the result, it can be suggested that activation of mu-opioid receptor potentiates the GABA(A) response through the mediation of PKA inhibition, and that PKC is not directly involved in the action mechanism of DAMGO.
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PMID:Roles of protein kinase A and C in the opioid potentiation of the GABAA response in rat periaqueductal gray neuron. 1266 43

Members of the R7 subfamily of regulators of G-protein signaling (RGS) proteins (RGS6, RGS7, RGS9-2, and RGS11) are found in the mouse CNS. The expression of these proteins was effectively reduced in different neural structures by blocking their mRNA with antisense oligodeoxynucleotides (ODNs). This was achieved without noticeable changes in the binding characteristics of labeled beta-endorphin to opioid receptors. Knockdown of R7 proteins enhanced the potency of antinociception promoted by morphine and [D-Ala(2), N-MePhe(4), Gly-ol(5)]-enkephalin (DAMGO)-both agonists at mu-opioid receptors. The duration of morphine analgesia was greatly increased in RGS9-2 and in RGS11 knockdown mice. The impairment of R7 proteins brought about different changes in the analgesic activity of selective delta agonists. Knockdown of RGS11 reduced [D-Ala(2)]deltorphin II analgesic effects. Those of RGS6 and RGS9-2 proteins caused [D-Ala(2)]deltorphin II to produce a smoothened time-course curve-the peak effect blunted and analgesia extended during the declining phase. RGS9-2 impairment also promoted a similar pattern of change for [D-Pen(2,5)]-enkephalin (DPDPE). RGS7-deficient mice showed an increased response to both [D-Ala(2)]deltorphin II and DPDPE analgesic effects. A single intracerebroventricular (i.c.v.) ED(80) analgesic dose of morphine gave rise to acute tolerance in control mice, but did not promote tolerance in RGS6, RGS7, RGS9-2, or RGS11 knockdown animals. Thus, R7 proteins play a critical role in agonist tachyphylaxis and acute tolerance at mu-opioid receptors, and show differences in their modulation of delta-opioid receptors.
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PMID:The R7 subfamily of RGS proteins assists tachyphylaxis and acute tolerance at mu-opioid receptors. 1290 95

Spinal application of opiates is the cornerstone of potent analgesia. In the present study, opiate analgesia was investigated after cutaneous application of a recombinant herpes simplex virus type-1 (HSV-1) encoding micro-opioid receptor (microOR) cDNA in reverse orientation with respect to the human cytomegalovirus early enhancer-promoter. Hind paw application of this recombinant vector was used in order to attenuate expression of the microOR in primary afferents and determine whether recombinant vector application would differentially affect the antinociceptive effects of the specific microOR agonist, [D-Ala(2),N-MePhe(4),Gly-ol(5)] enkephalin (DAMGO), on behavioral responses mediated by C- and Adelta-thermonociceptors. The recombinant vector encoding the Escherichia coli lacZ gene marker, KHZ, served as a control virus. Dorsal hind paw surfaces of female Swiss-Webster mice were treated with one of these two viruses (1x10(8)pfu, 10 microl) or vehicle (uninfected). Immunohistochemistry and quantitative image analyses revealed decreased microOR expression in the superficial dorsal horns ipsilateral to hind paws treated with AMOR, but not KHZ. To add, behavioral foot withdrawal latencies of AMOR- and KHZ-treated hind paws demonstrated dose-dependent antinociception after intrathecal DAMGO administration. However, cutaneous application of dorsal hind paw surfaces treated with AMOR, but not KHZ, caused a rightward shift in the C-fiber dose-response, thus, indicating a loss of potency of intrathecal DAMGO. Loss or diminution of DAMGO potency during Adelta-fiber-mediated responses was not observed. These immunohistochemistry and behavioral results of novel, recombinant HSV-1 vector microOR 'knock-down' in nociceptor afferent fibers provide additional evidence for presynaptic localization of microORs on central C-, but not Adelta-terminals.
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PMID:Afferent fiber-selective shift in opiate potency following targeted opioid receptor knockdown. 1465 19

