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)

Intraperitoneal administration of L-tyrosine (used as methyl ester HCl) produced dose-dependent analgesia in male Sprague-Dawley rats as measured by the tail-flick test. The maximal analgesic response was obtained with 200 mg/kg dose of tyrosine. Administration of morphine also produced a dose-dependent analgesic response. Tyrosine in doses of 50 mg/kg or higher potentiated morphine-induced analgesia. The analgesic response of tyrosine (200 mg/kg) was antagonized by naloxone (1 mg/kg), an opiate antagonist. Subcutaneous administration of methyl naltrexone bromide (MRZ 2663 BR, 1 and 10 mg/kg) had no effect on tyrosine-induced analgesia. Intracerebroventricular injection of MRZ 2663 BR (1 and 10 micrograms/rat) effectively blocked tyrosine-induced analgesia. It is concluded that tyrosine-induced analgesia and its potentiation of analgesic response to morphine may be mediated via either the opiate receptors or activation of endogenous opioidergic systems of central origin.
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PMID:Evidence for the involvement of central opioidergic systems in L-tyrosine methyl ester-induced analgesia in the rat. 342 Jan 62

The effects of L-tyrosine (L-TYR) on the analgesic activity of several opioids were determined utilizing a hot-plate test. L-TYR (200 mg/kg) significantly potentiated (P < .05) the analgesic activity of morphine sulfate (10 mg/kg) and codeine sulfate (30 mg/kg). The opioid-induced analgesia and its potentiation by L-TYR was abolished by naloxone pretreatment. Increasing the dose of L-TYR (25-200 mg/kg) resulted in a dose-dependent potentiation of morphine-induced analgesia. The observed potentiation was positively correlated with increases in brain TYR concentrations; blockade of L-TYR uptake into the brain by the coadministration of L-valine attenuated this potentiation. With the exception of L-tryptophan, all other L-amino acids, as well as D-TYR, failed to mimic the potentiating action of L-TYR. As determined by alpha-methyl-p-TYR pretreatment, the L-TYR-induced potentiation was dependent upon increased catecholamine synthesis. These results demonstrate that L-TYR dose dependently potentiates the analgesic activity of opioids and are consistent with the requirement of the central conversion of L-TYR to catecholamines via TYR hydroxylase for this response.
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PMID:L-tyrosine potentiation of opioid-induced analgesia utilizing the hot-plate test. 801 63

The effects of the methyl esters of L-tyrosine (L-Tyr-OMe) and L-tryptophan (L-Trp-OMe) on the analgesic action of trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidin)cyclohexyl]-benzene acetamide methane sulfonate (U-50,488H), a kappa-opioid receptor agonist, were determined in male Swiss-Webster mice using the tail-flick test. Intraperitoneal injections of U-50,488H produced a dose-dependent analgesic response. The analgesic response to all doses of U-50,488H was potentiated by L-Tyr-OMe at 200 mg/kg injected intraperitoneally 30 min prior to the injection of U-50,488H. The effect of various doses of L-Tyr-OMe (50, 100 and 200 mg/kg) on the analgesia produced by 20 mg/kg of U-50,488H was also determined. The lowest dose (50 mg/kg) of L-Tyr-OMe did not modify U-50,488H-induced analgesia but the two higher doses enhanced it significantly. L-Tyr-OMe by itself at all the doses tested had no effect on the tail-flick latency. L-Trp-OMe (200 mg/kg) enhanced the analgesic action of 10 and 20 mg/kg doses of U-50,488H but not that induced by a 5 mg/kg dose. The analgesia induced by 20 mg/kg of U-50,488H was potentiated by L-Trp-OMe at 100 and 200 mg/kg but not by a 50 mg/kg dose. L-Trp-OMe by itself also did not alter the tail-flick latency. Previously, the studies in this laboratory have shown that L-Try-OMe potentiates morphine, a mu-opioid receptor agonist-induced analgesia.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Enhancement of a kappa-opioid receptor agonist-induced analgesia by L-tyrosine and L-tryptophan. 808 53

N-(N-L-Threonyl-L-alpha-aspartyl)-L-tyrosine (CAS 115053-54-8, SPA-S-646) was originally derived from lysozyme. It has previously been found to have analgesic properties following oral and intravenous administration to laboratory rodents. In the rhesus monkey, intramuscular administration of SPA-S-646 caused a dose-related analgesia. This effect was not seen following oral administration, but when given via the rectum, analgesia was again observed. In the dog, a single dose of 50 mg/kg was active by the intramuscular route but not the oral route. It is thought that unlike the rat, the digestive systems of the rhesus monkey and the dog degrade the tripeptide into inactive constituents.
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PMID:Analgesic activity of the lysozyme peptide N-(N-L-threonyl-L-alpha-aspartyl)-L-tyrosine in the monkey and the dog. 857 26

