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 analgesic and hyperthermic effects of i.v. administered morphine were determined in age-matched male spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto (WKY) rats. Two doses of morphine (5 and 10 mg/kg) were used. In the doses used, morphine produced analgesia in WKY rats as measured by the tail-flick test and expressed as area under the time-response curve. The intensity and duration of the analgesic area under the time-response curve was significantly greater in SHR rats in comparison to WKY rats. For example, whereas the effect of a 10-mg/kg dose lasted for 4 hr in WKY rats; in SHR rats the effect lasted for 10 hr. Similarly, the intensity and duration of morphine-induced hyperthermic response was greater in SHR rats in comparison to WKY rats. In order to determine if the differences in responses to morphine in SHR and WKY were related to its kinetics, the pharmacokinetic parameters of morphine in serum were determined. The area under the serum morphine concentration-time curve, serum levels of morphine extrapolated to zero time, T1/2, apparent volume of distribution at steady state, terminal elimination rate constant and total body clearance values for morphine in SHR and WKY rats did not differ. Previous studies from this laboratory indicate that the density of mu opiate receptors labeled with [3H]D-Ala2.MePhe4,Gly-ol5-enkephalin and [3H]naltrexone and of kappa-opiate receptors labeled with [3H]ethylketocyclazocine in the brain of SHR rats is higher than in WKY rats.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Pharmacodynamics and pharmacokinetics of intravenously administered morphine in spontaneously hypertensive and normotensive Wistar-Kyoto rats. 156 Mar 74

Extracellular levels of amino acids were measured during the development of experimental arthritis in anesthetized monkeys. Levels of glutamate, aspartate, glycine, serine, glutamine, taurine, cysteic acid and asparagine were each measured in consecutive 30 min samples before, during and for several hours after injection of kaolin and carrageenan into the articular capsule of one knee. Samples were obtained via a microdialysis probe placed in the lumbar dorsal horn ipsilateral to the injected knee and assayed using HPLC with fluorescence detection. Glutamate, aspartate, glycine and serine increased transiently following intra-articular injection of inflammatory agents. During this period glutamine levels decreased. A second phase of release then occurred which included more prolonged changes in amino acid levels that were sometimes of greater magnitude than those immediately following the injection. In animals which were later observed to have depletion of SP in the dorsal horn of the inflamed side, taurine levels increased starting after the Glu, Asp and Gly had plateaued at near baseline concentrations. Thus during the first stages of joint inflammation EAAs are released into the dorsal horn, followed by increased levels of IAAs, possibly representing activation of the descending endogenous analgesia system. This phase is followed by a semiacute response consisting in part of increased extracellular levels of SP and Tau. While SP is presumably part of an ascending nociceptive transmission system, Tau could be part of a second system aimed at reducing excessive neural activity including neural transmission resulting in intense maintained pain.
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PMID:Neural changes in acute arthritis in monkeys. IV. Time-course of amino acid release into the lumbar dorsal horn. 163 74

The mu opioid receptor ligand [D-Ala2, NMePhe4, Gly-ol5]enkephalin (DAGO) and delta opioid receptor ligand [D-Pen2,D-Pen5]enkephalin (DPDPE) show similar specificity in competition binding studies in whole brain homogenate in rat and mouse. However, in saturation studies, the density and affinity of DPDPE binding sites were substantially greater in the mouse. There was no difference between the mouse and rat in the density and affinity of DAGO sites. Results from dose-response studies for analgesia using the same ligands administered i.c.v. in both species paralleled the binding studies. DAGO was approximately 2 times more potent in the mouse compared to the rat; while DPDPE was more than 15 times more potent in the mouse. Thus, binding capacity and affinity differences appear to be related to the functional potency of the mu and delta ligands in the two species. These results suggest that the difference in potency of DPDPE between rat and mouse is related to the differences in brain delta opioid receptors.
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PMID:Species differences in mu- and delta-opioid receptors. 164 25

