Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0344307 (analgesia)
 28,200 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To determine whether or not the CNS inhibitory activity of eel calcitonin (eCT) on adenylyl cyclase is the endocellular mechanism underlying the antinociceptive effect of the peptide, as shown for morphine analgesia, we administered Bordetella pertussis toxin (PTX) by intracerebroventricular (ICV) injection (0.5 microgram/rat) to block the receptor-mediated inhibition of adenylyl cyclase. In PTX-treated rats there was no change in eCT (2.5 micrograms/rat, ICV)-induced antinociceptive activity (hot-plate test) nor in eCT (100 ng/rat, ICV) inhibition of gastric acid secretion (Shay test) whereas morphine (5 micrograms/rat, ICV) analgesia was significantly reduced. In vitro studies showed no reduction of eCT binding in the CNS of rats treated with PTX in vivo. Moreover, PTX treatment did not change the inhibitory effect of eCT on adenylyl cyclase in isolated membranes from rat striatum in contrast with opiates (DAME and morphine) whose effects were lost. As PTX is known to inactivate the guanidine binding inhibitory protein Gi, these data suggest that a G protein, distinct from the Gi protein involved in the coupling of opiate receptors into a functional response, could be responsible for regulating the intracellular pathways resulting in eCT-induced antinociceptive effect and inhibition of gastric acid secretion.
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PMID:Treatment with pertussis toxin does not prevent central effects of eel calcitonin. 165 2

The periaqueductal gray (PAG) region of the midbrain has been implicated in both stimulation-produced and opioid-induced analgesia. High-affinity mu-selective opioid-binding sites associated with mu type opioid receptors have been detected in rat PAG-enriched P2 membranes, and these receptors have been shown to be coupled to guanine nucleotide-binding proteins (G-proteins). In the present study the potential G-protein-mediated coupling of mu type opioid receptors to the inhibition of adenylyl cyclase was examined utilizing in vitro adenylyl cyclase assays. In the presence of Na+, opioid agonists inhibited adenylyl cyclase in a mu selective, naloxone reversible, dose dependent, and pertussis toxin sensitive manner. Overall the data suggests that mu type opioid receptors in the rat PAG are coupled to G-protein-mediated inhibition of adenylyl cyclase.
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PMID:Mu type opioid receptors in rat periaqueductal gray-enriched P2 membrane are coupled to G-protein-mediated inhibition of adenylyl cyclase. 254 57

A heptadecapeptide was identified and purified from porcine brain tissue as a ligand for an orphan heterotrimeric GTP-binding protein (G protein)-coupled receptor (LC132) that is similar in sequence to opioid receptors. This peptide, orphanin FQ, has a primary structure reminiscent of that of opioid peptides. Nanomolar concentrations of orphanin FQ inhibited forskolin-stimulated adenylyl cyclase activity in cells transfected with LC132. This inhibitory activity was not affected by the addition of opioid ligands, nor did the peptide activate opioid receptors. Orphanin FQ bound to its receptor in a saturable manner and with high affinity. When injected intracerebroventricularly into mice, orphanin FQ caused a decrease in locomotor activity but did not induce analgesia in the hot-plate test. However, the peptide produced hyperalgesia in the tail-flick assay. Thus, orphanin FQ may act as a transmitter in the brain by modulating nociceptive and locomotor behavior.
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PMID:Orphanin FQ: a neuropeptide that activates an opioidlike G protein-coupled receptor. 748 66

