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)

Pain is powerfully modulated by circuitries within the CNS. Two major types of pain inhibitory systems are commonly believed to exist: opiate (those that are blocked by systemic opiate antagonists and by systemic morphine tolerance) and non-opiate (those that are not). We used intrathecal delivery of mu, delta, and kappa opiate receptor antagonists to examine 3 well-accepted non-opiate stress-induced analgesias. Combined blockade of all 3 classes of opiate receptors antagonized all of the 'non-opiate' analgesias. Further experiments demonstrated that blocking mu and delta or mu and kappa was sufficient to abolish 'non-opiate' analgesias. Combined blockade of kappa and delta receptors was without effect. The clear conclusion is that all endogenous analgesia systems may in fact be opiate at the level of the spinal cord. Phenomena previously thought to be non-opiate appear to involve parallel activation of multiple spinal opiate processes. These findings suggest the need for a fundamental shift in conceptualizations regarding the organization and function of pain modulatory systems in particular, and opiate systems in general.
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PMID:Parallel activation of multiple spinal opiate systems appears to mediate 'non-opiate' stress-induced analgesias. 133 66

This paper describes the synthesis and kappa and mu opioid receptor binding affinity of some conformationally restrained derivatives of the arylacetamide group in the selective kappa opioid receptor agonist (+/-)-trans-N-methyl-N-[2-(1-pyrrolidinyl) cyclohexyl]benzo [b]thiophene-4-acetamide monohydrochloride (1,PD117302), which is an analogue of U-50, 488. The methyl-substituted derivatives (+/-)-trans-N, alpha-dimethyl-N-[2-(1-pyrrolidinyl)cyclohexyl]benzo-[b] thiophene-4-acetamide monohydrochloride (6a,b) possess significantly weaker affinity than 1 for the kappa opioid receptor (Ki = 172 and 3.7 nM, respectively). It is proposed that this is due to the conformational restriction imposed by the methyl group of 6. In order to test this proposal the acenaphthene derivative and the 4,5-dihydro-3H-naphtho [1,8-bc]thiophene derivative were prepared. The acenaphthene derivative (+)-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro [4.5]dec-8-yl]acenaphthenecarboxamide monohydrochloride (9) was found to have high kappa opioid receptor affinity and selectivity (kappa Ki = 0.37 +/- 0.05 nM, mu/kappa = 659, delta/kappa = 1562) and is 100 times more potent than morphine as an analgesic in the rat paw pressure test for analgesia after intravenous administration (MPE50 = 0.014 and 1.4 mg/kg, respectively). The 4,5-dihydro-3H-naphtho[1,8-bc]thiophene derivative (-)-4,5-dihydro-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro [4.5]dec-8-yl]-3H-naphthol[1,8-bc]thiophene-5-carboxamide p-toluenesulfonate (17) also has high kappa opioid receptor affinity and selectivity (kappa Ki = 4.65 nM, mu/kappa = 109).
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PMID:Highly selective kappa opioid analgesics. 4. Synthesis of some conformationally restricted naphthalene derivatives with high receptor affinity and selectivity. 184 19

Morphine-treated rats exposed to restraint stress show potentiated magnitude and duration of analgesia compared to unstressed rats. The present study was performed to assess the pharmacological characteristics of stress-induced potentiation of opioid analgesia. We tested 10 opioids to determine whether restraint stress treatment would potentiate their ability to produce antinociception indexed by the tail-flick assay. We tested full mu, delta and kappa opioid receptor agonists (fentanyl, meperidine, DPDPE, U50488H, ethylketocyclazocine), and mixed agonist/antagonists representing a range of receptor selectivities and intrinsic activities (profadol, buprenorphine, pentazocine, butorphanol and nalbuphine). Dose-effect and time-response curves were generated for unrestrained and restrained rats after either subcutaneous (SC) and/or intracerebroventricular (ICV) injections. In restrained rats, all drugs except for SC-administered nalbuphine produced dose- and time-dependent analgesic effects of greater magnitude (1.5-3 times) than they produced in unrestrained rats. However, restrained rats given agonists with high intrinsic activity at the mu receptor displayed the most potent and consistent potentiation of analgesia compared to unrestrained controls. Our results suggest that activation of the mu receptor is of primary importance for restraint to potentiate analgesia, because restrained rats injected with delta and kappa agonists displayed potentiation of analgesia only at doses high enough to possibly exceed the selective activation of their respective receptor types.
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PMID:Pharmacological profile of the potentiation of opioid analgesia by restraint stress. 217 19

