Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Jimpy (B6CBA-A W-J/A-Ta jp) mice, which are known to be deficient in neuronal cerebroside sulfate (a putative component of the mu opioid receptor), were non-responsive in the tail flick test (compared to littermate controls and a standard Swiss strain of mouse) to analgesic doses of two mu opioid receptor agonists, morphine sulfate and [D-Ala2,MePhe4,Gly-ol5]enkephalin (DAGO). However, the jimpy mice responded normally (compared to controls) to the analgesic effects of the selective delta opioid receptor agonist [D-Pen2,L-Pen5]enkephalin (DPLPE). These results suggest (1) that delta opioid receptors can mediate analgesia and (2) that cerebroside sulfate is not necessary for delta opioid receptor activation.
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PMID:[D-Pen2,L-Pen5]enkephalin induced analgesia in the jimpy mouse: in vivo evidence for delta-receptor mediated analgesia. 303 73

In vitro data demonstrate that metkephamid (LY127623), an analog of methionine enkephalin, has a high affinity for the delta opioid receptor, as well as the mu-receptor. Data generated utilizing two in vivo measures of receptor selectivity, furthermore, indicate that metkephamid's analgesic activity is in part mediated by delta opioid receptors. The analgesic activity of metkephamid was investigated in the mouse writhing assay following chronic treatment with morphine, the prototypic mu agonist. Mice were treated chronically with increasing doses of morphine or saline and the inhibition of writhing measured in response to an acute injection of morphine or metkephamid. The dose response curve for morphine was shifted to the right 3- to 4-fold following chronic administration of morphine. In contrast, no such shift in the dose response curve for metkephamid was observed in these morphine-tolerant mice. In a further series of tests, a 50 mg/kg dose of naloxazone 20 hr prior to the assessment of morphine or metkephamid analgesia in the mouse hot plate test substantially shifted the dose-response curve for morphine to the right, while leaving the dose-response curve for metkephamid unchanged. These results suggest that delta-receptor activation contributes to the analgesia produced by metkephamid.
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PMID:Cross-tolerance studies distinguish morphine- and metkephamid-induced analgesia. 629 9

Morphiceptin (Tyr-Pro-Phe-Pro-NH2), a nonenkephalin peptide, is an opioid agonist highly selective for mu opiate receptors. Chemical modification of Tyr-Pro-Phe-Pro-NH2 was carried out by substituting structurally related amino acids at residues 2, 3 and 4. The morphiceptin analogs synthesized were then examined for receptor binding activities using 125I-labeled FK 33,824 (Tyr-D-Ala-Gly-NMePhe-Met(O)-ol) as the mu-ligand and 125I-labeled D-Ala2,D-Leu5-enkephalin as the delta-ligand, and for inhibitory activities on electrically evoked smooth muscle contraction of mouse vas deferens and isolated myenteric plexus-longitudinal muscle strips of guinea-pig ileum. All of these analogs showed virtually no activity at delta opiate receptor binding sites. Methylation of the nitrogen atom of phenylalanine and the substitution at the C-terminal of L-proline by D-proline produced potent mu-agonists, the prototype analog being Tyr-Pro-NMePhe-D-Pro-NH2 (PL017). The IC50 values of morphiceptin and its analogs for mu receptor binding were correlated to the ED50 values in the guinea-pig ileum assay, suggesting that the ileum effects were mediated by mu receptor interactions. A similar correlation between mu receptor binding activity and the ED50 values in the mouse vas deferens assay suggested that morphiceptin and its analogs also acted on mu receptors in this tissue. This idea is supported by the observation that naloxone has a high pA2 value of 8.71 against PL017 in mouse vas deferens. In in vivo studies, PL017 administered centrally into the rostral portion of the 4th ventricle produced long-lasting, naloxone-reversible analgesia in rats.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Potent morphiceptin analogs: structure activity relationships and morphine-like activities. 631 1

