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)

To investigate the possible mechanisms of the alterations in morphine-induced analgesia observed in diabetic mice, we examined the influence of streptozotocin-induced (STZ-induced) diabetes on analgesia mediated by the different opioid receptors. The antinociceptive potency of morphine (10 mg/kg), administered s.c., as determined by both the tail-pinch and the tail-flick test, was significantly reduced in diabetic mice as compared to that in controls. Mice with STZ-induced diabetes had significantly decreased sensitivity to intracerebroventricularly (i.c.v.) administered mu-opioid agonists, such as morphine (10 micrograms) and [D-Ala2,N-Me Phe4,Gly-ol5]enkephalin (DAMGO, 0.5 micrograms). However, i.c.v. administration of [D-Pen2,5]enkephalin (DPDPE, 5 micrograms), a delta-opioid agonist, and U-50,488H (50 micrograms), a kappa-opioid agonist, produced pronounced antinociception in both control and diabetic mice. Furthermore, there were no significant differences in antinociceptive potency between diabetic and control mice when morphine (1 microgram), DAMGO (10 micrograms), DPDPE (0.5 micrograms) or U-50,488H (50 micrograms) was administered intrathecally. In conclusion, mice with STZ-induced diabetes are selectively hyporesponsive to supraspinal mu-opioid receptor-mediated antinociception, but they are normally responsive to activation of delta- and kappa-opioid receptors.
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PMID:Streptozotocin-induced diabetes selectively alters the potency of analgesia produced by mu-opioid agonists, but not by delta- and kappa-opioid agonists. 131 65

TRIMU-5 (Tyr-D-Ala-Gly-NH-(CH2)2CH(CH3)2) is a potent enkephalin analog with analgesic actions. Detailed studies show high affinity for both mu 1 and mu 2 sites, with poor affinity for delta, kappa 1 and kappa 3 receptors. Of all the mu ligands examined in binding assays, TRIMU-5 was the most mu-selective. In mice, TRIMU-5 administered either intracerebroventricularly (i.c.v.) or intrathecally elicited analgesia which was readily reversed by the mu-selective antagonist beta-funaltrexamine (beta-FNA). However, the analgesia observed following i.c.v. injections differed from traditional mu ligands: (1) the dose of drug required for analgesic activity i.c.v. was 100-fold greater than those following intrathecal administration; (2) although sensitive to beta-FNA, the analgesia was not antagonized by naloxonazine; and (3) the analgesia was reversed by an opioid antagonist given intrathecally (i.t.) but not i.c.v. Thus, TRIMU-5 analgesia appeared to be mediated spinally through mu 2 receptors. TRIMU-5 did have supraspinal actions, inhibiting gastrointestinal transit, another mu 2 action. In binding studies TRIMU-5 had high affinity for mu 1 sites, but pharmacological studies revealed antagonist actions at this receptor. In mice, the analgesia produced by morphine given i.c.v. was antagonized by coinjection of a low TRIMU-5 dose which was inactive alone. Similarly, TRIMU-5 coadministered with morphine into the periaqueductal gray of rats reversed the analgesia seen with morphine alone. Thus, TRIMU-5 is a highly selective mixed mu 2 opioid receptor agonist/mu 1 opioid receptor antagonist.
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PMID:Analgesic potency of TRIMU-5: a mixed mu 2 opioid receptor agonist/mu 1 opioid receptor antagonist. 132 12

TRIMU-5 (Tyr-D-Ala-Gly-NHC2H4CH(CH3)2) is a potent mu 2-opioid agonist/mu 1-opioid antagonist. A supraspinal dose (0.5 micrograms i.c.v.) of TRIMU-5 which is not analgesic when given alone antagonizes the analgesia produced by intracerebroventricular (i.c.v.) morphine, a mu 1 action. In contrast, in a synergy model consisting of the simultaneous administration of intrathecal morphine (0.1 micrograms) with multiple doses of i.c.v. morphine, the same supraspinal TRIMU-5 dose (0.5 micrograms i.c.v.) enhances analgesia. Supraspinal TRIMU-5 also potentiates spinal morphine directly, shifting its dose-response to the left. These results imply that within the brainstem mu 1 receptors mediate supraspinal analgesia while mu 2 receptors mediate the synergy with spinal mu systems.
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PMID:Supraspinal mu 2-opioid receptors mediate spinal/supraspinal morphine synergy. 133 Jun 18