The pharmacological effects of morphine, namely analgesic, hyperthermic and cataleptic effects, were assessed in rats rendered tolerant to U-50,488H, a kappa opioid receptor agonist. Male Sprague-Dawley rats were injected intraperitoneally with U-50,488H (25 mg/kg) twice a day for four days. The rats which served as controls were injected similarly with the vehicle. Chronic administration of U-50,488H resulted in the development of tolerance to its analgesic and hypothermic effects, but not to its diuretic effect. The development of tolerance to the pharmacological effects of U-50,488H was associated with decreased binding of [3H]ethylketocyclazocine [( 3H]EKC) to brain and spinal cord membranes. The decreased binding of [3H]EKC in U-50,488H-treated rats was due to changes in the Bmax value; the Kd values remained unaltered. Intraperitoneal administration of morphine (8 mg/kg) to rats produced analgesia (as determined by the tail-flick test) and hyperthermia. A dose of 50 mg/kg of morphine produced cataleptic response. The intensity of analgesic, hyperthermic and cataleptic effects of morphine were unaltered in rats tolerant to U-50,488H. The development of tolerance to analgesic and hypothermic effects of U-50,488H were associated with down-regulation of brain and spinal cord kappa opioid receptors. Finally, U-50,488H does not confer cross-tolerance to morphine, a predominantly mu opioid receptor agonist.
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PMID:Effects of morphine in rats treated chronically with U-50,488 H, a kappa opioid receptor agonist. 254 58

An in vitro binding assay, using 125I-YLFQPQRFamide, a newly synthetized iodinated analog of FLFQPQRFamide, in which Phe1 (F) has been substituted by a Tyr (Y), was developed to demonstrate and characterize putative binding sites of this brain morphine modulating peptide. This radioligand bound in a time-dependent manner to rat spinal cord membrane preparation. This binding was dose-dependent, saturable and reversible. Both kinetic data and saturation measured at equilibrium lead to the existence of a homogenous population of high affinity binding sites with a Kd value of 0.09-0.1 nM and a maximal capacity Bmax of 14.5 +/- 2 fmol/mg protein. Results of competition experiments show that both FLFQPQRFamide and its analog YLFQPQRFamide had a similar capacity to inhibit the 125I-YLFQPQRFamide binding, suggesting that this radioiodinated analog is a good tool to study binding characteristics of FLFQPQRFamide receptors. The related octadecapeptide AGEGLSSPFWSLAAPQRFamide, another mammalian morphine modulating peptide competes for radioligand binding with similar potency. Our results also show that mu, delta and kappa opiate receptor agonists as well as the antagonist naloxone were not able to affect binding either in presence or in absence of 120 mM NaCl. Together, these data demonstrate that FLFQPQRFamide does not function as an endogenous opiate receptor antagonist and that is capacity to reduce opiate-induced analgesia is supported by specific binding sites.
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PMID:Characterization of rat spinal cord receptors to FLFQPQRFamide, a mammalian morphine modulating peptide: a binding study. 255 56

In both rats and humans there is an analgesia associated with pregnancy. This analgesia is spinally mediated and involves the kappa type of opiate receptor. The current study demonstrates that intrathecal administration of high affinity dynorphin antibodies produces a significant reduction in jump thresholds during pregnancy (day 20). The administration of pre-adsorbed antisera fails to produce this effect. These results support the hypothesis that a spinal dynorphin/kappa opiate receptor system is activated during gestation.
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PMID:Spinal dynorphin involvement in the analgesia of pregnancy: effects of intrathecal dynorphin antisera. 256 43

The purpose of these investigations was to determine 1) whether peripherally located mu, delta and kappa opioid receptors can inhibit the rate of gastrointestinal transit and, if so, 2) do peripheral opioid receptors mediate the constipation caused by systemic morphine? and 3) whether constipation can be separated from analgesia on the basis of different sites of action. We studied the effects of peripherally administered (s.c.) mu, delta and kappa opioid receptor selective agonists on the rate of gastrointestinal transit in mice. We used peptidergic agonists with high peripheral selectivity (limited ability to cross the blood-brain barrier) including [MePhe3,D-Pro4]morphiceptin (PL017) (mu), [D-Pen2,D-Pen5]enkephalin (DPDPE) (delta) and Tyr-Gly-Gly-Phe-Leu-Arg-Arg-Ile-Arg (dynorphin 1-9) (kappa). As peripheral selectivity is dose-related, we included the hot-plate test as an index of that dose at which each compound lost its peripheral selectivity and entered the central nervous system. When given s.c., [MePhe3,D-Pro4]morphiceptin inhibited transit (IC50 = 0.37 mg/kg s.c.) at doses much lower than those needed to produce analgesia (A50 = 30 mg/kg s.c.), indicating that peripheral mu receptors can inhibit transit independently of central mu receptors. The independence of peripheral mu antitransit receptors from central receptors was demonstrated further as the lack of antagonism of s.c. [MePhe3,D-Pro4]morphiceptin antitransit effects by simultaneous i.c.v. administration of the mu receptor antagonist D-Phe-Cys-Tyr-D-Trp-Lys-Thr-Pen-Thr-NH2 (CTP) (1 microgram i.c.v.).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Peptide opioid antagonist separates peripheral and central opioid antitransit effects. 282 48