Ohmefentanyl has been shown to be 6300 times more potent than morphine for analgesia. The receptor binding characteristics and distribution of [3H]ohmefentanyl in rat brain sections are presented. [3H]Ohmefentanyl bound with high affinity to opioid receptors in a saturable manner (Kd = 0.95 +/- 0.08 nM, Bmax = 337 +/- 14 fmol/mg protein). We used various currently available specific mu, delta and kappa ligands to show that [3H]ohmefentanyl has a high selectivity for the mu opioid receptor. However, [D-Ala2,MePhe4,Gly-ol5]enkephalin (DAGO) was unable to completely inhibit [3H]ohmefentanyl specific binding, while complete inhibition was observed with fentanyl derivatives and the benzomorphan derivative, ethylketocyclazocine. This remaining 20% DAGO-inaccessible [3H]ohmefentanyl specific binding did not correspond to either mu1, delta or kappa sites. Haloperidol and 1,3-di-o-tolylguanidine were able to inhibit DAGO-inaccessible [3H]ohmefentanyl specific binding, suggesting that [3H]ohmefentanyl might also bind to haloperidol-sensitive sigma sites. The topographical distribution of [3H]ohmefentanyl found by autoradiography was generally similar to that of [3H]DAGO. However, in agreement with the biochemical results, quantitative analysis revealed additional sites in several rat brain regions, the greatest discrepancies with [3H]DAGO distribution being observed in cerebellum, central grey, hippocampal formation and locus coeruleus. Finally, our results suggest that this capacity of binding to both mu and sigma sites is shared by various fentanyl derivatives.
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PMID:[3H]ohmefentanyl preferentially binds to mu-opioid receptors but also labels sigma-sites in rat brain sections. 164 20

The opioid activity and the selectivity for opioid receptor (subtypes) of newly synthesized fluorinated enkephalin (Enk) analogues, [2R, 4R], [2R, 4S], [2S, 4S] and [2S, 4R] trifluoro-Leu5-Enk (KKF-31, 32, 33 and 34) were investigated. The inhibitory effect of KKF-compounds on the electrically induced contractions of guinea-pig ileum (GPI) and mouse vas deferens (MVD) were dose-dependent but relatively lower than that of L-Leu5-Enk, except that KKF-34 was rather slightly more potent than L-Leu5-Enk in MVD preparations. In GPI preparations, the pA2 values of naloxone for these compounds were higher than those of naltrindole while the values of naltrindole for KKF-compound were higher than those of naloxone in MVD preparations. Intracerebroventricular KKF-31 and KKF-32 at doses of 20 and 10 nmol/mouse, respectively, produced analgesia comparable to 0.1 nmol Tyr-D-Arg-Phe-Lys-NH2 and 100 nmol Tyr-D-Thr-Gly-Phe-Leu-Thr; however, neither KKF-33 nor 34 produced analgesia up to the doses of 100 nmol/mouse. Both naloxone, 1 mg/kg, i.p., and naltrindole, 10 mg/kg, i.p., antagonized KKF-31- and KKF-32-induced analgesia. The results suggest that the introduction of trifluoromethyl group in Leu5 results in the alternation of the opioid activity and receptor selectivity. Although KKF-33 and KKF-34 possessed a more potent in vitro inhibitory effect than KKF-31 and KKF-32, mediated through mu- and delta-opioid receptors in both preparations, they did not show any appreciable analgesic effect. KKF-31 and KKF-32 produce naloxone- and naltrindole-reversible analgesia irrespective of in vitro mu- and delta-opioid activity.
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PMID:The opioid activity and receptor selectivity of fluorinated Leu5 enkephalin analogues in vitro and in vivo. 165 91

