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)

The periaqueductal gray (PAG) region of the midbrain has been implicated in both stimulation produced and opioid induced analgesia. In the present study the opioid binding characteristics of the PAG were examined with an in vitro radioligand binding technique. [3H]Ethylketocyclazocine (EKC), 2 nM, was used as a tracer ligand to nonselectively label mu, delta, and kappa binding sites in PAG enriched P2 membrane. The mu selective ligand [D-Ala2,N-methylPhe4,Glyol5]enkephalin (DAGO) competed with [3H]EKC for more than one population of binding sites with both high and low affinity. In contrast the delta selective ligand [D-Pen2,D-Pen5]enkephalin (DPDPE) and the kappa selective ligand trans-3,4-dichloro-N-methyl-N-[2-(1- pyrrolidinyl)cyclohexyl]benzeneacetamide, methane sulfonate, hydrate (U50,488H) each competed with [3H]EKC for a single population of binding sites with low affinity. DPDPE and U50,488H also competed with 2 nM [3H]DAGO for a single population of binding sites with similar low affinity. DAGO and not DPDPE competed with 2 nM [3H][D-Ala2,D-Leu5]enkephalin (DADLE) with high affinity. 2 nM [3H]DPDPE did not substantially label PAG enriched P2 membrane, and 1 nM DAGO competed with all specific [3H]DPDPE binding which was observed. These binding data are consistent with the presence of a single population of mu selective high affinity binding sites in PAG enriched P2 membrane to which delta ligands and kappa ligands have low affinity.
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PMID:Characterization of high affinity opioid binding sites in rat periaqueductal gray P2 membrane. 254 13

Mu, delta and kappa opiate receptors have been implicated in the production of analgesia. In order to study the relative contributions of these receptor types to supraspinally mediated analgesia, apparent pA2 values and rank order potencies were determined for i.c.v. injected highly selective opioid agonists in the mouse using a thermal nociceptive test. Drugs used included the prototypical mu agonist morphine, putative mu agonists [D-Ala2, N-methyl-Phe4, Gly5-ol] enkephalin and BAM 22P, putative delta agonists [D-Pen2, D-Pen5] enkephalin, [D-Thr2, Thr6, Leu5] enkephalin and [D-Ser2, Leu5, Thr6] enkephalin and the putative kappa agonists [trans-3,4-dichloro-N-methyl-N[2-(1-pyrrolidinyl)-cyclohexyl]- benzeneacetamide methane sulfonate hydrate] and Dynorphin A (1-13). We were unable to demonstrate significant analgesic potencies for i.c.v. injected Dynorphin A (1-13) or BAM 22P in the absence of marked behavioral abnormalities. The rank order potency of the remaining compounds studied was found to be: [D-Ala2, N-methyl-Phe4, Gly5-ol] enkephalin greater than [D-Thr2, Thr6, Leu5] enkephalin greater than [D-Ser2, Leu5, Thr6] enkephalin greater than Morphine greater than [D-Pen2, D-Pen5] enkephalin greater than [trans-3, 4-dichloro-N-methyl-N[2-(1-pyrrolidinyl)-cyclohexyl]-benzeneacetamide methane sulfonate hydrate]. Apparent pA2 values of morphine, [D-Ala2, N-methyl-Phe4, Gly5-ol] enkephalin and [D-Pen2, D-Pen5] enkephalin in naloxone antagonism trials did not differ significantly. These results indicate that although both mu- and delta-selective ligands produce potent analgesia, a single receptor (mu) is sufficient to explain the supraspinal effects of opiate drugs.
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PMID:Action at the mu receptor is sufficient to explain the supraspinal analgesic effect of opiates. 301 17

The peripheral activity of the quaternary narcotic antagonist N-methyl levallorphan-methane sulphonate (SR 58002 C) at opioid sites located in the periphery and in the central nervous system (CNS), was studied by different approaches in rats after subcutaneous injection (s.c.). Pretreatment with SR 58002 C 2,8 or 32 mg/kg s.c. 10, 50 or 110 min before buprenorphine consistently reduced buprenorphine in vivo binding only in the small intestinal longitudinal muscle with attached myenteric plexus (MP), whereas naloxone (1 mg/kg s.c.) 10 min before buprenorphine lowered buprenorphine binding in MP and brain (without cerebellum). Plasma levels were not altered by SR 58002 C or naloxone. The same doses of SR 58002 C injected 10, 50 or 110 min before morphine selectively antagonized the inhibition of transit of a charcoal meal along the small intestine (mainly a peripheral effect) induced by the agonist, but did not antagonize morphine-elicited analgesia in the hot-plate test (central effect). Naloxone (1 mg/kg s.c.) injected 10 min before morphine antagonized both agonist effects simultaneously. In morphine-dependent rats SR 58002 C (0.25, 1, 4 and 32 mg/kg s.c.) induced diarrhea, dose-dependently, in most animals within the first 30 min, while jumping, measured in the same rats, occurred in some animals, not dose-dependently, from 60 min on. Naloxone (1 mg/kg s.c.) induced both effects in most rats. These findings suggest that, although SR 58002 C probably penetrates the blood-brain barrier in some morphine-dependent rats, it discriminates peripheral and CNS opioid effects.
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PMID:Antagonism by N-methyl levallorphan-methane sulphonate (SR 58002 C) of morphine-elicited acute and chronic central and peripheral effects. 338 93

