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)

We designed phethiol (1-amino-1-benzyl-2-mercaptoethane) as a potent and selective inhibitor of Zn-containing aminopeptidases. This compound inhibited purified aminopeptidase M (EC.3.4.11.2) with a Ki of 5 nM but was at least 1000 times less potent against other metallopeptidases comprising angiotensin-converting enzyme EC 3.4.15.1), enkephalinase (EC 3.4.24.11), thermolysin (EC 3.4.24.4), or dipeptidylaminopeptidases. Phethiol alone significantly but partially protected endogenous (Met5) enkephalin released from depolarized brain slices, total protection being achieved when it was associated with an enkephalinase inhibitor. In order to obtain a parenterally-active inhibitor of cerebral aminopeptidases, the prodrug carbaphetiol, a readily hydrolyzable S-phenylcarbamoyl derivative of phethiol, was designed. Carbaphethiol (i.v.) elicited a rapid rise in mouse striatal level of Tyr-Gly-Gly, a characteristic extracellular metabolite of enkephalins. Carbapethiol alone and, even more, when associated with an enkephalinase inhibitor, exerted a potent naloxone-reversible antinociceptive activity. Carbaphethiol appears as the first parenterally-active inhibitor of cerebral aminopeptidases, potentially useful in neuropeptides degradation studies and as a pain-suppressing agent.
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PMID:Potent inhibition of cerebral aminopeptidases by carbaphethiol, a parenterally active compound. 324 26

1. The effect of bradykinin (BK) and some analogues of BK on the human blister base was studied. 2. BK produced reproducible dose-related increases in pain responses. A characteristic delay, which was not dose-related occurred between application of BK and the resultant response. 3. The rank order of potency of several kinin analogues on the pain response was BK much much greater than sigma-cyclo-(Lys1-Gly6)-BK = sigma-cyclo-kallidin greater than des-Arg9-BK. 4. No increase in pain response was seen with repeated application of the selective B1 receptor agonist des-Arg9-BK to the same blister base at 4 h intervals. The B1 receptor antagonist des-Arg9-Leu8-BK was without effect against BK-induced responses. 5. The B2 receptor antagonists, D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-D-Phe-Thi-Arg-TEA and D-Pro-Phe-Arg-heptylamide produced significant antagonism of the bradykinin-induced pain responses at doses which had no effect against 5-hydroxytryptamine or potassium chloride. 6. It is concluded that the kinin receptor mediating pain on the human blister base is of the B2 type.
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PMID:The effect of kinin agonists and antagonists on the pain response of the human blister base. 344 81

Highly sensitive radioimmunoassays were developed and used in studies of the distribution and chromatographic properties of two mammalian FMRF-NH2-like peptides recently isolated from bovine brain; an octapeptide with the structure Phe-Leu-Phe-Gln-Pro-Gln-Arg-Phe-NH2 (F-8-F-NH2) and on octadecapeptide, Ala-Gly-Glu-Gly-Leu-Ser-Ser-Pro-Phe-Trp-Ser-Leu-Ala-Ala-Pro-Gln-Arg-Phe-NH2 (A-18-F-NH2). F-8-F-NH2 and A-18-F-NH2 immunoreactivities are unevenly distributed in bovine brain. The highest concentrations (pmol g-1) of F-8-F-NH2 and A-18-F-NH2 are found in dorsal spinal cord (9.8 and 16.4 respectively), periaqueductal grey (8.6 and 6.8) and pons medulla (7.0 and 8.9); lowest quantities are in cortex, cerebellum and striatum. HPLC analysis coupled with radioimmunoassay reveals that the major immunoreactivities are identical to synthetic F-8-F-NH2 and A-18-F-NH2 while there are additional immunoreactive materials, distinct from NPY, whose structures still remain to be determined. The enrichment of these peptides in dorsal cord and periaqueductal grey, areas important in opioid-mediated pain perception, suggest that they may play a role in mediating antinociception.
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PMID:Distribution and characterization of two putative endogenous opioid antagonist peptides in bovine brain. 362 81