The single amino acid replacement of 2',6'-dimethyl-L-tyrosine in deltorphin B (H-Dmt-D-Ala-Phe-Glu-Val-Val-Gly-NH2) yielded high affinity for mu- and delta-binding sites. [Dmt1]Deltorphin B lacks activity at kappa-opioid binding sites. Bioactivity in vitro with guinea-pig ileum confirmed that [Dmt1]deltorphin B interacted with mu-opioid receptors by reducing electrically induced contractions in a naloxone-reversible manner and was 150-fold more potent than morphine and comparable to [D-Ala2,NMePhe4,Gly-ol5]enkephalin (DAGO). The inhibition of spontaneous contractions of rabbit jejunum provided evidence for delta-opioid receptor interaction. Analgesia (hot plate and tail flick tests) revealed that [Dmt1]deltorphin B was 180- to 200-fold more potent than morphine. Pretreatment with naloxone, naltrindole or H-Dmt-Tic-Ala-OH (a highly selective delta-opioid receptor antagonist) prevented [Dmt1]deltorphin B antinociception. Thus, [Dmt1]deltorphin B exhibited remarkably high dual affinity and bioactivity toward delta- and mu-opioid receptors.
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PMID:Opioid receptor selectivity alteration by single residue replacement: synthesis and activity profile of [Dmt1]deltorphin B. 879 Sep 89

Unique opioid mimetic substances containing identical N-terminal aromatic residues separated by an unbranched alkyl chain containing two to eight methylene groups were developed. Regardless of the length of interposing alkyl chain, the bis-Tyr and bis-Phe compounds were inactive; however, replacement by a single Dmt (2',6'-dimethyl-L-tyrosine) residue enhanced activity by orders of magnitude. Moreover, the bis-Dmt compounds were another 10-fold more potent with an optimum intra-aromatic ring distance of about four to six methylene units. 1,4-Bis(Dmt-NH)butane (7) had high mu-opioid receptor affinity (K(i) = 0.041 nM) and functional mu-opioid agonist bioactivity (IC(50) = 5.3 nM) with in vivo central (intracerebroventricular) and systemic (subcutaneous) analgesia in mice (1.5- to 2.5-fold greater than and 10-12% relative to morphine, respectively); these activities were reversed by naloxone to the same degree. It appears that the bis-Dmt compounds indiscriminately act as both message and address domains.
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PMID:Unique high-affinity synthetic mu-opioid receptor agonists with central- and systemic-mediated analgesia. 1285 51

Kyotorphin (Kyo) is synthesized in specific brain regions where it may modulate synaptic transmission. Kyo directly excites cortical neurons, and indirectly exerts opioid actions to produce analgesia via the release of [Met]-enkephalin. Kyo is formed by a specific enzyme from L-tyrosine, L-arginine (L-arg) and ATP in the presence of Mg2+. Kyo and its analogues Tyr-cav and Tyr(Cl2)-cav exert naloxone-reversible antinociception in the paw-pressure test. The aim of the present study was to investigate the effect of D-arginine (D-arg) on the analgesic effects of Kyo, Tyr-cav and Tyr(Cl2)-cav during acute pain. The changes in the nociceptive effects were examined in male Wistar rats using the tail flick (TF) and hot plate (HP) tests. Kyo, Tyr-cav, Tyr(Cl2)-cav, L-canavanine (L-cav) and D-arg were applied in rats intracerebroventricularly (i.c.v.) at a dose of 20 microg/20 microl. Kyo, Tyr-cav, Tyr(Cl2)-cav and L-cav exerted antinociceptive activity in both tests used. Applied alone, D-arg had no antinociceptive activity in TF and HP tests. D-arg decreased the TF and HP latency of the Kyo, Tyr-cav, Tyr(Cl2)-cav and L-cav. Taken together, these results reveal D-arg as a potential inhibitor of the investigated peptides during acute pain.
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PMID:Effect of D-arginine on antinociception induced by kyotorphin, Tyr-cav, L-cav and Tyr(Cl2)-cav in rats. 1531 11

