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)

At the present time there is evidence for two families of related peptides which act as ligands for opiate receptor sites. The endorphin group of peptides are derived from the ACTH/LPH precursor pro-opiocortin. The enkephalins appear to be formed from a separate precursor or precursors that have yet to be fully characterized. There appear to be a number of different types of opiate receptors and this may be related to the multiplicity of peptide ligands that have so far been identified. The enkephalins and related peptides appear to have a much wider distribution than the endorphins but the latter may act as circulating hormones unlike the enkephalins. It is likely that both endorphins and enkephalins are involved in sensory modulation processes and release of these peptides has been demonstrated during brain stimulation for pain relief. The enkephalins are very rapidly inactivated by tissue proteases, the aminopeptidases appear largely responsible for the inactivation of exogenously administered enkephalins but the dipeptidyl carboxypeptidase, termed enkephalinase, may have a special inactivating function at enkephalinergic synapses. Evidence will be presented for the biosynthesis, the release and inactivation of the enkephalins relating to the above points.
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PMID:Opioid peptides: aspects of their origin, release and metabolism. 625 71

The effect of the inhibition of aminopeptidase and enkephalinase A on the pain threshold of mice and rats was investigated, using bestatin and thiorphan as selective peptidase inhibitors. The results indicate that both enzymes are relevant to the catabolism of enkephalins in vivo; however, their simultaneous activation requires particular conditions. These conclusions are based on the following observations: (1) Only concomitant intracerebral treatment with both inhibitors led to an increase in the threshold of animal pain, whereas, in the presence of exogenous peptides, the concomitant injection of both inhibitors in mice elicited an analgesic response greater than the sum of the effects of each single inhibitor. (2) This response could be seen only after acute trauma; in fact, when the drugs were injected through a plastic cannula, only enkephalinase A inhibition was effective in increasing analgesia induced by exogenous peptides.
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PMID:Effect of inhibition of neuropeptidases on the pain threshold of mice and rats. 636 60

Spontaneously hypertensive (SH), Wistar Kyoto (WKY) or Sprague-Dawley (SD) rats were tested for their responsiveness to noxious mechanical pressure before and after a subplantar yeast injection to the right rear paw. Prior to the yeast injection, hypertensive animals were less responsive to pain relative to normotensive animals, as seen in the significantly greater pre-yeast latencies of SH compared to WKY or SD rats. Subplantar yeast injection produced hyperreactivity in the inflamed paws of WKY or SD rats, with no effect on the contralateral non-injected paw. However, identical subplantar yeast injections to hypertensive animals produced a robust, long-lasting antinociceptive effect in both rear paws of SH rats. This effect was not reversed by naloxone (opiate antagonist), labetalol (beta-blocker/vasodilator antihypertensive), or hydralazine (peripheral vasodilator antihypertensive); the antinociception was not potentiated by thiorphan (enkephalinase inhibitor). However, the alpha 2-receptor antagonist yohimbine (0.1-5 mg/kg s.c.), produced a dose-related reversal of the yeast-induced antinociception in SH rats. These results suggest that the subplantar yeast injection is triggering descending noradrenergic pain inhibitory pathways in SH rats.
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PMID:Subplantar yeast injection induces a non-naloxone reversible antinociception in spontaneously hypertensive rats. 673 19

The role of endogenous opioids in modulating pain transmission in amphibians was examined by two methods known to activate endogenous opioids in mammals. Analgesia was assessed using the acetic acid test in the Northern grass frog, Rana pipiens. One or 2 h of immobilization produced a significant analgesia lasting for at least 90 min. Systemic, but not spinal, administration of naloxone before immobilization prevented the analgesic effects seen in saline-pretreated controls. Spinal administration of the enkephalinase inhibitor, thiorphan, but not bestatin (both at 100 nmol/frog), produced significant analgesia. The analgesic effect of thiorphan was blocked by coadministration of intraspinal naloxone. These data are the first to suggest a role for endogenous opioid modulation of noxious stimuli in lower vertebrates by examination of stress-induced analgesia and the action of agents that inhibit enkephalin degradation.
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PMID:Analgesia produced by immobilization stress and an enkephalinase inhibitor in amphibians. 767 42

