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)

The effect of cyclo(Leu-Gly) on U-50,488H- induced pharmacological actions was determined in male Sprague-Dawley rats. Intraperitoneal (i.p.) administration of U-50,488H to rats produced analgesia (tail-flick) and increased urinary output. Cyclo (Leu-Gly) (1-4 mg/kg, s.c.) antagonized the analgesic response to U-50,488H (25 mg/kg; i.p.). A dose of 10 mg/kg (i.p.) of U-50,488H increased the spontaneous urinary output which was antagonized by cyclo (Leu-Gly) (1-4 mg/kg; s.c.). To determine whether cyclo (Leu-Gly) was acting as a kappa-opioid receptor antagonist, the effect of cyclo (Leu-Gly) on the binding of [3H]ethylketocyclazocine (EKC) to membranes of rat cerebral cortex and spinal cord was determined. The IC50 values of cyclo(Leu-Gly) in displacing [3H]EKC from its binding sites in cortex and spinal cord were 1.44 and 0.40 mM, respectively. Chronic administration of U-50,488H (25 mg/kg; i.p., b.i.d.) for 4 days induced tolerance to its analgesic effect. The latter was not affected by cyclo(Leu-Gly) (2 to 8 mg/kg; s.c.) given once a day for 4 days. It is concluded that cyclo(Leu-Gly) antagonizes acute actions of U-50,488H and that such effects of cyclo(Leu-Gly) are not mediated via a direct action on kappa-opioid receptors.
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PMID:Antagonism of kappa opioid mediated effects in the rat by cyclo(Leu-Gly). 255 73

The effects of body rotation in a horizontal plane and various opiate antagonists on the nociceptive responses of a day-active microtine rodent, the meadow vole, Microtus pennsylvanicus, were examined. Intermittent rotation (70 rpm, schedule of 30 sec on, 30 sec off) for 30 min induced significant analgesic responses in the voles for 15 min after rotation. These increases in thermal response latency were blocked by intraperitoneal pretreatment with either naloxone or the irreversible mu opiate receptor antagonist beta-funaltrexamine (beta-FNA; 10 mg/kg; 24 hr pretreatment). This antagonistic effect of beta-FNA indicates mu opioid involvement in the mediation of rotation-induced analgesia. The antiopiate peptides MIF-1 (Pro-Leu-Gly-NH2) and Tyr-MIF-1 also significantly reduced, though did not completely block, body rotation-induced opiate analgesia. This suggests that Tyr-MIF-1 and MIF-1 have significant antagonistic effects on mu opioid systems that are involved in the mediation of stress (rotation)-induced analgesia.
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PMID:Differential inhibitory effects of MIF-1, Tyr-MIF-1, naloxone and beta-funaltrexamine on body rotation-induced analgesia in the meadow vole, Microtus pennsylvanicus. 257 Nov 38

To elucidate the mechanism for the suppression by concurrent footshock (FS) exposure of the development of morphine tolerance, the effect of adrenalectomy and a possible participation of glucocorticoids in the mechanism were examined. The analgesic effect of morphine was potentiated in adrenalectomized (ADX) mice, and further enhancement of the effect was shown by the simultaneous exposure to FS (2 mA, 0.2 Hz, 1 sec duration for 15 min) stress, while no such effects were observed in sham-operated (Sham) animals. Daily morphine treatment developed tolerance in Sham and ADX mice. The combined treatment with FS stress suppressed the development of morphine tolerance in Sham mice, whereas such suppression was abolished by adrenalectomy. The suppression of tolerance development was restored in ADX mice by supplement of prednisolone. In contrast to FS stress which produces analgesia through an opioid receptor, forced swimming stress which exerts analgesia through a non-opioid mechanism did not affect the development of morphine tolerance in both Sham and ADX mice. Thus, an opioid mediated stress, FS, could prevent the development of morphine tolerance, and adrenal glucocorticoids play an essential role in the mechanism.
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PMID:Role of adrenal glucocorticoids in the blockade of the development of analgesic tolerance to morphine by footshock stress exposure in mice. 262 90