Opiate receptor occupation leads to a variety of intracellular events including inhibition of adenylyl cyclase and cAMP formation. We have examined the opiate binding characteristics, effects on cAMP formation and [3H]noradrenaline release of morphine, morphine-6 (M6G) and -3 (M3G)-glucuronides, and fentanyl in SH-SY5Y human neuroblastoma cells. M6G and M3G are the major metabolites of morphine formed in vivo whose cellular action remains to be fully elucidated. In binding experiments morphine (affinity, K50 = 96 nM) and fentanyl (K50 = 99 nM) were more potent than M6G (K50 = 393 nM), while M3G was inactive. However, for cAMP inhibition morphine (half maximum inhibition, IC50 = 193 nM) and M6G (IC50 = 113 nM) were roughly equipotent, with fentanyl (IC50 = 27 nM) being more potent and producing a greater maximum inhibition (56%). M3G was inactive. These in vitro data are in general agreement with the in vivo effects of these glucuronides. Moreover, all of the opiates tested failed to inhibit K(+)-evoked release of [3H]noradrenaline. Whilst these data do not support a role for cAMP in neurotransmitter release, alterations in cAMP formation may still have a role to play in the mechanism of analgesia.
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PMID:Effects of morphine and its metabolites on opiate receptor binding, cAMP formation and [3H]noradrenaline release from SH-SY5Y cells. 821 64

Cannabimimetic compounds, such as delta 9-tetrahydrocannabinol (delta 9-THC), evoke analgesia in addition to other behavioral responses in humans and animals. The cannabinoid receptor mediating this response has been characterized by its ability to bind the cannabinoid agonist [3H]CP-55,940 and to inhibit adenylyl cyclase via Gi. An investigation of structural requirements for antinociceptive activity of cannabinoid structures led to the development of a simple bicyclic cannabinoid agonist, CP-47,497, that possessed a spectrum of cannabinoid activities in animals that resembled that of delta 9-THC. The present investigation examines several series of CP-47,497 analogs for their binding affinity at the cannabinoid receptor and their ability to evoke analgesia in rodents. Analogs substituted at the C-3 alkyl side chain exhibited maximal affinity for the cannabinoid receptor with side chains of seven or eight carbons in length. Analgesic potency paralleled the receptor-binding affinity. The cyclohexyl ring was optimized as a six- or seven-membered ring structure for binding as well as analgesic activity. Cyclohexyl alkyl side chain extensions of up to four carbons in length had little influence on the affinity for the receptor or analgesic activity. Hydroxyalkyl side chains exhibited optimal binding affinity and antinociceptive activity at three or four carbon atoms in length; however, polar groups closer to the ring diminished binding to the receptor. The importance of the phenolic and cyclohexyl hydroxyl groups for binding affinity was demonstrated. In general, analgesic activity correlated well with the affinity of these analogs for the cannabinoid receptor. Exceptions could be explained by metabolic transformations likely to occur in vivo.
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PMID:Structure-activity relationships for cannabinoid receptor-binding and analgesic activity: studies of bicyclic cannabinoid analogs. 824 4

Chronic morphine administration induces an up-regulation of several components of the cyclic adenosine 5'-monophosphate (cAMP) signal transduction cascade. The behavioral and biochemical consequences of opiate withdrawal were investigated in mice with a genetic disruption of the alpha and Delta isoforms of the cAMP-responsive element-binding protein (CREB). In CREBalphadelta mutant mice the main symptoms of morphine withdrawal were strongly attenuated. No change in opioid binding sites or in morphine-induced analgesia was observed in these mutant mice, and the increase of adenylyl cyclase activity and immediate early gene expression after morphine withdrawal was normal. Thus, CREB-dependent gene transcription is a factor in the onset of behavioral manifestations of opiate dependence.
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PMID:Reduction of morphine abstinence in mice with a mutation in the gene encoding CREB. 870 16