New compounds were designed to fully inhibit the in vitro metabolism of enkephalins, ensured by three different metallopeptidases. For this purpose, bidentate ligands as hydroxamate and N-hydroxy-N-formylamino groups were selected as highly potent metal coordinating agents and introduced on Phe-Gly and Phe-Ala related structures. Compounds corresponding to the general formula HC(O)N(OH)CH2CH(CH2Ph)CONHCH2COOH (compound 7) and HN(OH)C(O)CH2CH(CH2Ph)CONHCH(R)COOH (compound 11, R = H; compound 13, R = CH3) behave as full inhibitors of the three enzymes, with IC50's in the nanomolar range for enkephalinase, from 0.3 microM to 1 nM for dipeptidylaminopeptidase, and in the micromolar range for a biologically relevant aminopeptidase. Two diastereoisomers of the most active inhibitor 13 were separated by HPLC and their stereochemistry was assigned by 1H NMR spectroscopy. Both isomers were efficient as enkephalinase blockers, but only the RS isomer, designated kelatorphan, was able to strongly inhibit aminopeptidase and dipeptidylaminopeptidase. Intracerebroventricular injection in mice of these mixed inhibitors, especially kelatorphan, led to naloxone reversible analgesic responses (hot-plate test) that were slightly better than those produced by a mixture of thiorphan and bestatin, two potent inhibitors of enkephalinase and aminopeptidase, respectively. Kelatorphan was also more efficient in potentiating the analgesia induced by a subanalgesic dose of Met-enkephalin. All these results support a physiological role in pain transmission for enkephalinase and a probably synaptic aminopeptidase M.
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PMID:New bidentates as full inhibitors of enkephalin-degrading enzymes: synthesis and analgesic properties. 389 41

To investigate the role of multiple opiate receptors in spinal mechanisms of antinociception the activity of various opiate receptor agonists was determined against different nociceptive stimuli in the mouse and rat. Intrathecal administration of the putative kappa-receptor agonists dynorphin A (DYN), bremazocine, and ethylketocyclazocine, as well as the delta-agonist D-Ala2,D-Leu5-enkephalin and the mu-agonists, Tyr-D-Ala-Gly-MePhe-NH-(CH2)2OH and morphine resulted in a dose-dependent antinociceptive effect. The order of potencies was similar for visceral and thermal pain. Inhibition of writhing in mice was much more strongly antagonized by MR 2266 than by naloxone, and des-Tyr1-DYN1-13 was 50 times less potent than DYN in this test suggesting that DYN acts through the kappa-receptor. It is concluded that mu-, delta- and kappa-opiate receptors are involved in spinally mediated antinociception related to kinds of noxious stimuli.
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PMID:Analgesic effects of mu-, delta- and kappa-opiate agonists and, in particular, dynorphin at the spinal level. 614 5

The naturally occurring brain peptide Tyr-MIF-1 (Tyr-Pro-Leu-Gly-NH2) was tested for its ability to block and reverse the actions of morphine in the tail-flick test. Injected peripherally either 10 minutes before or after morphine, Tyr-MIF-1, like MIF-1, was found to significantly reduce the antinociceptive actions of morphine on thermal pain. The results indicate that Tyr-MIF-1 may act, in part, as an endogenous opiate antagonist.
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PMID:Tyr-MIF-1 acts as an opiate antagonist in the tail-flick test. 615 69

Vasopressin (VP) neurons project to extrahypothalamic sites involved in pain perception, including the substantia gelatinosa of the spinal cord as well as the trigeminal and vagus nerves. Previous studies have reported antinociceptive activity following intracerebroventricular (ICV) or subcutaneous (SC) VP injections (16-100 microgram) on the tail-flick test while hyperalgesia has been observed in rats either genetically deficient in VP or treated with antisera to VP. The present study investigated whether nanogram (ng) doses of lysine-vasopressin (LVP) and a VP analogue with prolonged activity increased tail-flick latencies and flinch-jump thresholds following ICV or SC injections. LVP (150 and 500 ng, ICV) significantly increased tail-flick latencies while the analogue 1-deamino-(8-Lys-N epsilon-(Gly-Gly-Gly))-VP (500 ng, ICV) produced more powerful and prolonged analgesia. In contrast, latencies were not increased by SC injections of LVP (150-1500 ng). Further, flinch-jump thresholds were affected minimally by either ICV or SC LVP injections. These data suggest a role for VP in pain modulation and a central site of this action.
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PMID:Central antinociceptive effects of lysine-vasopressin and an analogue. 713 29