Electrical stimulation of the ventral midbrain in freely moving rats led to an antinociception against both noxious heat and noxious pressure. Recurrent stimulation was associated with a progressive loss of the antinociceptive efficacy of stimulation. Rats adapted ("tolerant") to stimulation revealed a significant reduction in the antinociceptive potency of a low dose of the systemically applied selective mu-opioid agonist, morphine. In distinction, the antinociceptive effect of the selective kappa-agonist, trans-3,4-dichloro-N-methyl-N[2-(1-pyrrolidinyl)cyclohexyl]benzeneacetam ide (U50488H) was not modified. In the presence of naloxone, delivered subcutaneously via minipumps at a low dose for 7 days, the antinociceptive action of morphine was abolished, whereas that of U50488H was not attenuated: this reflects the selective blockade of mu-receptors. Rats receiving naloxone failed to develop an antinociception upon midbrain electrical stimulation. Removal of the pumps led to a supersensitivity to the antinociceptive effects of morphine but not U50488H. Similarly, midbrain stimulation-produced antinociception was enhanced. These data demonstrate that (1) midbrain stimulation-produced analgesia is selectively cross-tolerant to a mu- as compared to a kappa-agonist; (2) a very low dose of naloxone selective for the mu-receptor blocks midbrain stimulation-produced analgesia, and (3) chronic naloxone treatment leads to a selective supersensitivity to a mu-agonist as compared to a kappa-agonist and an enhancement of midbrain stimulation-produced analgesia. Collectively, the data indicate that a mu-opioid receptor mediates midbrain stimulation-produced analgesia in the rat against both noxious heat and noxious pressure.
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PMID:Evidence that mu-opioid receptors mediate midbrain "stimulation-produced analgesia" in the freely moving rat. 282 72

This study was essentially an in vivo protection experiment designed to test further the hypothesis that stress induces release of endogenous opioids which then act at opioid receptors. Rats that were either subjected to restraint stress for 1 hr or unstressed were injected ICV with either saline or 2.5 micrograms of beta-funaltrexamine (beta-FNA), an irreversible opioid antagonist that alkylates the mu-opioid receptor. Twenty-four hours later, subjects were tested unstressed for morphine analgesia (tail-flick assay) or were sacrificed and opioid binding in brain was determined. [3H]D-Ala2NMePhe4-Gly5(ol)enkephalin (DAGO) served as a specific ligand for mu- opioid receptors, and [3H]-bremazocine as a general ligand for all opioid receptors. Rats injected with saline while stressed were significantly less sensitive to the analgesic action of morphine 24 hr later than were their unstressed counterparts. Beta-FNA pretreatment attenuated morphine analgesia in an insurmountable manner. Animals pretreated with beta-FNA while stressed were significantly more sensitive to the analgesic effect of morphine than were animals that received beta-FNA while unstressed, consistent with the hypothesis that stress induces release of endogenous opioids that would protect opioid receptors from alkylation by beta-FNA. beta-FNA caused small and similar decreases in [3H]-DAGO binding in brain of both stressed and unstressed animals. Stressed rats injected with saline tended to have increased levels of [3H]DAGO and [3H]-bremazocine binding compared to the other groups. This outcome may be relevant to the tolerance to morphine analgesia caused by stress.
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PMID:Effects of stress and beta-funal trexamine pretreatment on morphine analgesia and opioid binding in rats. 282 50

The kappa-opioid compound U-69,593 was studied in rats in vitro in binding assays to assess its selectivity at the single types of opioid sites and in vivo to assess its analgesic activity and effect on intestinal propulsion. In vitro the U-69,593 inhibition curve of [3H]-(-)-bremazocine binding suppressed at mu- and alpha-sites was biphasic and the inhibition constant (Kl) at the high-affinity site (10-18 nM) was two orders of magnitude smaller than the Kl at the low-affinity site. The Kl at mu- and alpha-sites were respectively 3.3 and 8.5 microM. Thus [3H]-(-)-bremazocine, suppressed at mu- and alpha-sites, may still bind more than one site, which U-69,593 might distinguish. In vivo U-69,593 i.p. prolonged the reaction time of rats on a 55 degrees C hot-plate and the dose of naloxone required to antagonize this effect was 40 times the dose that antagonized morphine-induced antinociception, suggesting the involvement of the kappa-receptor. In the intestinal transit test U-69,593 at doses between 0.5 and 15 mg/kg i.p. only slightly slowed intestinal transit of a charcoal meal in rats with no dose-relation; it partly but significantly antagonized morphine-induced constipation. These results suggest that the kappa-type of opioid receptor, with which U-69,593 interacts may induce analgesia, but has no appreciable role in the mechanisms of opioid-induced inhibition of intestinal transit in rats.
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PMID:Interaction of U-69,593 with mu-, alpha- and kappa-opioid binding sites and its analgesic and intestinal effects in rats. 282 59