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

Administration of the anesthetic gas nitrous oxide (N2O) evoked a concentration-dependent antinociceptive effect in mice as assessed by the abdominal constriction test. Depending on the dose and route of pretreatment with the opioid receptor blocker naloxone, the N2O drug effect was either antagonized or potentiated. After s.c. pretreatment with milligram per kilogram doses of naloxone, dose-related antagonism occurred; picogram per kilogram doses potentiated N2O-induced antinociception. The i.c.v. pretreatment with microgram quantities of naloxone also antagonized N2O antinociception in a dose-related fashion; i.c.v. pretreatment with femtogram doses was without effect. On the other hand, intrathecal (i.t.) pretreatment with femtogram quantities of naloxone potentiated N2O antinociception; i.t. pretreatment with microgram quantities continued to antagonize the antinociceptive effect. The same pattern of interaction was observed in mice challenged with the kappa opioid analgesic drug trans (+- 3,4-dichlow-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl] benzeneacetamide methane sulfonate (U-50, 488H) after s.c., i.c.v. or i.t. pretreatments with high and low doses of naloxone. These results 1) demonstrate further similarities in the opioid receptor mediation of N2O and U-50, 488H antinociceptive effects and also 2) support the concept of high-affinity spinal opioid receptors, whose blockade by s.c.- or i.t.- but not i.c.v.-administered low-dose naloxone can potentiate the antinociceptive effects of both N2O and U-50,488H. These findings suggest that the antinociceptive effect of N2O might be modulated by a descending opioid system that inhibits analgesia.
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PMID:Dose-dependent antagonism and potentiation of nitrous oxide antinociception by naloxone in mice. 822 38

Orphanin FQ/nociceptin (OFQ/N) is a recently identified neuropeptide with high affinity for the orphan opioid receptor. OFQ/N blocked morphine analgesia in mice in a dose-dependent manner, as well as the analgesic actions of [D-Pen2, D-Pen5]enkephalin (DPDPE), morphine-6 beta-glucuronide, trans-3,4-dichloro-N-[2-(1-pyrrolindinyl)-cyclohexyl]-benzeneac eta mide, methane sulfonate hydrate (U50,488H) and naloxone benzoylhydrazone. These actions are anti-analgesic, because OFQ/N also blocked clonidine analgesia and OFQ/N was inactive against the inhibition of gastrointestinal transit by morphine. Although OFQ/N was quite potent in these paradigms, two truncated forms, OFQ/N(1-11) and OFQ/N(1-7), were inactive. An antisense oligodeoxynucleotide targeting the first coding exon of KOR-3, the mouse homolog of the orphan opioid receptor, effectively prevented the anti-opioid actions of OFQ/N, confirming the importance of the orphan opioid receptor in this action.
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PMID:Functional blockade of opioid analgesia by orphanin FQ/nociceptin. 1007 48

The aim of this paper is to study the influence of salmon calcitonin (SCT) on opioid analgesia when opioid transduction pathways are functionally uncoupled from Gi/o proteins by treatment with pertussis toxin (PTX). The antinociceptive effect of morphine and three selective opioid agonists, [D-Ala2,N-Me-Phe2,Gly5-ol]enkephalin (DAMGO) (OP(3-mu receptor agonist), [D-Pen2.5]-enkephalin (OP-1-delta receptor agonist) and trans-( +/- )-3,4-dichloro-N-methyl-N-[2-1(-pyrrolidinyl)-cyclohexyl]-benzene-acetam ide methane sulfonate (U-50, 488H) (OP1-kappareceptor agonist) was evaluated, using the tail flick test, in mice treated with PTX or with PTX and SCT. PTX blocked the antinociceptive effect of the opioids, being the antinociception similar in control animals and in mice treated with PTX and SCT. Thus, SCT prevents the effect of the blockade of Gi/o-proteins. From this it could be suggested that calcitonin activates alternative antinociceptive mechanisms that are not dependent on Gi/o-proteins.
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PMID:Calcitonin reverts pertussis toxin blockade of the opioid analgesia in mice. 1051 87