Alterations in brain opioid binding and opioid pharmacodynamics following chronic (8-day) naltrexone (NTX) treatment were determined in pertussis toxin (PTX)-treated mice. Intrathecal (IT) and intracerebroventricular (ICV) PTX produced a time-dependent, long-lasting inhibition of morphine (SC) analgesia without modifying basal nociception. Inhibition was maximal 16 days following PTX treatment, and was still observed at 40 days. Relative to placebo controls, NTX treatment produced supersensitivity to morphine analgesia in all control mice and in mice pretreated with PTX 1 day before NTX. Supersensitivity was not observed in 7-day PTX-pretreated mice. [3H][D-Ala2-D-Leu5]enkephalin ([3H]DADLE) and [3H][D-Ala2-MePhe4-Gly(ol)5]enkephalin ([3H]DAMGO) binding sites were increased by NTX treatment in saline- and PTX-pretreated groups. KDs were unchanged. These results indicate that PTX does not alter opioid antagonist-induced receptor upregulation. However, PTX treatment can diminish morphine potency in upregulated and control mice. Therefore, opioid analgesia in control and upregulated mice appears to be mediated by receptors linked to a common PTX-sensitive G-protein. Furthermore, in 7-day PTX-pretreated mice, NTX increased binding sites without altering morphine potency, which suggests that new binding sites can appear without being functionally coupled.
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PMID:Dissociation of opioid receptor upregulation and functional supersensitivity. 165 19

Central morphine analgesia is significantly greater in male than in female rats. Since mu and delta opioid receptor subtypes have been implicated in supraspinal analgesia, the present study evaluated whether gender or adult gonadectomy altered (a) analgesia on the tail-flick and jump tests following central administration of the mu-selective agonist, [D-Ala2, Me-Phe4, Gly(ol)5] enkephalin (DAMGO) and the delta-selective agonist, [D-Ser2,Leu5] enkephalin-Thr6 (DSLET) and (b) mu1, mu2 and delta opioid receptor binding. Sham-operated male rats displayed significantly greater magnitudes of peak and total analgesia than sham-operated females on the tail-flick test following DAMGO, but not DSLET. Gender differences were not observed for DAMGO and DSLET analgesia on the jump test. Gonadectomy failed to consistently affect either DAMGO or DSLET analgesia. Regression analyses failed to reflect significant shifts in the dose-response functions for either agonist on either measure. Gender differences were not observed for mu1, mu2, or delta binding in hypothalamus or cortex. These data are compared with analgesic responses sensitive to gender differences.
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PMID:Gender effects and central opioid analgesia. 167 51

The opioid receptor types involved in supraspinal and spinal heroin-induced analgesia in Swiss Webster and ICR mice were determined by intracerebroventricular (i.c.v.) and intrathecal (i.t.) administration of opioid agonists and antagonists. Also, comparisons were made with morphine. Antinociception was measured by changes in tail-flick latency. In Swiss Webster mice, i.c.v. heroin like [D-Pen2-D-Pen5]enkephalin, a delta receptor opioid agonist, activated supraspinal delta opioid receptors as evidenced by inhibition of analgesia by coadministration of naltrindole, a delta receptor antagonist. Lack of effect of i.t. yohimbine and methysergide vs. i.c.v. heroin indicated that spinal descending noradrenergic and serotonergic systems were not involved. Heroin and [D-Pen2-D-Pen5]enkephalin were also matched in producing additive interactions with i.t. opioids. Also, i.c.v. heroin like [D-Pen2-D-Pen5]enkephalin did not activate a dynorphin-mediated antianalgesic system. In ICR mice, i.c.v. heroin receptor selectivity matched that of i.c.v. Tyr-D-Ala2-Gly-NMePhe4-Gly-ol5, a selective mu receptor opioid agonist. Analgesia was inhibited by pretreatment with i.c.v. beta-funaltrexamine, a nonequilibrium mu receptor antagonist. Intrathecal administration of methysergide inhibited i.c.v. heroin-induced analgesia whereas i.t. yohimbine had no effect, which indicated that a descending serotonergic system but not a noradrenergic system was involved. Low doses of i.t. naloxone and nor-binaltorphimine increased the analgesic effect. This effect was consistent with activation of an antianalgesic system by i.c.v. heroin, which was mediated by dynorphin A in the spinal cord. Desensitization of the antianalgesic system also resulted in increased analgesia. In both Swiss Webster and ICR mice, i.t. heroin-induced analgesia involved spinal mu receptors like those stimulated by Tyr-D-Ala2-Gly-NMePhe4-Gly-ol5. Analgesia was inhibited by i.t. naloxone. In both strains, i.t. heroin, like i.t. Tyr-D-Ala2-Gly-NMePhe4-Gly-ol5, produced an additive interaction with i.t. clonidine. In conclusion, the supraspinal receptors activated by heroin are different between Swiss Webster and ICR mice. In both strains, the receptor selectivities assigned to heroin did not match those for morphine. Heroin did not act by being biotransformed to morphine.
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PMID:Heroin acts on different opioid receptors than morphine in Swiss Webster and ICR mice to produce antinociception. 184 96