The effect of intracellular modulators and ions on the analgetic action of the two tetrapeptide analogs, Tyr-D-Ala-Gly-Phe-NH2 and Tyr-D-Ala-Gly-Phe (NO) NH2, was studied in rat experiments. The threshold of pain reaction to electrical stimulation of the tail, evidenced by vocalization, was measured. PGE1, PGE2, PGE2 alpha, cAMP, and dibutyryl cAMP were shown to diminish the effect of the above-mentioned enkephalin analogs. In contrast to cAMP, cGMP was not active in this respect. Among the ions under study (calcium, lithium, rubidium, and cesium), cesium was shown to be the most active. It prevented the increase of the pain reaction threshold and shortened the duration of analgesia. Lithium had no antagonistic effect as regards the enkephalin-induced analgesia. Comparison of these findings with the previously obtained data on the antagonism of the substances under consideration with morphine suggests similarities in the mechanisms of modulation of the effects of opiates and opioids. At the same time the failure of lithium to antagonize the enkephalin analogs and the presence of morphine antagonism point out that the similarities in the mechanisms of ion regulation of exogenous analgetics and enkephalins cannot be regarded as complete enough.
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PMID:[Effect of prostaglandins, cyclic nucleotides and ions on the analgesic effect of enkephalin analogs]. 715 Jul 67

Bone marrow cells of various animal species and men produce a group of bioregulatory peptides called myelopeptides (MPs). A highly purified MP fraction and some individual molecules have been isolated from the supernatant of porcine bone marrow cell cultures by reverse phase chromatography. MPs have a wide spectrum of functional activities: immunoregulatory, differentiating and opiate-like. They evoke 2.5-fold stimulation of antibody production to various antigens. They correct some immune defects in MRL/lpr mice with spontaneous autoimmune disorders that results in 2-fold prolongation of the life span of these mice. MPs influence the differentiation of bone marrow and peripheral blood cells derived from healthy and leukemic donors. They induce terminal differentiation in the leukemic human HL-60 cell line. MPs also show an effect on pain sensitivity. A new immunocorrective drug Myelopid has been developed on the basis of MP mixtures. This drug is effectively used in Russia both in medicine and veterinary practice for prophylaxis and treatment of diseases accompanied by immunodeficiency. Two individual MPs were isolated and identified: Phe-Leu-Gly-Phe-Pro-Thr (MP-1) and Leu-Val-Val-Tyr-Pro-Trp (MP-2). MP-1 displays immunoregulatory activity; MP-2 abolishes the inhibitory effect of leukemic cells on T-lymphocyte functional activity. MPs seem to provide not only immunoregulation but also to participate in complex interactions between different systems in the organism.
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PMID:Myelopeptides: bone marrow regulatory mediators. 764 88

Substance P (SP) appears to mediate many processes of the central nervous system, including pain. This report deals with modulation of opioid binding in the mouse brain by SP and SP fragments, as well as by salts and guanine nucleotides. Binding studies of the selective mu opioid receptor agonist [D-Ala2, MePhe4,Gly(ol)5]enkephalin (DAMGO) to mouse brain membrane preparations demonstrated that guanine nucleotide modulation of DAMGO binding affinity was modified by SP. However, SP had little or no influence on inhibition of DAMGO binding induced by salts, such as MgCl2, CaCl2, or NaCl. By replacing GTP with GppNHp, SP (0.1 nM) produced multiple affinity forms of the DAMGO receptor, while at a higher concentration (10 nM), SP lost its influence on DAMGO binding. Furthermore, 0.1 nM SP changed DAMGO binding parameters in a medium containing NaCl, CaCl2, and GppNHp such that the high- and low-affinity conformations of the receptor converted to a single site following the addition of SP to the incubation medium. While the C-terminal SP fragment SP(5-11) was without effect, the N-terminal SP fragments SP(1-9) and SP(1-7) appeared to imitate SP in modifying GppNHp-modulated DAMGO binding. These results suggest that SP functions as a modulator of opioid binding at the mu receptor and it appears that the N-terminus of SP plays a role in the modulatory process.
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PMID:DAMGO binding to mouse brain membranes: influence of salts, guanine nucleotides, substance P, and substance P fragments. 768 1


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