The icv injection of morphine or DADLE ED50 a few min before the alkylating agent beta-FNA resulted in complete protection of their respective analgesic effects when evaluated 24h later, although a little cross-protection could be observed. The analgesia evoked by DADLE was partially protected using higher doses of morphine before beta-FNA. However, higher doses of DADLE did not protect the analgesia induced by morphine. On the other hand, the antagonistic action of KCl on opioid analgesia was found to be dependent on the opioid utilized to protect the opioid receptor against the effect of beta-FNA. These results are discussed in terms of multiple receptors mediating opioid analgesia at supraspinal level in the mouse.
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PMID:Opioid analgesia in the mouse: evidence for multiple receptors using beta-FNA. 282 93

Clinically, patients often demonstrate incomplete cross-tolerance between opiate analgesics. Although dispositional and pharmacokinetic factors may be a factor, our results suggest that differences in selectivity of various opioids for those opioid receptor subtypes involved in analgesia, mu 1, kappa and delta, also play an important role. In binding studies, levorphanol potently labelled all 3 classes whereas morphine was relatively selective for mu sites. Levorphanol infusions yielded tolerance to both morphine and levorphanol while morphine infusions selectively produced tolerance to morphine. This unidirectional tolerance might be due to the selectivity of morphine for mu receptors compared to levorphanol's ability to interact more potently with other relevant receptor subtypes. These observations raise the possibility that the order in which different opioid analgesics are administered may be of clinical significance.
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PMID:Unidirectional analgesic cross-tolerance between morphine and levorphanol in the rat. 283 16

The 4-(m-OH-phenyl)piperidines are a flexible fragment of the morphine/benzomorphan fused-ring opioids. Analogs in this family were synthesized with varying 4-alkyl substituents increasing in bulk from H through methyl, n-propyl, to t-butyl, each with the three N-substituents methyl, allyl, and phenethyl. These twelve compounds were evaluated for analgetic agonism in mice using two different models for antinociceptive activity, acetic acid writhing and tail-flick, the latter by both subcutaneous and intracerebroventricular routes of administration. Antagonism to morphine analgesia was also measured by the mouse tail-flick procedure. Binding affinities of these new analogs to different opioid receptor subtypes were determined. Energy conformational calculations on these compounds were also carried out using the empirical energy program called MOLMEC, in order to better understand how the 4-R substituents modulate receptor binding affinities and efficacies. The results obtained show that, in general, the compounds studied are mu-selective and vary in agonist potency from weak to morphine-like. Significant differences in rank order of analgetic potencies and their relationship to receptor affinities were obtained from the results of subcutaneous and intracerebroventricular administration. Results of energy-conformational calculations for twelve N-methyl compounds indicate that those with 4-alkyl substituents favor a common, non-morphine-like phenyl axial conformation. The 4-t-butyl compounds are, in fact, the first simple mono-alkyl-substituted 4-phenyl-piperidines predicted to definitely exist in a phenyl axial conformation, as confirmed by X-ray analysis. On the basis of this common phenyl axial conformation, the observed variation in mu receptor affinities and efficacies of the 4-methyl, 4-n-propyl, and 4-t-butyl compounds could be understood and the behavior of 4-ethyl and 4-isopropyl analogs predicted. Two equatorial conformers (rotamers) were found to be the preferred forms of the analogs with 4-R being H or an ester group, or with a 3-methyl group added trans (beta) to the 4-R group. Taking into account the rotational flexibility of these analogs, these two conformers could be used to understand differences in high and low efficacy compounds observed among analogs with preferred phenyl equatorial conformations. None of the analogs exhibit a fused-ring-like N-substituent modulation of efficacy. This result can, perhaps, be understood by their inability in any proposed conformer to totally mimic key receptor interactions of both the phenol-OH and N-substituent portions of the fused compounds.
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PMID:Structure-activity studies of morphine fragments. I. 4-alkyl-4-(m-hydroxy-phenyl)-piperidines. 284 51

Chronic treatment with opioid antagonists increases the potency of opioid agonists and produces an increase in brain opioid binding sites. In the present study, 8 day treatment with naltrexone blocked morphine and DADLE analgesia for the entire treatment period and increased mu 1, mu 2 and delta opioid receptor binding sites in mouse brain. mu 1 and mu 2 binding were increased by 81 and 67%, respectively, while delta binding was increased by 31%. Consistent with these binding changes, the potency of ICV morphine to produce analgesia was increased by over 3-fold, while the potency of ICV DADLE was increased by only 1.7. These findings indicate that relative increases in opioid receptor subtypes agree with pharmacodynamic studies on potency changes of opioid agonists.
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PMID:Upregulation of opioid receptor subtypes correlates with potency changes of morphine and DADLE. 284 19


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