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Query: UMLS:C0030193 (pain)
 261,466 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Interactions between selective opioid agonists acting at spinal mu-, delta-, and kappa-opioid receptors were evaluated by co-administering a low-antinociceptive dose of the selective delta-agonist, DPDPE, or the selective kappa-agonist, U50,488H, with sequentially increasing doses of the selective mu-agonist, DAMGO, intrathecally. Antinociceptive synergy (i.e., a more than additive antinociceptive effect) was observed with both combinations of opioid agonists tested. The demonstration of antinociceptive synergy suggests that the subtypes of spinal opioid receptors can act, at least in part, through a common neural circuit. Since our measure of antinociception, the Randall-Selitto paw-withdrawal test, is dependent on a normally functioning motor system, we also evaluated the effects of these same combinations of opioid peptides on motor coordination using a rotarod treadmill. A low-antinociceptive dose of DPDPE or U50,488H co-administered intrathecally, with sequentially increasing doses of DAMGO, did not worsen the decrement in rotarod performance observed with the same doses of DAMGO administered as a single agent. In fact, the low-antinociceptive dose of DPDPE significantly attenuated the decrease in rotarod performance produced when the same dose of DAMGO was administered as a single agent. The results of this study suggest that intrathecal combinations of selective mu- with both delta- or kappa-selective opioid agonists can produce antinociceptive synergy without producing an increase in motor side effects.(ABSTRACT TRUNCATED AT 250 WORDS)
Pain 1992 Apr
PMID:Antinociceptive and motor effects of delta/mu and kappa/mu combinations of intrathecal opioid agonists. 149 67

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

This study investigated the regulation of serotonin (5-HT) and its major metabolite 5-hydroxyindoleacetic acid (5-HIAA) in the dorsal spinal cord of awake, freely moving rats, using microdialysis coupled to HPLC with electrochemical detection and tested the hypothesis that opioids exert their analgesic effect in part through the increased release of 5-HT in the dorsal horn. A dialysis tube was placed transversely at the L4 segment of the dorsal spinal cord and the basal concentration of 5-HT in the dialysate was characterized by infusion of a variety of substances through the dialysis probe: tetrodotoxin (TTX), KCl, imipramine, fluoxetine and amphetamine (AMPH). To evaluate the contribution of opioids, we also studied the effects of either systemic or intracerebroventricular (i.c.v.) injection of morphine or DAMGO. Extracellular concentrations of 5-HT and 5-HIAA were partially and reversibly reduced by TTX. In the presence of KCl, imipramine, fluoxetine or AMPH, 5-HT levels significantly increased. Under these conditions, extracellular 5-HIAA levels usually decreased. By contrast, the effects of opioids on 5-HT concentrations were highly variable. Low doses of morphine administered systemically increased 5-HT concentrations in only 3 of 6 rats. This was paralleled by a decrease in 5-HIAA. Higher doses of morphine, alone or in the presence of fluoxetine, did not change 5-HT concentrations. Intracerebroventricular injection of morphine or DAMGO increased the extracellular concentrations of 5-HT in only about one third of the animals. After intracerebroventricular opioid injection, extracellular concentrations of 5-HIAA either decreased by about 20% or did not change.(ABSTRACT TRUNCATED AT 250 WORDS)
Pain 1992 Mar
PMID:Do opioids evoke the release of serotonin in the spinal cord? An in vivo microdialysis study of the regulation of extracellular serotonin in the rat. 137 24

N-([(R,S)-2-benzyl-3[(S)(2-amino-4-methylthio)butyl dithio]-1-oxopropyl)-L-phenylalanine benzyl ester (RB101) is the first systemically active prodrug generating through a biologically dependent cleavage of the disulfide bond the potent (S)2-amino-1-mercapto-4-methylthio butane (aminopeptidase N) (IC50 = 11 nM) and N-[(R,S)-2-mercapto-methyl-1-oxo-3-phenylpropyl]-L-phenylalanine (neutral endopeptidase) (IC50 = 2 nM) inhibitors (aminopeptidase N). RB101 easily crosses the blood-brain barrier, as shown by the observed complete inhibition of cerebral endopeptidase 24.11 after i.v. injection in mice. The prodrug induces strong, dose-dependent antinociceptive responses in mice after i.v., i.p. or s.c. administration, in the hot plate (ED50 = 9 mg/kg) and phenylbenzoquinone-induced writhing (ED50-3.25 mg/kg) tests in mice, which are currently used in analgesics screening. RB101 is also active in the tail-flick and tail-electric stimulation tests in rats. In contrast, under disulfide forms, the above selective aminopeptidase N or endopeptidase 24.11 inhibitors are inactive after i.v. administration and their association 3 times less potent than RB101 alone. In all the tests used, the pain-alleviating effect of RB101 was suppressed by naloxone, but, except for the tail-flick and the motor response to tail-electric stimulation, not by the delta-selective antagonist naltrindole. The preferential involvement of mu opioid receptors in the analgesic effects of endogenous enkephalins, whose extracellular levels are increased by the two RB101-generated inhibitors, is suggested by the similar apparent pA2 values for RB101-naloxone (pA2: 7.53 +/- 0.046) and DAMGO (mu-selective ligand)-naloxone (pA2: 7.38 +/- 0.049).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Inhibition of the enkephalin-metabolizing enzymes by the first systemically active mixed inhibitor prodrug RB 101 induces potent analgesic responses in mice and rats. 156 Mar 64

