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)

Possible changes in blood-brain barrier (BBB) function as a result of diabetes were investigated by assessing antagonism of morphine analgesia in diabetic mice by methylnaltrexone (MeNTX), an opioid receptor blocker that does not cross the BBB when administered subcutaneously (SC). In streptozotocin (STZ)-treated diabetic mice--but not vehicle-treated, non-diabetic mice--treatment with SC MeNTX significantly reduced morphine analgesia. In vehicle-treated, non-diabetic mice, morphine analgesia was antagonized by MeNTX administered intracerebroventricularly and by SC naltrexone, which crosses the BBB. Reduction of STZ-induced hyperglycemia by insulin reversed the effectiveness of SC MeNTX in antagonizing morphine analgesia. We hypothesize that in STZ diabetic mice, MeNTX was able to cross the BBB and block brain opioid receptors.
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PMID:Central pharmacological activity of a quaternary ammonium compound in streptozotocin diabetic mice. 284 78

The molecular basis of opioid tolerance/dependence has long eluded researchers, but recent advances in receptor regulation have suggested a useful conceptual approach to the problem. In NG108-15 neuroblastoma x glioma hybrid (NG) cells, opioid agonists inhibit adenylate cyclase in a dose-dependent, naloxone-antagonizable fashion. Chronic treatment with opioid agonists results in a series of molecular processes that, in a tolerance-like fashion, counteract this inhibition. These processes include desensitization and down-regulation of receptors and an increase in adenylate cyclase activity. Opioid inhibition of adenylate cyclase and opioid receptor down-regulation also have been observed in the brain. However, most studies have found that the receptors coupled to adenylate cyclase are not of the mu type, which are thought to be the primary mediators of opioid analgesia. Down-regulation has been observed for both mu and delta opioid receptors in the brain. However, in most cases, the time course of down-regulation is not correlated with that for tolerance development, and chronic morphine treatment does not result in down-regulation. Thus, opioid receptors in the brain, like those in NG cells, are subject to dynamic regulation by agonists, which probably has an important role in their function. However, it remains to be established that opioid receptor regulation is the basis of opioid tolerance and dependence.
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PMID:Role of receptor regulation in opioid tolerance mechanisms. 284 42

The influence of replacing the phenolic hydroxyl by the methoxy group on opioid receptor binding, analgesic and antitussive action was investigated in the corresponding couples morphine-codeine, hydromorphone-hydrocodone and O-desmethyltramadol (L 235)-tramadol. Binding was studied on rat whole brain membranes (without cerebellum) with the radioligands dihydromorphine (mu-site), ethylketocyclazocine (k-site), D-Ala2-D-Leu5-enkephalin (delta-site) and naloxone (no selective binding). Analgesia (tail flick) and antitussive action (NH3-vapour induced cough) was investigated in rats and ED50 values 10 min after i.v. application were calculated to compare efficacy. All free hydroxyl compounds had higher opioid receptor affinities than the corresponding methoxy derivatives and were more active at the mu-site. The methoxy derivatives codeine and tramadol only had low affinities lacking selectivity towards mu-, kappa-, or delta-binding. Hydrocodone in contrast showed strong and mu-selective binding. The hydroxy compounds had higher analgesic activity than the methoxy congeners and analgesia appeared to correlate with mu-binding affinity. Codeine and hydrocodone were weaker antitussives than the corresponding hydroxy compounds, whereas no significant difference was found between O-desmethyltramadol and tramadol. Only in the tramadol group the methoxy substitution increased antitussive potency in relation to analgesic potency.
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PMID:Receptor binding, analgesic and antitussive potency of tramadol and other selected opioids. 284 50

The effect of i.p. administration of kappa-opioid receptor agonists, bremazocine, tifluadom and U-50,488H on morphine (8 mg/kg i.p.)-induced analgesia in morphine-naive and morphine tolerant male Sprague-Dawley rats was determined using the tail-flick test. The tolerance to morphine in the rats was induced by s.c., implantation of six morphine pellets during a 7-day period. Implantation of morphine pellets resulted in the development of tolerance as evidenced by the decrease in the analgesic response to morphine when compared to placebo pellets implanted rats. Bremazocine (0.3, 1.0 and 3.0 mg/kg) and U-50,488H (16 mg/kg) antagonized morphine-induced analgesia in morphine-naive rats while tifluadom (8 and 16 mg/kg) potentiated the effect. In morphine-tolerant rats, bremazocine (3 mg/kg) and U-50,488H (16 mg/kg) potentiated morphine-induced analgesia. Tifluadom at any of the doses had no effect on morphine-induced analgesia in morphine-tolerant rats. These results provide evidence that different kappa-opioid agonists modify morphine-induced analgesia differentially in morphine-naive and morphine-tolerant rats.
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PMID:Effect of kappa-opioid receptor agonists on morphine analgesia in morphine-naive and morphine-tolerant rats. 285 74