This paper describes the synthesis, structure-activity relationships (SAR) of mu and kappa opioid binding affinities, and analgesic properties of a series of novel highly selective kappa opioid N-[(2-aminocyclohexyl)aryl]acetamide and N-[(2-aminocyclohexyl)aryloxy] acetamide derivatives. Ten compounds, 14, 15, 31-37, and 39 (Tables I and II), show a marked kappa selectivity of greater than 100:1 over mu binding, with high affinity for the kappa opioid receptor (approximately 10(-8) - 10(-9) M). Compound 39, (S,S-trans)-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-4-benzo[b] furanacetamide hydrobromide, has the highest mu/kappa selectivity, 780:1 (kappa Ki = 4.2 nM), reported to date. Four of these compounds, 14, 15, and their S,S-trans enantiomers, 37 and 39, respectively, produce effective analgesia by oral administration, as assayed by a rat-paw pressure test (RPP) (MPE50 = 24, 26, 8.3, and 12 mg/kg, respectively). The R,R-trans isomer, 38, was inactive in binding and RPP. The analgesic effect was reversed by administration of naloxone, confirming these effects are opioid in character. Optimal activity is produced when the basic nitrogen atom is in a pyrrolidine ring, the aryl group is a 10-pi-electron-rich aromatic system, such as 4-benzo[b]thiophene, 4-benzo[b]furan, or 4-chlorophenoxy, and overall lipophilicity lies within the range log P = 3.5-5.0.
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PMID:Highly selective kappa opioid analgesics. Synthesis and structure-activity relationships of novel N-[(2-aminocyclohexyl)aryl]acetamide and N-[(2-aminocyclohexyl)aryloxy]acetamide derivatives. 283 3

Stress can induce a naloxone reversible and a naloxone non reversible analgesia according to its parameters. We showed that naloxone non reversible analgesia can be reversed by antagonists of the kappa opiate receptor and that naloxone reversible analgesia can be related to mu receptors and beta-endorphin, while the kappa receptor mediated analgesia can be related to dynorphin. We have also shown that the characteristics of the receptors might change in consequence to stress and that the analgesic responses might be modulated by benzodiazepine agonists and antagonists.
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PMID:Endogenous opioids and their receptors in stress-induced analgesia. 285 67

A new series of 12 dermorphin tetrapeptides, W-Tyr-D-MetO-Phe-Xaa-Y (W = H, H2NC = (NH); Xaa = Gly, Sar, D-Ala; Y = OH, OCH3, NH2) were prepared by traditional methods in solution and tested for opioid activity. In binding studies based on displacement of mu, delta, and kappa opioid receptor selective radiolabels from guinea pig brain membranes, the new analogues showed a negligible affinity for the kappa binding site and a preference for mu- over delta-receptors with an evident dependence on N- and/or C-terminal modifications; H-Tyr-D-MetO-Phe-Gly-OCH3 was shown to be one of the most selective mu-receptor ligands reported to date. All these tetrapeptides display dose-related naloxone-reversible antinociceptive effects following intracerebroventricular (icv) or subcutaneous (sc) administrations in mice. In comparison to morphine, H-Tyr-D-MetO-Phe-Sar-NH2 and the guanidino derivative H2NC = (NH)-Tyr-D-MetO-Phe-Gly-NH2 showed lower affinity for mu, delta, and kappa sites but exceptionally stronger analgesia: respectively they are 560 and 1550 times as potent an analgesic as morphine. Among analogues tested after sc administration, H-Tyr-D-MetO-Phe-Sar-NH2 and H-Tyr-D-MetO-Phe-D-Ala-OH displayed the highest activities; they were respectively 22 and 30 times more potent than morphine on a molar basis. These results indicate that N- or C-terminal modifications and substitution at position 2 or 4 of dermorphin-(1-4) peptide do not only influence the affinity of the resulting analogues to opioid receptors but also may favorably alter their pharmacokinetic properties.
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PMID:Synthesis and activity profiles of new dermorphin-(1-4) peptide analogues. 288 56


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