Two analogues of the aminopeptidase inhibitor bestatin, Z 4212 (N-[(2S, 3R)-3-Amino-2-hydroxy-4-(4-methylsulphonyl-phenyl)-1-oxobutyl]-1- aminocyclopentanecarboxylic) and Z 1796 ((2S)-N-[(2S,3R)-3-Amino-2-hydroxy-4-(4-methylsulphonyl-phenyl)-1- oxobutyl]-L-leucine) were found to behave as hypoalgesics when intracerebroventricularly (i.c.v.) administered to mice in the hot-plate test. At high doses, Z 4212 was also found to reduce the pain threshold after intraventricular (i.v.) administration. Hypoalgesia induced by bestatin analogues was prevented by prior treatment with the opiate receptor blocker naloxone. Thiorphan, a potent inhibitor of NEP, was found to enhance the hypoalgesic effect of low doses of either Z 4212 or Z 1796. These results indicate that both the major opioid-degrading peptidases, i.e. aminopeptidases and neutral endopeptidase (NEP), are individually implicated in the hypoalgesia induced by peptidase inhibitors. In vitro studies showed that these new bestatin analogues readily inhibit aminopeptidases in membranes from mouse c. striatum whereas more than 1000 times the concentration was required for NEP to be blocked. Ex vivo experiments showed that, at variance with bestatin, the hypoalgesic action of Z 4212 or Z 1796 appeared to implicate central aminopeptidases but not NEP, so partially sparing the metabolism of other NEP substrates that might produce additional alterations (substance P and ANP). On the basis of the antitumour and immunomodulatory actions of bestatin, these new analogues might be potentially useful as mixed antitumour and hypoalgesic agents in malignancy.
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PMID:Hypoalgesic action of bestatin analogues that inhibit central aminopeptidases, but not neutral endopeptidase. 824 55

A limited number of enzymes such as membrane metalloendopeptidase (enkephalinase) and angiotensin converting enzyme appear to be involved in deactivation and modulation of circulatory regulatory peptides. Peptides such as the enkephalins are also involved in a large number of physiological processes. This multiplicity of physiological roles has made it difficult to establish the therapeutic role of enkephalin-degrading enzyme inhibitors. Other factors such as difficulty in quantification and thus measurement of processes involved in pain and mental illness have also hindered the process of establishing any therapeutic role of enkephalin-degrading enzyme inhibitors in these conditions. However, they have proved to be useful pharmacological 'tools'. The most likely therapeutic role at present appears to be in the treatment of cardiovascular disorders. As a 'profile' of pharmacological actions of enkephalin-degrading enzymes emerges, it is becoming apparent that bioavailability rather than a high degree of specificity or inhibitory potency may be the most important factor. This may be used to an advantage in future developments by the use of less specific or combined inhibitors in the form of prodrugs, designed to be active at specific sites such as the central nervous system.
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PMID:Inhibitors of enkephalin-degrading enzymes as potential therapeutic agents. 830 36

Cholecystokinin (CCK) may act as an endogenous anti-opioid and blockade of CCK receptors can enhance the potency and efficacy of morphine. This effect is blocked by opioid delta (delta) receptor antagonists, suggesting a tonic inhibitory action of CCK to diminish the release and/or availability of endogenous enkephalins. The present studies have further evaluated this possibility by studying the antiallodynic actions of a CCKB antagonist (L365,260) alone, or in the presence of thiorphan (a neutral endopeptidase inhibitor) in a model of peripheral neuropathy. Animals subjected to nerve injury, but not sham controls, exhibited long lasting, stable mechanical allodynia. Intrathecal (i.t.) administration of L365,260 or thiorphan alone did not alter allodynia. However, co-administration of these compounds produced a significant antiallodynic action which was antagonized by receptor selective doses of naltrindole, an opioid delta receptor antagonist. In addition, antisera to [Leu5]enkephalin, but not to [Met5]enkephalin, also blocked the antiallodynic action of thiorphan plus L365,260. These data suggest that blockade of CCKB receptors may enhance the actions or availability of endogenous [Leu5]enkephalin or a like substance which can elicit a significant antiallodynic action via opioid delta receptors when its degradation is by inhibited by thiorphan. The data suggest that delta opioids are involved in regulation of some aspects of nerve-injury induced pain.
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PMID:Antiallodynic effects of a CCKB antagonist in rats with nerve ligation injury: role of endogenous enkephalins. 889 38