Endogenous opioids have been studied extensively since their discovery, in the hope of findings a perfect analgesic, devoid of the secondary effects of alkaloid opioids. However, the design of selective opioid agonists and or antagonists has proved very difficult. First, structural studies of peptides in general are hampered by their intrinsic flexibility. Second, the relationship between constitution and the so called "bioactive conformations" is far from obvious. Ideally, a direct structural study of the complex between a peptide and its receptor should answer both questions, but such a study is not possible, because opioids receptors are large membrane proteins, difficult to study by standard structural techniques. Thus, conformational studies of opioid peptides are still important for drug design and also for indirect receptor mapping. This review deals the pharmacological activity of : a) a new mu and deltaagonist: The single amino acid replacement of 2',6'-dimethyl-L-tyrosine in deltorphin B (H-Dmt-D-Ala-Phe-Glu-Val-Val-Gly-NH2) yielded high affinity for mu- and delta-binding sites. [Dmt1]Deltorphin B lacks activity at kappa-opioid binding sites. Bioactivity in vitro with guinea-pig ileum confirmed that [Dmt1]deltorphin B interacted with mu-opioid receptors by reducing electrically induced contractions in a naloxone-reversible manner and was 150-fold more potent than morphine and comparable to [D-Ala2,NMePhe4,Gly-ol5]enkephalin (DAGO). The inhibition of spontaneous contractions of rabbit jejunum provided evidence for delta-opioid receptor interaction. Analgesia (hot plate and tail flick tests) revealed that [Dmt1]deltorphin B was 180- to 200-fold more potent than morphine. Pretreatment with naloxone, naltrindole or H-Dmt-Tic-Ala-OH (a highly selective delta-opioid receptor antagonist) prevented [Dmt1]deltorphin B antinociception. Thus, [Dmt1]deltorphin B exhibited remarkably high dual affinity and bioactivity toward delta- and mu-opioid receptors. b) two new delta opioid peptide receptor antagonists (Dmt-Tic-OH (DTOH) and Dmt-Tic-Ala-OH (DTAOH): Dmt-Tic-OH (DTOH) and Dmt-Tic-Ala-OH (DTAOH), effective antagonists in vitro, represent a new potent opioid dipeptides for the delta-opioid receptor (Ki delta of 0.022 nM and a selectivity, Ki mu/Ki delta, of 150,000 for DTOH; Ki delta of 0.285 nM and a selectivity Ki mu/Ki delta, of 20,4 for DTAOH). In the present study we considered the pharmacological activity of these two new delta opioid peptide receptor antagonists in vivo. Therefore, we have evaluated their possible antagonistic activity against the antinociception induced by the highly selective delta opioid receptor agonist, [D-Ala2]deltorphin II (DEL). Furthermore, these two delta opioid peptide receptor antagonists were injected centrally or peripherally in order to assess their ability to act also after systemic administration. Concurrent i.c.v. injection of DTOH or DTAOH (0.5-1.0-2.0 nM) with DEL (5 nmol) induced a significant reduction of DEL antinociception. By contrast, while DTOH (10-20-40 mg/kg) administered peripherally (i.p., s.c. or i.v.) was also able to reduce DEL antinociception, DTAOH failed. The present results indicate that DTOH is the first opioid dipeptide with delta antagonist activity after systemic administration and it could be important in the clinical and therapeutic applications. c) a new mu selective opioid dipeptide antagonists: the potent delta selective opioid antagonist dipeptides were designed on the basis of a simple conformational analysis. Following a similar procedure we found a mu selective dipeptide antagonist, 2,6-dimethyl-Tyr-D-Phe-NH2. Although its selectivity is not as high as those of the quoted delta selective dipeptides it has good in vitro activity and looks very promising for further development since the 2,6-dimethyl-Tyr-D-Phe message, like the delta selective 2,6-dimethyl-Tyr-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid counterpart, seems able to impart antagonism to longer peptides.
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PMID:Bioactivity of new mu and delta opioid peptides. 1789 75

[Tyr(6)]-gamma2-MSH(6-12) with a short effecting time of about 20 min is one of the most potent rMrgC receptor agonists. To possibly increase its potency and metabolic stability, a series of analogues were prepared by replacing the Tyr(6) residue with the non-canonical amino acids 3-(1-naphtyl)-L-alanine, 4-fluoro-L-phenylalanine, 4-methoxy-L-phenylalanine and 3-nitro-L-tyrosine. Dose-dependent nociceptive assays performed in conscious rats by intrathecal injection of the MSH peptides showed [Tyr(6)]-gamma2-MSH(6-12) hyperalgesic effects at low doses (5-20 nmol) and analgesia at high doses (100-200 nmol). This analgesic activity is fully reversed by the kyotorphin receptor-specific antagonist Leu-Arg. For the two analogues containing in position 6, 4-fluoro-L-phenylalanine and 3-nitro-L-tyrosine, a hyperalgesic activity was not observed, while the 3-(1-naphtyl)-L-alanine analogue at 10 nmol dose was found to induce hyperalgesia at a potency very similar to gamma2-MSH(6-12), but with longer duration of the effect. Finally, the 4-methoxy-L-phenylalanine analogue (0.5 nmol) showed greatly improved hyperalgesic activity and prolonged effects compared to the parent [Tyr(6)]-gamma2-MSH(6-12) compound.
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PMID:Dual effects of [Tyr(6)]-gamma2-MSH(6-12) on pain perception and in vivo hyperalgesic activity of its analogues. 2062 98

For over 30 years empirical studies have repeatedly demonstrated that the biosynthesis of morphine by diverse animal and human tissues occurs. Recently, the blue mussel's neural tissues and human white blood cells were used to demonstrate the de novo biosynthesis of morphine for small precursor molecules derived from the aromatic amino acid L-tyrosine. Because catecholamine precursors, i.e., L-3,4-dihydroxyphenylalanine (L-DOPA), were also found to be utilized as morphine precursors, a novel reciprocally interactive mechanism is apparent that links catecholamine and opioid pathways in the activation and inhibition of diverse tissue responses. Additionally, these observations provide new insights into morphinergic signalling that transcend analgesia and addiction. We have also linked the biological effects of nitric oxide into a common effect in endogenous morphine signalling. Given the singular importance of dopamine and morphine's interaction in the CNS, the presence and association of this signalling with nitric oxide all promises to provide novel answers for mental health phenomena, which have been lacking because of the inability in accepting the empirical endogenous morphine studies.
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PMID:Psychiatric implications of endogenous morphine: up-to-date review. 2132 64


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