Conformationally constrained cyclic enkephalin analogs which possess a high selectivity for the delta opioid receptor were used to determine the relative contribution of mu and delta receptors to brain-mediated changes in small intestinal propulsion and increases in hot-plate response time. Receptor preferences were determined by comparing the relative potencies of several opioid agonists in suppressing the electrically evoked contractions of the guinea-pig ileum and mouse vas deferens preparations. The ratio of IC50 values obtained in the guinea-pig ileum and the mouse vas deferens was used as an index of delta receptor selectivity. Effects on intestinal transit were determined in rats in which a silastic cannula had been implanted in the proximal duodenum and a polyethylene cannula in the right lateral cerebral ventricle (i.c.v.). Movement of a radioactive marker along the length of the small intestine after instillation into the duodenum was used to evaluate drug-induced changes in intestinal transit. The analgesic effects of i.c.v. administered opioids were determined in a second group of rats in which i.c.v. cannulas alone had been implanted. After i.c.v. administration of the agonist, the rats were placed on a 55 degrees C hot plate and the latency to rear paw-lick was timed. Compounds which showed a preference for the mu receptor [( D-Ala2, N-methyl-Phe4, Gly5 -ol]enkephalin and morphine/normorphine) were the most potent agonists at producing thermal analgesia and inhibition of small intestinal transit, whereas nonselective compounds (beta-endorphin and [D-Ala2, Met5]enkephalinamide) were slightly less potent in these assays.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Cerebral delta opioid receptors mediate analgesia but not the intestinal motility effects of intracerebroventricularly administered opioids. 632 67

Opioid effects of 14 beta-(thioglycolamido)-7,8-dihydro-N(cyclopropylmethyl)- normorphinone (N-CPM-TAMO) were studied in the mouse tail-flick and acetic acid writhing assays. In the tail-flick test, N-CPM-TAMO failed to produce any antinociception after i.c.v. administration of up to 300 nmol. However, pretreatment of mice with N-CPM-TAMO produced a time- and dose-dependent antagonism of morphine-induced antinociception. The antagonism by N-CPM-TAMO lasted up to 48 hr, with a maximal effect at 24 hr after i.c.v. administration. Similarly, pretreatment of mice with N-CPM-TAMO at 24 hr also produced a dose-dependent antagonism of kappa-mediated antinociception, induced by U50,488 However, the antagonistic potency of N-CPM-TAMO against U50,488 was 100-fold less than against morphine. Pretreatment with N-CPM-TAMO had no effect on delta opioid receptor-mediated antinociception, as measured with [D-Pen2,D-Pen5]enkephalin. In the writhing assay, N-CPM-TAMO produced a time- and dose-dependent antinociception after i.c.v. administration, with a value of the dose producing 50% analgesia of 18.4 (10.6-31.9) nmol. The antinociceptive effect lasted up to 3 hr after administration. N-CPM-TAMO-induced antinociception was antagonized by coadministration of the kappa-selective antagonist, norbinaltorphimine. Pretreatment of mice with N-CPM-TAMO also produced a time- and dose-dependent antagonism of U50,488-induced antinociception, which lasted up to 72 hr, with a maximal effect at 24 hr after administration. These data indicate that N-CPM-TAMO is a mu-selective, long-term antagonist.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Pharmacological study of 14 beta-(thioglycolamido)-7,8-dihydro-N(cyclopropylmethyl)-normor phinone (N-CPM-TAMO). 768 Jul 15

Opioid tolerance is a significant clinical phenomenon. Patients may develop opioid tolerance within several hours even after a single bolus of opioid. Animal studies have revealed that there were two kinds of opioid tolerance, namely acute opioid tolerance and chronic opioid tolerance. Acute opioid tolerance may develop within 4 hours after a single bolus of fentanyl or morphine, and 1 hour after a single injection of alfentanil. Chronic opioid tolerance may develop with an incubation period of 8-10 days and last for a long period. The characteristics of acute opioid tolerance may differ from those of chronic opioid tolerance. The mechanisms underlying acute and chronic opioid tolerance are not well studied and need to be further explored. However, in the future, the combined administration of delta opioid receptor antagonists or opioid agonist-antagonists along with opioid agonist (such as morphine) may not only provide less opioid tolerance but also maintain adequate analgesia in clinical practice.
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PMID:Acute and chronic opioid tolerance: a pharmacological review. 789 24