The endogenous opioid receptor-like1 (ORL1) ligand, nociceptin/orphanin FQ (FGGFTGARKSARKLANQ), a heptadecapeptide structurally resembling dynorphin A, has recently been identified. The wide distribution of ORL1 mRNA and nociceptin/orphanin FQ precursor in the CNS, particularly in the limbic system regions and in several areas known to be involved in pain perception, suggests that nociceptin/orphanin FQ is potentially endowed with various central functions. In general, activation and/or inactivation of regulatory peptides occur through the action of cell surface peptidases. The physiological mechanisms under which nociceptin/orphanin FQ is metabolized should lead to a better understanding of its physiological functions. Mouse brain cortical slices were incubated in medium containing the heptadecapeptide in the presence or in the absence of peptidase inhibitors. The critical sites of enzymatic cleavage are Phe1-Gly2, Ala7-Arg8, Ala11-Arg12, and Arg12-Lys13 bonds. The major role played by metallopeptidases was confirmed by the complete protection of metabolism in the presence of EDTA. Aminopeptidase N and endopeptidase 24.15 are the two main enzymes involved in nociceptin/orphanin FQ metabolism, whereas endopeptidase 24.11 (involved in enkephalin [YGGFM(L)] catabolism) does not appear critically involved in nociceptin/orphanin FQ metabolism. The physiological relevance of aminopeptidase N and endopeptidase 24.15 in the heptadecapeptide metabolism remains to be determined.
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PMID:Nociceptin/orphanin FQ metabolism: role of aminopeptidase and endopeptidase 24.15. 897 46

Certain types of cancer pain fail to respond well either to systemic drug therapy or to spinal opioids because of the occurrence of intolerable adverse effects. In addition to spinal opioids other drugs may produce an antinociceptive effect when administered by the spinal route, such as local anesthetics, NSAID, alpha 2-agonists, calcium-channel blockers, NMDA antagonists, cholinergic drugs, peptides such as somatostatin, octreotide or calcitonin, adenosine agonists, benzodiazepines, neurokinin and cholecystokinin antagonists, nitric oxide synthase inhibitors, corticosteroids, and enkephalinase inhibitors. All these drugs may be administered in combination between them, realising the so called balanced spinal analgesia. The aim of this study is to analyse: the available methods for the evaluation of pharmacological interactions, the types of interaction between different spinal antinociceptive drugs and the role of balanced spinal analgesia in the treatment of cancer pain. Analysis of the presented data shows that the spinal synergism between opioids-local anesthetics and opioids-alpha 2-agonists can be useful in the treatment of opioid refractory cancer pain. Furthermore, the use of cholinergic drugs combined with opioids and alpha 2-agonists may be promising. Finally, even if the synergism between NSAID or NMDA antagonists with opioids or alpha 2-agonists have been proved, at the moment their use in man by the spinal route is not advisable because of the absence of adequate studies on their neurotoxicity and adverse effects.
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PMID:[Balanced spinal analgesia in the treatment of oncologic pain. Review of the literature]. 910 86

RB 101 (N-((R,S)-2-benzyl-3[(S)(2-amino-4-methylthio)butyldithio]-1-oxopr opyl)-L-phenylalanine benzyl ester) is a full inhibitor of the enkephalin-catabolizing enzymes, which induces strong naloxone-reversible antinociceptive responses after i.v. or i.p. administration, but is only slightly active after oral administration. Chemical modifications were introduced on this compound, resulting in molecules such as RB 120 (N-((S)-2-benzyl-3[(S)(2-amino-4-methylthio)butyldithio]-1-oxoprop yl)-L-alanine benzyl ester), which was selected for a complete study, after oral administration, in various assays commonly used to select analgesics: mouse hot plate test, rat tail-flick test, electrical stimulation of the tail in rats, paw pressure test on inflamed paws in rats, acetic acid-induced writhing test and the formalin test in mice. RB 120 induced potent dose-dependent antinociceptive responses in all these tests after oral administration. The differences in antinociceptive effects induced by RB 120 in the various assays is probably related to the amount of enkephalins released and to the efficiency of peptidase inactivation in particular brain regions implicated in the control of a given nociceptive input. The goal of discovering orally active analgesics endowed with a potency similar to that of morphine but devoid of its major side-effects, seems now to have been reached with mixed neutral endopeptidase/aminopeptidase N (NEP/APN) inhibitors, although these compounds have yet to be evaluated in clinical trials.
Pain 1997 Dec
PMID:Pain-suppressive effects on various nociceptive stimuli (thermal, chemical, electrical and inflammatory) of the first orally active enkephalin-metabolizing enzyme inhibitor RB 120. 946 29


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