The effect of chronic opioid antagonist-induced functional supersensitivity and receptor upregulation on morphine tolerance was examined in Swiss Webster mice obtained from Taconic Farms and Charles River Laboratories. Mice were implanted s.c. with either naltrexone (NTX) or placebo pellets for 8 days. After 8 days, the pellets were removed, and 24 h later mice were either injected with morphine (50 or 100 mg/kg) or saline (acute tolerance protocol) or implanted with a 75-mg morphine or placebo pellet for 72 h (chronic tolerance protocol). Mice were tested for morphine analgesia 24 h after injections or 72 h after pellet implantations. Mice from Taconic Farms were more sensitive to morphine analgesia than Charles River mice, although the degree of tolerance in both strains was similar. Acute morphine produced a 1.7- and 1.9-fold increase in the ED50 for morphine analgesia in NTX and placebo pretreated mice, respectively. the chronic tolerance protocol produced the same shift (2.4-fold) in the ED50 in both NTX and placebo pretreated mice. In both tolerance protocols, NTX-pretreated mice were significantly more sensitive to the analgesic effects of morphine than placebo pretreated controls. Binding studies ([3H][D-Ala,2NMePhe4,Gly-ol5]enkephalin) indicated an approximately 40% increase in opioid receptor density with no significant alteration in affinity after chronic NTX treatment. These results indicate that acute and chronic tolerance to morphine develops comparably in control and upregulated, supersensitive mice. These findings suggest that new binding sites in upregulated mice mediate tolerance similarly to existing binding sites and that the degree of tolerance is unrelated to the density of opioid receptors.
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PMID:The role of opioid receptor density in morphine tolerance. 184 2

The peptidase-resistance and bioavailability of BUBU [H-Tyr-D.Ser(OtBu)-Gly-Phe-Leu-Thr(OtBu)-OH], a highly selective and potent agonist of the delta opioid receptor, have been investigated in vitro and in vivo. In vitro at 37 degrees C, the peptide was fully resistant to degradation by rat serum and strongly resistant to degradation by rat brain membranes. In vivo 0.065% of the dose of [3H]BUBU injected intravenously to the mouse was present 15 min later in the brain. The percentage determined for [3H]DAGO [H-Tyr-D.Ala-Gly-(NMe)Phe-Gly-ol], a selective ligand for mu sites, was 0.038%. Specific binding to mouse brain membranes, determined after intracerebroventricular injection of [3H]BUBU, was saturable and a high affinity (KDapp = 25 pmol) was evaluated for the delta-agonist. Competition experiments showed that BUBU is a selective ligand for delta receptors in vivo. Comparison of the analgesic potency (hot plate test) of ICV or IV administered increasing doses of BUBU and DAGO with their in vivo binding properties supports the preferential involvement of mu receptors in supraspinal analgesia. BUBU also induced an increase in spontaneous locomotion after IV administration at a dose lower than that which produced analgesia. The quantitative results obtained in the present study demonstrate that BUBU and DAGO could be used to characterize the pharmacological responses induced by selective stimulation of delta and mu receptors after systemic administration.
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PMID:Brain passage of BUBU, a highly selective and potent agonist for delta opioid receptors: in vivo binding and mu versus delta receptors occupancy. 185 Jan 35


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