The nucleus locus coeruleus (LC) plays an important role in analgesia produced by opioids and by modulation of the descending noradrenergic pathway. The functional role of micro-opioid receptors (muOR) in regulation of the excitability of spinally projecting LC neurons has not been investigated. In the present study, we tested the hypothesis that activation of presynaptic mu-opioid receptors excites a population of spinally projecting LC neurons through attenuation of gamma-aminobutyric acid (GABA)-ergic synaptic inputs. Spinally projecting LC neurons were retrogradely labeled by a fluorescent dye injected into the spinal dorsal horn of rats. Whole-cell current- and voltage-clamp recordings were performed on labeled LC neurons in brain slices. All labeled LC noradrenergic neurons were demonstrated by dopamine-beta-hydroxylase (DbetaH) immunofluorescence. In 37 labeled LC neurons, (D-Ala(2),N-Me-Phe(4),Gly-ol(5))-enkephalin (DAMGO) significantly increased the discharge activity of 17 (45.9%) neurons, but significantly inhibited the firing activity of another 15 (40.5%) cells. The excitatory effect of DAMGO on seven labeled LC neurons was diminished in the presence of bicuculline. DAMGO significantly decreased the frequency of GABA-mediated miniature inhibitory postsynaptic currents (mIPSCs) in all nine labeled LC neurons. However, DAMGO had no effect on glutamate-mediated miniature excitatory postsynaptic currents (mEPSCs) in 12 of 15 neurons. Furthermore, DAMGO significantly inhibited the peak amplitude of evoked inhibitory postsynaptic currents (eIPSCs) in all 11 labeled neurons, but had no significant effect on the evoked excitatory postsynaptic currents (eEPSCs) in 10 of these 11 neurons. Thus, data from this study suggest that activation of micro-opioid receptors excites a population of spinally projecting LC neurons by preferential inhibition of GABAergic synaptic inputs. These findings provide important new information about the descending noradrenergic modulation and analgesic mechanisms of opioids.
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PMID:Activation of mu-opioid receptors excites a population of locus coeruleus-spinal neurons through presynaptic disinhibition. 1471 51

The rostral ventromedial medulla (RVM) is a major locus for the descending control of nociception and opioid analgesia. However, it is not clear how opioids affect synaptic inputs to RVM neurons. In this study, we determined the effect of mu-opioid receptor activation on excitatory and inhibitory synaptic transmission in spinally projecting RVM neurons. RVM neurons were retrogradely labeled with a fluorescent tracer injected into the dorsal horn of the spinal cord in rats. Whole-cell voltage-clamp recordings were performed on labeled RVM neurons in brain slices in vitro. The mu-receptor agonist [D-Ala(2),N-Me-Phe(4),Gly(5)-ol]-enkephalin (DAMGO, 1 microM) significantly decreased the amplitude of evoked excitatory postsynaptic currents (EPSCs) in 52% (9 of 17) of labeled cells. DAMGO also significantly reduced the amplitude of evoked inhibitory postsynaptic currents (IPSCs) in 69% (11 of 16) of cells examined. Furthermore, DAMGO significantly decreased the frequency of miniature EPSCs in 55% (15 of 27) of cells and significantly decreased the frequency of miniature IPSCs in all 12 cells studied. Although most EPSCs and IPSCs were mediated by glutamate and GABA, the nicotinic and glycine receptor antagonists attenuated EPSCs and IPSCs, respectively, in some labeled RVM neurons. Immunocytochemical labeling revealed that only 35% of recorded RVM neurons were tryptophan hydroxylase-positive, and 15% cells had GABA immunoreactivity. Thus, this study provides important functional evidence that activation of mu-opioid receptors decreases the release of both excitatory and inhibitory neurotransmitters onto most spinally projecting RVM neurons.
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PMID:Activation of mu-opioid receptors inhibits synaptic inputs to spinally projecting rostral ventromedial medulla neurons. 1472 27