Chronic treatment with an opioid antagonist, such as naltrexone, increases opioid receptor density and opioid agonist potency. Since stimulants such as d-amphetamine can increase opioid potency and opioid abusers may administer stimulants during naltrexone treatment, the effect of chronic d-amphetamine on naltrexone-induced opioid receptor upregulation and supersensitivity was examined in mice. Mice were implanted s.c. with a 15 mg naltrexone or placebo pellet for 8 days. Mice were injected daily with saline or d-amphetamine (7.5 or 5.0 mg/kg per day s.c.) for 7 days beginning 24 h following implantation. Naltrexone and placebo pellets were removed on the 8th day, and 24 h later mice were tested for morphine analgesia (tail-flick) or whole brain was removed and opioid receptor binding studies were conducted. Chronic naltrexone significantly enhanced the analgesic potency of morphine in saline-treated mice. However, naltrexone treatment did not increase morphine potency in mice treated with d-amphetamine. In binding studies, naltrexone increased [3H][D-Ala2,NMePhe4,Gly-ol5]enkephalin (DAGO) Bmax (+60-70%) without altering KD in both saline- and d-amphetamine-treated mice. Results from studies with 2 nM [3H][D-Pen2,D-Pen5]enkephalin (DPDPE) were similar. These studies indicate that daily d-amphetamine can limit naltrexone-induced supersensitivity but not receptor upregulation. Thus, upregulation can be dissociated from functional supersensitivity.
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PMID:Chronic d-amphetamine inhibits opioid receptor antagonist-induced supersensitivity. 133 Jun 22

A recently developed series of highly selective and systemically active delta-agonists such as Tyr-X-Gly-Phe-Leu-Thr(OtBu), with X = D-Ser (OtBu) in BUBU and X = D-Cys(OtBu) in BUBUC, and complete inhibitors of enkephalin metabolism (Kelatorphan, RB 38A, RB 101) have enabled the major role played by mu-opioid receptors in supraspinal analgesia to be demonstrated. This is in agreement with the results of in vivo mu-receptor occupancy measured by taking into account the cross-reactivity of the delta-ligand for mu-sites. In contrast mu and delta binding sites seem to act independently to control pain at the spinal level. Strong analgesic effects can also be obtained by complete protection of tonically or phasically released endogenous enkephalins with mixed inhibitors. Chronic i.c.v. administration of the mu agonist DAMGO, led to a severe naloxone precipitated withdrawal syndrome whilst a weak dependence was seen with the delta agonist, DSTBULET or with RB 38A and none after repeated i.p. injection of RB 101, a systemically active mixed inhibitor. Moreover, chronic administration of RB 101 did not induce antinociceptive tolerance, a major side effect observed during chronic administration of opiates. These differences could be related to a more efficient and selective stimulation of opioid receptors by the endogenous enkephalins. This suggest that the large changes in receptor density, adenylate cyclase activity or phosphorylation of proteins following chronic morphine treatment is not significantly triggered by occupation of the opioid receptors by their natural ligands. All these data emphasize the interest in developing delta-agonists and mixed inhibitors with appropriate bioavailability for clinical evaluation.
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PMID:[Selective opioid agonists and inhibitors of enkephalin degradation enzymes: pharmacological and clinical values]. 133 50

The endogenous opioid peptides are known to play a significant role in the modulation and/or mediation of numerous environmental or experimental stressors. However, the specific opioid peptide(s) and receptor type(s) involved, under what physiologic conditions they are engaged and within which regions of the CNS is not well understood. We therefore examined the effects of both a chronic and an acute stressor-90-h water deprivation and a single 20-min foot shock on opioid receptor binding in 17 specific rat brain nuclei. [3H]DSTLE (Tyr-D-Ser-Gly-Phe-Leu-Thr) and [3H]DAGO(Tyr-D-Gly-Phe-NMe-Phe-Gly-ol) were used to label delta and mu receptors, respectively. Foot shock induced profound antinociception as measured by tail-flick latency which outlasted the stressor by several minutes. However, only the septum responded with a decrease in [3H]DAGO binding to this type of stress-induced analgesia. No other alterations in either [3H]DAGO or [3H]DSTLE binding were seen in response to foot shock. In contrast, water deprivation induced increases in [3H-DAGO] binding in the septum as well as increases in [3H]DSTLE binding in the caudate and accumbens nuclei. Moreover, the presumptive mild stress of handling in the foot shock control group was sufficient to decrease mu or delta receptor binding in seven out of 17 brain regions investigated (including the frontal cortex and olfactory tubercle where both mu and delta binding were increased) when compared to unhandled deprivation control animals. These changes in opioid receptor binding may have been the result of alterations in treatment-induced peptide release, receptor regulation, or interactions with other released neurotransmitter ligand/receptor complexes.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effects of stress on opioid receptor binding in the rat central nervous system. 133 24