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

Mu opioid receptors mediate the analgesia induced by morphine. Prolonged use of morphine causes tolerance development and dependence. To investigate the molecular basis of tolerance and dependence, the cloned mouse mu opioid receptor with an amino-terminal epitope tag was stably expressed in human embryonic kidney (HEK) 293 cells, and the effects of prolonged opioid agonist treatment on receptor regulation were examined. In HEK 293 cells the expressed mu receptor showed high affinity, specific, saturable binding of radioligands and a pertussis toxin-sensitive inhibition of adenylyl cyclase. Pretreatment (1 h, 3 h, or overnight) of cells with 1 microM morphine or [D-Ala2MePhe4,Gly(ol)5]enkephalin (DAMGO) resulted in no apparent receptor desensitization, as assessed by opioid inhibition of forskolin-stimulated cAMP levels. In contrast, the morphine and DAMGO pretreatments (3 h) resulted in a 3-4-fold compensatory increase in forskolin-stimulated cAMP accumulation. The opioid agonists methadone and buprenorphine are used in the treatment of addiction because of a markedly lower abuse potential. Pretreatment of mu receptor-expressing HEK 293 cells with methadone or buprenorphine abolished the ability of opioids to inhibit adenylyl cyclase. No compensatory increase in forskolin-stimulated cAMP accumulation was found with methadone or buprenorphine; these opioids blocked the compensatory effects observed with morphine and DAMGO. Taken together, these results indicate that methadone and buprenorphine interact differently with the mouse mu receptor than either morphine or DAMGO. The ability of methadone and buprenorphine to desensitize the mu receptor and block the compensatory rise in forskolin-stimulated cAMP accumulation may be an underlying mechanism by which these agents are effective in the treatment of morphine addiction.
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PMID:Differential opioid agonist regulation of the mouse mu opioid receptor. 899 64

2-Arachidonoyl-glycerol (2-Ara-GI) has been isolated from various tissues and identified as an endogenous ligand for both cannabinoid receptors, CB1 and CB2. Here we report that in spleen, as in brain and gut, 2-Ara-GI is accompanied by several 2-acyl-glycerol esters, two major ones being 2-linoleoyl-glycerol (2-Lino-Gl) and 2-palmitoyl-glycerol (2-Palm-Gl). These two esters do not bind to the cannabinoid receptors, nor do they inhibit adenylyl cyclase via either CB1 or CB2; however, they significantly potentiate the apparent binding of 2-Ara-Gl and its apparent capacity to inhibit adenylyl cyclase. Together these esters also significantly potentiate 2-Ara-Gl inhibition of motor behavior, immobility on a ring, analgesia on a hot plate and hypothermia caused by 2-Ara-Gl in mice. 2-Lino-Gl, but not 2-Palm-GI, significantly inhibits the inactivation of 2-Ara-Gl by neuronal and basophilic cells. These data indicate that the biological activity of 2-Ara-Gl can be increased by related, endogenous 2-acyl-glycerols, which alone show no significant activity in any of the tests employed. This effect ('entourage effect') may represent a novel route for molecular regulation of endogenous cannabinoid activity.
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PMID:An entourage effect: inactive endogenous fatty acid glycerol esters enhance 2-arachidonoyl-glycerol cannabinoid activity. 972 Oct 36

Previous pharmacological studies have indicated the possible existence of functional interactions between mu-, delta- and kappa-opioid receptors in the CNS. We have investigated this issue using a genetic approach. Here we describe in vitro and in vivo functional activity of delta- and kappa-opioid receptors in mice lacking the mu-opioid receptor (MOR). Measurements of agonist-induced [35S]GTPgammaS binding and adenylyl cyclase inhibition showed that functional coupling of delta- and kappa-receptors to G-proteins is preserved in the brain of mutant mice. In the mouse vas deferens bioassay, deltorphin II and cyclic[D-penicillamine2, D-penicillamine5] enkephalin exhibited similar potency to inhibit smooth muscle contraction in both wild-type and MOR -/- mice. delta-Analgesia induced by deltorphin II was slightly diminished in mutant mice, when the tail flick test was used. Deltorphin II strongly reduced the respiratory frequency in wild-type mice but not in MOR -/- mice. Analgesic and respiratory responses produced by the selective kappa-agonist U-50,488H were unchanged in MOR-deficient mice. In conclusion, the preservation of delta- and kappa-receptor signaling properties in mice lacking mu-receptors provides no evidence for opioid receptor cross-talk at the cellular level. Intact antinociceptive and respiratory responses to the kappa-agonist further suggest that the kappa-receptor mainly acts independently from the mu-receptor in vivo. Reduced delta-analgesia and the absence of delta-respiratory depression in MOR-deficient mice together indicate that functional interactions may take place between mu-receptors and central delta-receptors in specific neuronal pathways.
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PMID:Activity of the delta-opioid receptor is partially reduced, whereas activity of the kappa-receptor is maintained in mice lacking the mu-receptor. 973 49


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