We have shown previously that D-Phe-Cys-Tyr-D-Trp-Lys-Thr-Pen-Thr-NH2 (CTP) produces selective antagonism of mu, but not delta or kappa, opioid receptor-selective ligands in the guinea pig ileum and mouse vas deferens bioassays, and in radioligand binding assays using homogenized rat brains. In the present study we characterized the agonist and opioid antagonist profile of CTP in analgesic (hot-plate test, abdominal stretch test) and in gastrointestinal assays (transit time test) in mice. CTP was a potent antagonist of the supraspinal and spinal analgesic effects of the mu selective agonist [MePhe3, D-Pro4]morphiceptin (PL017) in both assays. The gastrointestinal antitransit actions of PL017 were also antagonized by CTP at both supraspinal and spinal sites. CTP did not alter the effects of the kappa agonist trans-3,4-dichloro-N-methyl-N-(2-(1-pyrolidinyl)cyclohexyl)benz eneacetamine in any test. Surprisingly, CTP also antagonized the analgesia produced by i.c.v. and intrathecal administration of [D-Pen2, D-Pen5]enkephalin (DPDPE), a highly delta selective agonist, in both analgesic tests. Differential antagonism of DPDPE, but not PL017, by the delta selective antagonist N,N-diallyl-Tyr-Aib-Aib-Phe-Leu-OH in the hot-plate test indicates that PL017 and DPDPE may act at separate receptors to produce analgesia (mu and delta, respectively). In contrast, CTP did not reverse the gastrointestinal antitransit effects of intrathecal DPDPE. Schild analysis of the interactions of CTP with supraspinal mu and delta agonists in the hot-plate test indicated that although CTP antagonized PL017 in a competitive fashion (Schild slope = -1.0), the interaction of CTP with DPDPE was not competitive (Schild slope = -0.5).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Mu opioid antagonist properties of a cyclic somatostatin octapeptide in vivo: identification of mu receptor-related functions. 288 35

Like other opioids, the dynorphins play a role in wide variety of physiological parameters, including pain regulation, motor activity, cardiovascular regulation, respiration, temperature regulation, feeding behavior, hormone balance, and the response to shock or stress. The dynorphins are unusual if not unique, however, in that they frequently modulate the activity of other opioids, rather than having direct effects themselves. Thus, they are not analgesic in brain, yet they antagonize opioid analgesia in naive animals and potentiate it in tolerant animals. They have little or no effect by themselves on temperature regulation or respiration, but they enhance the acute effects of morphine on these parameters. Their beneficial effects on stroke are like those of opioid antagonists rather than like agonists. Consistent with such a wide variety of physiological effects, the dynorphins bind to all three of the major opioid receptor types in brain, mu, delta, and kappa, though they exhibit some preference toward kappa sites. They also seem to interact with other physiologically relevant sites; though on the basis of their sensitivity to des-Tyr fragments of dynorphine and/or their insensitivity to naloxone, these sites have been termed "non-opioid". No second messenger systems have been directly associated with dynorphine binding, but several likely candidates exist.
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PMID:Pharmacology of dynorphin. 289 33