These studies examined the effect of cocaine on the analgesia produced by systemically and centrally administered opioid agonists. Cocaine (50 mg/kg, s.c.) increased the analgesic potency of systemic, ICV and IT morphine; and the ICV and IT analgesic effects of the delta selective peptide, [D-Pen2,D-Pen5]enkephalin (DPDPE). Cocaine also increased the analgesic potency of the mu selective ligand [D-Ala2,NMePhe4,Gly-ol5]enkephalin (DAGO) administered ICV. However, cocaine did not alter the ED50 for IT DAGO. GC-MS studies indicated that brain cocaine concentration was approximately 3.0 micrograms/g wet weight 45 min following s.c. administration. These results suggest that cocaine-induced increases in opioid analgesic potency are mediated at brain mu and delta receptors and spinal mu receptors. Furthermore, there might be functional differences between spinal and supraspinal sites at which DAGO produces analgesia.
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PMID:Potentiation of opioid analgesia by cocaine: the role of spinal and supraspinal receptors. 134 44

Dynorphin A-(1-13)-Tyr-Leu-Phe-Asn-Gly-Pro (Dyn Ia; 1-8 nmol) injected intracerebroventricularly in the mouse produces two independent behavioral effects: (1) a norbinaltorphimine (kappa opioid antagonist)-reversible analgesia in the acetic acid-induced writhing test and (2) motor dysfunction characterized by wild running, pop-corn jumping, hindlimb jerking and barrel rolling and antagonized by the irreversible phencyclidine (PCP) and sigma (sigma) receptor antagonist, metaphit and the non-competitive N-methyl-D-aspartate (NMDA) receptor antagonists, dextromethorphan and ketamine. The specific involvement of the PCP receptor in the motor effects of Dyn Ia is supported by the direct competitive interaction of the peptide with the binding of [3H]MK-801 (Ki: 0.63 microM) and [3H]TCP (Ki: 4.6 microM) to mouse brain membrane preparations.
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PMID:Selective involvement of kappa opioid and phencyclidine receptors in the analgesic and motor effects of dynorphin-A-(1-13)-Tyr-Leu-Phe-Asn-Gly-Pro. 135 18

Pharmacological assays in isolated tissues and binding tests have recently shown that two peptides, with the sequence Tyr-D-Ala-Phe-Asp-(or Glu)- Val-Val-Gly-NH2, isolated from skin extracts of Phyllomedusa bicolor and named [D-Ala2]deltorphin I and II, respectively, possess a higher affinity and selectivity for delta-opioid receptors than any other known natural compound. Since much evidence supports the role of spinal delta-opioid sites in producing antinociceptive effects, we investigated whether analgesia might be detected by direct spinal cord administration of [D-Ala2]deltorphin II (DADELT II) in the rat. The thermal antinociceptive effects of intrathecal DADELT II and dermorphin, a potent mu-selective agonist, were compared at different postinjection times by means of the tail-flick test. The DADELT II produced a dose-related inhibition of the tail-flick response, which lasted 10-60 min depending on the dose and appeared to be of shorter duration than the analgesia produced in rats after intrathecal injection of dermorphin (20-120 min). The analgesic effect of infused or injected DADELT II was completely abolished by naltrindole, the highly selective delta antagonist. These results confirm the involvement of delta receptors in spinal analgesic activity in the rat.
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PMID:Spinal antinociceptive effects of [D-Ala2]deltorphin II, a novel and highly selective delta-opioid receptor agonist. 136 79

There is evidence suggesting that the endogenous tetrapeptide, Tyr-MIF-1 (Tyr-Prol-Leu-Gly-amide), has antagonistic or modulatory effects on opioid-mediated analgesia. There is also substantial evidence for sex differences in opioid effects, whereby male rodents display greater levels of opioid-mediated analgesia than females. In the present study, determinations were made of the effects of Tyr-MIF-1 on morphine- and restraint stress-induced opioid analgesia in adult male and female deer mice, Peromyscus maniculatus. Intraperitoneal treatment with Tyr-MIF-1 (0.10-10 mg/kg) reduced morphine- and stress-induced analgesia in both male and female mice, with Tyr-MIF-1 having markedly greater antagonistic effects in male than female mice. These results indicate that there are sex differences in the modulatory (antiopiate) effects of Tyr-MIF-1 on opioid-mediated analgesia.
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PMID:Sex differences in the effects of Tyr-MIF-1 on morphine- and stress-induced analgesia. 136 81


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