Spinal dorsal horn (SDH) is one of important regions in both nociceptive transmission and antinociception. Opioid peptides produce analgesia via regulation of neurotransmitter release through modulation of voltage-dependent Ca(2+) channel (VDCC) in neuronal tissues. The modulatory effect of micro-opioid receptor (MOR) activation on VDCC was investigated in acutely isolated rat SDH neurons under the conventional whole-cell patch-clamp recording mode. The Ba(2+) current passing through VDCC was reversibly inhibited by a MOR agonist, [D-Ala(2),N-MePhe(4),Gly(5)-ol]-enkephalin (DAMGO, 1 microM). Among 108 SDH neurons tested, VDCC of 39 neurons (36%) were inhibited by MOR activation, while other 69 neurons (64%) were not affected. The L-, N-, P/Q-, and R-type VDCC components shared 58.4+/-18.9%, 29.3+/-12.1%, 8.7+/-7.2%, and 3.4+/-4.8% of the total VDCC, respectively. Among VDCC subtypes inhibited by MOR activation, L- and N-types were 61.4+/-12.8% and 30.7+/-14.4%, respectively, while both P/Q- and R-types were 7.9+/-11.8%. A depolarizing pre-pulse increased the amplitude of VDCC and suppressed most of the inhibitory effect of MOR activation. Application of 1 microM phorbol-12-myristate-13-acetate completely antagonized the inhibitory effect of MOR activation without any alteration of basal VDCC amplitude. In contrast, the response of MOR activation was not altered by application of 4-alpha-phorbol (1 microM), 2-[3-Dimethylaminopropyl]indol-3-yl]-3-(indol-3-yl) maleimide (GF109203X, 1 microM), forskolin (1 microM), N-(2-[p-Bromocinnamylamino]ethyl)-5-isoquinolinesulfonamide hydrochloride (H-89, 1 microM). These results indicate that activation of MOR coupled to G-proteins inhibits VDCC, and that this G-protein-mediated inhibition is antagonized by PKC-dependent phosphorylation.
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PMID:Activation of protein kinase C antagonizes the opioid inhibition of calcium current in rat spinal dorsal horn neurons. 1526 Nov 6

Nociceptin activation of ORL1 (opioid receptor-like 1 receptor) has been shown to antagonize mu receptor-mediated analgesia at the supraspinal level. ORL1 and mu-opioid receptor (muR) are co-expressed in several subpopulations of CNS neurons involved in regulating pain transmission. The amino acid sequence of ORL1 also shares a high degree of homology with that of mu receptor. Thus, it is hypothesized that ORL1 and muR interact to form the heterodimer and that ORL1/muR heterodimerization may be one molecular basis for ORL1-mediated antiopioid effects in the brain. To test this hypothesis, myc-tagged ORL1 and HA-tagged muR are co-expressed in human embryonic kidney (HEK) 293 cells. Co-immunoprecipitation experiments demonstrate that ORL1 dimerizes with muR and that intracellular C-terminal tails of ORL1 and muR are required for the formation of ORL1/muR heterodimer. Second messenger assays further indicate that formation of ORL1/muR heterodimer selectively induces cross-desensitization of muR and impairs the potency by which [D-Ala(2),N-methyl-Phe(4),Gly-ol(5)]enkephalin (DAMGO) inhibits adenylate cyclase and stimulates p42/p44 mitogen-activated protein kinase (MAPK) phosphorylation. These results provide the evidence that ORL1/muR heterodimerization and the resulting impairment of mu receptor-activated signaling pathways may contribute to ORL1-mediated antiopioid effects in the brain.
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PMID:Heterodimerization of opioid receptor-like 1 and mu-opioid receptors impairs the potency of micro receptor agonist. 1574 48