Intrathecal administration of morphine, Tyr-D-Ser(otbu)-Gly-Phe-Leu-Thr or dexmedetomidine for 5 to 10 days rendered rats tolerant to the test drug as measured by both behavioral and electrophysiological tests. Tolerance to the alpha-2 adrenergic agonist dexmedetomidine required a longer induction time and was not as pronounced as the tolerance to the opioid agonists, probably because lower doses of dexmedetomidine relative to the ED50 dose were used to avoid sedation. In the behavioral studies we used the tail-flick test and in the electrophysiological studies recordings were made from dorsal horn nociceptive neurons under halothane anesthesia. After completion of the behavioral testing the same animals were then used in the electrophysiological study. Cross-tolerance developed clearly between the mu opioid agonist morphine and the alpha-2 adrenergic agonist dexmedetomidine, whereas no cross-tolerance was seen between the delta opioid agonist Tyr-D-Ser(otbu)-Gly-Phe-Leu-Thr and either morphine or dexmedetomidine. This is further evidence to support the assumption that in the dorsal horn the mu opioid and the alpha-2 adrenergic receptor are linked functionally, whereas the delta opioid receptor operates independently. These results have also important clinical implications indicating the potential of delta opioid agonists to restore analgesia in a morphine-tolerant patient.
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PMID:Cross-tolerance between mu opioid and alpha-2 adrenergic receptors, but not between mu and delta opioid receptors in the spinal cord of the rat. 809 59

Antisense oligodeoxynucleotides (18-20 bases) to a cloned delta opioid receptor (DOR-1) lower delta binding in NG108-15 cells by 40%-50%. Changing 4 bases to generate a mismatch antisense oligodeoxynucleotide or mixing the corresponding sense and antisense oligodeoxynucleotides prior to treatment of the cells eliminates the inhibition of binding, confirming the specificity of the response. In vivo, an antisense oligodeoxynucleotide to DOR-1 given intrathecally lowers delta, but not mu or kappa 1 spinal analgesia. The mismatch antisense oligodeoxynucleotide is inactive. Delta analgesic sensitivity gradually returns by 5 days after the last antisense treatment, indicating the lack of irreversible damage or toxicity. These studies demonstrate that DOR-1 mediates delta analgesia at the level of the spinal cord and confirm at the molecular level traditional pharmacological studies implying distinct receptor mechanisms for delta, mu, and kappa 1 analgesia. The use of antisense approaches may prove valuable in understanding the receptors mediating opioid pharmacology.
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PMID:Selective loss of delta opioid analgesia and binding by antisense oligodeoxynucleotides to a delta opioid receptor. 816 52

The effects of endogenous opioid peptides are limited by proteolytic enzymes such as endopeptidase 24.11 ("enkephalinase"), which cleaves the Gly-Phe bonds in Met- and Leu-enkephalin. SCH 34826 [(S)-N-[n-[1-[(2,2-dimethyl-1,3-dioxolan-4- yl)methoxy]carbonyl]-2-phenylethyl]-L-phenyl-alanine-B-alanine] is a potent, highly specific, enkephalinase inhibitor that has marked analgesic effects in laboratory rodents. The present study compared the effects of SCH 34826 on nociception and restraint stress-induced opioid analgesia in reproductive adult male and female deer mice, Peromyscus maniculatus. SCH 34826 had significantly greater antinociceptive actions and facilitatory effects on stress-induced analgesia in male than female mice. These antinociceptive effects of SCH 34826 were reduced by the general opioid antagonist naloxone and completely blocked by the specific delta opioid receptor antagonist, ICI 174,864, and nonsignificantly affected by the mu and kappa opioid receptor antagonists, beta-funaltrexamine and nor-binaltorphimine, respectively. These results show that there are sex differences in the effects of the enkephalinase inhibitor, SCH 34826, on opioid-mediated antinociception and that these sex differences are associated with delta opioid mechanisms.
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PMID:Sex differences in the antinociceptive effects of the enkephalinase inhibitor, SCH 34826. 830 54

Pharmacological data from several laboratories support a modulatory role for the delta opioid receptor in morphine analgesia, tolerance, and physical dependence. We examined the role of the delta opioid receptor in these processes using an in vivo antisense strategy in mice. Intracerebroventricular administration of a 20mer antisense or a mismatch control oligodeoxynucleotide (ODN) targeting the mRNA of the cloned delta opioid receptor (DOR-1) for 3 days did not affect baseline nociceptive thresholds or morphine analgesia compared to untreated or saline-treated mice. However, dose-response studies indicate that the induction of morphine tolerance following 3 days of chronic morphine administration was blocked in antisense but not mismatch ODN or saline-treated mice. Antisense ODN treatment also blocked the development of acute morphine dependence, whereas similar protection was not afforded to mice treated with saline or mismatch ODN. This study demonstrates the relevance of the cloned DOR-1 in morphine tolerance and dependence and provides new evidence for a modulatory role of the delta opioid receptor using this novel approach.
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PMID:An antisense oligodeoxynucleotide to the delta opioid receptor (DOR-1) inhibits morphine tolerance and acute dependence in mice. 886 95


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