The effect of fluoxetine, a selective 5-HT reuptake inhibitor on the analgesic and hypothermic response of trans-(+/-)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]-benzeneacetamide methane sulphonate (U-50,488H) and (+/-)-trans-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl] benzo[b] thiophene-4-acetamide (PD 117302), kappa-opioid receptor agonists, was determined in female Sprague-Dawley rats using the tail-flick method and telethermometer, respectively. Intraperitoneal injections of U-50,488H (U50) and PD 117302 (PD117) produced a dose-dependent analgesic and hypothermic response. Fluoxetine (10 mg/kg, i.p.) by itself did not produce an analgesic response. The analgesic response to U50 (10, 20, and 40 mg/kg, i.p.) and PD117 (7.5, 15, and 22.5 mg/kg, i.p.) was potentiated by fluoxetine injected intraperitoneally 60 min prior to the injection of kappa-opioid agonists. Similarly, the hypothermic response of U50 (20 and 40 mg/kg, i.p.) and PD117 (7.5, 15, and 22.5 mg/kg, i.p.) was potentiated by fluoxetine. The results indicate that selective kappa-opioid receptor agonists-induced analgesia and hypothermia is potentiated by fluoxetine, suggesting the role of extracellular 5-HT in the kappa-opioid receptor-mediated analgesia and hypothermia.
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PMID:Potentiation of kappa-opioid receptor agonist-induced analgesia and hypothermia by fluoxetine. 1142 85

The heritability of nociception and antinociception has been well established in the mouse. The pharmacogenetics of morphine analgesia are fairly well characterized, but far less is known about other analgesics. The purpose of this work was to begin the systematic genetic study of non-mu-opioid analgesics. We tested mice of 12 inbred mouse strains for baseline nociceptive sensitivity (49 degrees C tail-withdrawal assay) and subsequent antinociceptive sensitivity to systemic administration of (trans)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]benzeneacetamide methane-sulfonate hydrate (U50,488; 10-150 mg/kg), a kappa-opioid receptor agonist; (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone (WIN55,212-2; 0.5-480 mg/kg), a synthetic cannabinoid receptor agonist; epibatidine (7.5-150 microg/kg), a nicotinic receptor agonist; clonidine (0.1-5 mg/kg), an alpha(2)-adrenergic receptor agonist; and, for purposes of comparison, the prototypic mu-opioid receptor agonist, morphine (5-200 mg/kg). Robust interstrain variability was observed in nociceptive sensitivity and in the antinociceptive effects of each of the drugs, with extreme-responding strains exhibiting antinociceptive potencies differing up to 37-fold. Unexpectedly, we observed moderate-to-high genetic correlations of strain sensitivities to the five drugs (r = 0.39-0.77). We also found moderate-to-high correlations between baseline nociceptive sensitivity and subsequent analgesic response to each drug (r = 0.33-0.68). The generalizability of these findings was established in follow-up experiments investigating morphine and clonidine inhibition of formalin test nociception. Despite the fact that each drug activates a unique receptor, our results suggest that the potency of each drug is affected by a common set of genes. However, the genes in question may affect antinociception indirectly, via a primary action on baseline nociceptive sensitivity.
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PMID:The heritability of antinociception: common pharmacogenetic mediation of five neurochemically distinct analgesics. 1253 6

We have previously demonstrated that both endomorphin-1 (EM-1) and endomorphin-2 (EM-2) at high doses (1.75-35 nmol) given intrathecally (i.t.) or intracerebroventricularly produce antinociception by stimulation of mu-opioid receptors. Now, we report that EM-2 at small doses (0.05-1.75 nmol), which injected alone did not produce antinociception, produces anti-analgesia against opioid agonist-induced antinociception. The tail-flick (TF) response was used to test the antinociception in male CD-1 mice. Intrathecal pretreatment with EM-2 (0.02-1.75 nmol) 45 min before i.t. morphine (3.0 nmol) injection dose dependently attenuated morphine-induced TF inhibition. On the other hand, a similar dose of EM-1 (1.64 nmol) failed to produce any antianalgesic effect. The EM-2 (1.75 nmol)-produced anti-analgesia against morphine-induced TF inhibition was blocked by i.t. pretreatment with the mu-opioid antagonist naloxone or 3-methoxynaltrexone, but not delta-opioid receptor antagonist naltrindole, kappa-opioid receptor antagonist nor-binaltorphimine, or N-methyl-d-aspartate (NMDA) receptor antagonist MK-801. The EM-2-induced antianalgesic effect against morphine-induced TF inhibition was blocked by i.t. pretreatment with antiserum against dynorphin A(1-17), but not beta-endorphin, [Met]-enkephalin, [Leu]-enkephalin, or cholecystokinin antiserum (200 microg each). The i.t. EM-2 pretreatment also attenuated the TF inhibition induced by other mu-opioid agonists, [d-Ala2,N-Me-Phe4,Gly-ol5]-enkephalin, EM-1 and EM-2, delta-opioid agonist deltorphin II, and kappa-opioid agonist (trans)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]benzeneacetamide methane-sulfonate hydrate (U50,488H). It is concluded that EM-2 at subanalgesic doses presumably stimulates a subtype of mu-opioid receptor and subsequently induces the release of dynorphin A(1-17) to produce antianalgesic effects against mu-, delta-, or kappa-agonists-induced antinociception. The EM-2-induced antianalgesia is not mediated by the release of [Met]-enkephalin, [Leu]-enkephalin, beta-endorphin, or cholecystokinin, nor does it involve kappa- or delta-opioid or NMDA receptors in the spinal cord.
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PMID:Dynorphinergic mechanism mediating endomorphin-2-induced antianalgesia in the mouse spinal cord. 1455 78


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