Opioids can evoke analgesia by inhibiting neuronal targets in either the brain or spinal cord, and multiple presynaptic and postsynaptic inhibitory mechanisms have been implicated. The relative significance of presynaptic and postsynaptic inhibition to opioid analgesia is essentially unknown, as are the identities and relevant locations of effectors mediating opioid actions. Here, we examined the distribution of G-protein-gated potassium (GIRK) channels in the mouse spinal cord and measured their contribution to the analgesia evoked by spinal administration of opioid receptor-selective agonists. We found that the GIRK channel subunits GIRK1 and GIRK2 were concentrated in the outer layer of the substantia gelatinosa of the dorsal horn. GIRK1 and GIRK2 were found almost exclusively in postsynaptic membranes of putative excitatory synapses, and a significant degree of overlap with the mu-opioid receptor was observed. Although most GIRK subunit labeling was perisynaptic or extrasynaptic, GIRK2 was found occasionally within the synaptic specialization. Genetic ablation or pharmacologic inhibition of spinal GIRK channels selectively blunted the analgesic effect of high but not lower doses of the mu-opioid receptor-selective agonist [D-Ala(2),N-Me-Phe(4),Gly(5)-ol]-enkephalin. Dose-dependent contributions of GIRK channels to the analgesic effects of the -opioid receptor-selective agonists Tyr-D-Ala-Phe-Glu-Val-Val-Gly amide and [D-Pen(2,5)]-enkephalin were also observed. In contrast, the analgesic effect of the agonist (trans)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl] benzeneacetamide methanesulfonate hydrate was preserved despite the absence of GIRK channels. We conclude that the activation of postsynaptic GIRK1 and/or GIRK2-containing channels in the spinal cord dorsal horn represents a powerful, albeit relatively insensitive, means by which intrathecal mu- and -selective opioid agonists evoke analgesia.
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PMID:Spinal G-protein-gated potassium channels contribute in a dose-dependent manner to the analgesic effect of mu- and delta- but not kappa-opioids. 1581 85

The central nucleus of the amygdala (CeA) plays an important role both in stimulus-reward learning for the reinforcing effects of drugs of abuse and in environmental condition-induced analgesia. Both of these two CeA functions involve the opioid system within the CeA. However, the pharmacological profiles of its opioid receptor system have not been fully studied and the synaptic actions of opioid receptors in the CeA are largely unknown. In this study with whole-cell voltage-clamp recordings in brain slices in vitro, we examined actions of opioid agonists on glutamate-mediated excitatory postsynaptic currents (EPSCs) in CeA neurons. Opioid peptide methionine-enkephalin (ME; 10 microM) produced a significant inhibition (38%) in the amplitude of evoked EPSCs, an action mimicked by the mu-opioid receptor agonist [D-Ala(2),N-MePhe(4),Gly-ol(5)]-enkephalin (DAMGO; 1 microM, 44%). Both effects of ME and DAMGO were abolished by the mu receptor antagonist CTAP (1 microM), suggesting a mu receptor-mediated effect. Neither delta-opioid receptor agonist [D-Pen(2),D-Pen(5)]-enkephalin (1 microM) nor kappa-opioid receptor agonist U69593 (300 nM) had any effect on the glutamate EPSC. ME significantly increased the paired-pulse ratio of the evoked EPSCs and decreased the frequency of miniature EPSCs without altering the amplitude of miniature EPSCs. Furthermore, the mu-opioid inhibition of the EPSC was blocked by 4-aminopyridine (4AP; 100 microM), a voltage-dependent potassium channel blocker, and by phospholipase A(2) inhibitors AACOCF(3) (10 microM) and quinacrine (10 microM). These results indicate that only the mu-opioid receptor is functionally present on presynaptic glutamatergic terminals in normal CeA neurons, and its activation reduces the probability of glutamate release through a signaling pathway involving phospholipase A(2) and the presynaptic, 4AP-sensitive potassium channel. This study provides evidence for the presynaptic regulation of glutamate synaptic transmission by mu-opioid receptors in CeA neurons.
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PMID:Mu-opioid-mediated inhibition of glutamate synaptic transmission in rat central amygdala neurons. 1589 34

Glucose or sucrose solutions administered orally provide effective analgesia for procedural pain in neonates. Because analgesia with sugar solutions can be decreased by opioid receptor antagonists, we tested the hypothesis that glucose directly activates opioid receptors. Mu opioid receptors (MOR-1) were expressed in Xenopus oocytes, a well recognized expression system, and glucose was tested for possible agonist, antagonist, and modulatory effects on the receptor. In control experiments, 10 nM of Tyr-D-Ala-Gly-Me-Phe-Gly-ol (DAMGO), a synthetic enkephalin and specific mu agonist, activated the MOR-1, whereas 20 mM of glucose had no effect. In addition, glucose had no effect on the activation of the mu receptor by DAMGO. Finally, glucose did not modulate acute receptor desensitization induced by DAMGO. We conclude that glucose does not directly interact with MOR-1 in an in vitro expression system and that the purported interaction between glucose and the opioid system may be an indirect one, involving release of endogenous opioids.
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PMID:Sugar solution analgesia: the effects of glucose on expressed mu opioid receptors. 1597 7


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