The synthetic opioid agonist [D-Pro10]-dynorphin(1-11) (DPDYN) binds kappa receptors with both high affinity and selectivity in vitro. We have examined the in vivo characteristics (i.e., analgesic properties) of the peptide in mice. The analgesic effects of i.c.v. administered DPDYN were determined in two nociceptive tests, involving thermal cutaneous (tail-flick) and chemical visceral (AcOH-induced writhing) stimuli, in which mu and kappa receptors are known to be activated differentially. The antinociceptive action of DPDYN was compared with that of 1) morphine and U-50,488H, which are, respectively, the prototypical mu and kappa agonists, 2) dynorphin A which is the endogenous parent peptide and 3) Leu-enkephalin, which represents the N-terminal sequence of DPDYN. DPDYN did not show any activity against thermal stimulus but, in contrast, produced a dose-related effect against chemical pain. In the AcOH-writhing test, there was no significant cross-tolerance between morphine and DPDYN in mice made tolerant to morphine. Pretreatment with low doses of s.c. naloxone (less than 1 mg/kg) antagonized completely the antinociceptive action of morphine but only partially reversed the analgesic action of DPDYN. In gastrointestinal studies, DPDYN as well as U-50,488H were ineffective (maximum effect lower than 25%) in inhibiting intestinal transit in mice, in contrast to morphine which produced a dose-related antitransit effect reaching 100%. These data indicate that the in vivo properties, and particularly analgesia, of i.c.v. administered DPDYN are mediated by a "non-mu" (presumably kappa) opioid receptor at the supraspinal level of the opioid system of the mouse.
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PMID:[D-Pro10]-dynorphin(1-11) is a kappa-selective opioid analgesic in mice. 289 27

This paper illustrates the use of antagonists to study receptor mediation of the discriminative stimulus effects of opioids and to determine if their analgesic effects are mediated in a similar manner. Analysis by pA2 was used to quantify interactions between the opioid antagonist quadazocine and several opioid agonists. Interactions were examined under a drug discrimination procedure and under a tail withdrawal analgesia procedure. Values of pA2 for quadazocine in combination with the kappa agonists bremazocine, ethylketazocine, and U50,488 ranged between 6.1 and 6.4 under the drug discrimination and tail withdrawal procedures. In contrast, the pA2 values for the mu agonists etorphine, fentanyl, and morphine under these procedures ranged between 7.6 and 8.2. The difference between these pA2 values indicates that the affinity of quadazocine for the receptors mediating the effects of the kappa agonists is over one log unit lower than its affinity for the receptors mediating the effects of the mu agonists. This suggests that the discriminative stimulus and analgesic effects of kappa opioid agonists are mediated at the same opioid receptor type, which is different from the type of opioid receptor at which mu agonists produce their discriminative stimulus and analgesic effects.
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PMID:Discriminative and analgesic effects of mu and kappa opioids: in vivo pA2 analysis. 289 16

The ability of the selective cyclic mu-opioid receptor antagonist, D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP), to inhibit the acute and chronic effects of morphine in vivo was studied in mice. Intracerebroventricular (i.c.v.) administration of CTOP antagonized the analgesic effect of morphine in a dose-dependent manner, as measured by the heat-irradiant (tail-flick) method. CTOP was more effective than naloxone in inhibiting analgesia on a molar basis. CTOP also antagonized the acute morphine-induced hypermotility. CTOP caused withdrawal hypothermia and a loss of body weight in morphine-dependent animals. After the development of morphine-induced chronic dependence, CTOP administered i.c.v. caused a dose-dependent loss of body weight and hypothermia, and was about 10-400 times more potent than naloxone. CTOP administered alone to drugnaive mice did not cause antinociception, changes in body weight or body temperature.
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PMID:Central effects of the potent and highly selective mu opioid antagonist D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP) in mice. 290 58

The level of opioid peptides: beta-endorphin and dynorphin, binding to the mu and kappa opioid receptors and the analgesic response of those endogenous opioid systems to stress were investigated in two strains of mice: C57BL/6 (C57) and DBA/2 (DBA). The nociceptive threshold of DBA mice was higher than that of C57 mice. KD values for spinal mu receptors were lower in C57, while KD for cerebral kappa receptors were higher in this strain. DBA mice have significantly higher concentrations of dynorphin in the hypothalamus and neurointermediate lobe of the pituitary. Stress-induced analgesia was much greater in C57 than in DBA mice. In the hypothalamus both stress procedures depressed the concentrations of beta-endorphin in C57, and dynorphin in DBA mice. The level of beta-endorphin increased in the neurointermediate lobe in C57 and in anterior lobe of the pituitary in DBA mice. In the spinal cord both stress procedures depressed the dynorphin level. The above data indicate that C57 and DBA mice differ in the endogenous opioid peptide content, stress-induced alteration and opioid receptor affinity, the effects which might correlate with their different responses to environmental factors and pharmacological agents.
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PMID:The difference in stress-induced analgesia in C57BL/6 and DBA/2 mice: a search for biochemical correlates. 290 36


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