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.
Pain 1991 Apr
PMID:Gender effects and central opioid analgesia. 167 51

The mu opioid receptors are unquestionably implicated both in supraspinal and spinal analgesia, but there is some controversy about the role of delta receptors in the control of pain at the supraspinal level. This could be due, at least in part, to the local or i.c.v. administration of the opioid agonists. It was therefore interesting to reassess the overall contribution of mu and delta opioid receptors in modulating nociceptive thermal stimuli in the hot plate-test in mice after i.v. injections of DAMGO (Tyr-D-Ala-Gly-(NMe)Phe-Gly-ol) and BUBU (Tyr-D-Ser(O-tert-butyl)-Gly-Phe-Leu-Thr(O-tert-butyl), two highly selective mu and delta receptor agonists, respectively, whose passage into the brain has been demonstrated recently. Both agonists induced dose-dependent, short-lasting (less than 30 min), antinociceptive responses that peaked 5 min after the administration of DAMGO and 10 min after the administration of BUBU. At these times, DAMGO [ED50: 1.26 mumols (0.65 mg)/kg] was 34 times more potent than BUBU [ED50: 42.5 mumols (34 mg)/kg] in the jump response and 13 times more potent in the paw lick. Apparent pA2 values of naloxone (0.004-0.1 mg/kg s.c.) antagonism for DAMGO and BUBU did not differ significantly, 6.95 +/- 0.054 and 7.28 +/- 0.030 for paw lick tests and 7.11 +/- 0.045 and 7.25 +/- 0.027 for jump tests, respectively. The slopes of the pA2 plots were close to the theoretical -1 value for competitive antagonism.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Systemic administration of (Tyr-D-Ser(O-tert-butyl)-Gly-Phe-Leu-Thr(O-tert-butyl), a highly selective delta opioid agonist, induces mu receptor-mediated analgesia in mice. 185 37

This study evaluated the effects of intrathecal administration of a low-analgesic dose of the selective mu-agonist DAMGO co-administered with sequentially increasing doses of either the selective delta-agonist DPDPE or the selective kappa-agonist, U50,488H on mechanical nociceptive thresholds in the rat. Potent analgesic synergy was observed with both combinations. Since an elevation in nociceptive threshold can result from motor deficits, as well as true analgesia, we also evaluated the effects of the combination regimens on motor coordination using a rotarod apparatus. The combination regimens produced significantly less motor deficits than those observed when DPDPE and U50,488H were administered as single agents. These findings of enhanced analgesia with decreased motor side-effects associated with administration of fixed mu/delta or mu/kappa combinations suggest that co-administration of opiates that act at different receptors may constitute a superior approach to the treatment of pain.
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PMID:Analgesic synergy and improved motor function produced by combinations of mu-delta- and mu-kappa-opioids. 197 30

Sprague-Dawley rats drank sweetened (3% dextrose + 0.144% saccharin, w/v) or unflavored water for 18 days and subsequent pain reactivity was assessed using a hot plate. Compared to the rats that consumed unflavored water, the rats that consumed sweet water responded more quickly on the hot plate indicating that their threshold for pain was lowered. Another group of rats given identical exposure to the fluids had their brains prepared for measuring opiate receptor binding using the delta-receptor ligand [3H]D-Ala-D-Leu-enkephalin ([3H]DADLE) and the mu-receptor selective ligand [3H]Tyr-D-Ala-Gly-MePhe-Gly-ol ([ 3H]DAGO). Binding of these opiates to mu- and delta-receptors in the cerebral cortex, striatum, hippocampus, hypothalamus, brain stem, and remaining brain regions was the same for the rats that drank sweet fluids and those that drank unflavored water. These findings suggest that drinking sweet fluids lowers pain thresholds but does not alter mu- and delta-receptors.
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PMID:Chronic sweet intake lowers pain thresholds without changing brain mu- or delta-opiate receptors. 284 10

Anterior cingulate cortex (ACC) has one of the highest densities of opioid receptors in the CNS and it has been implicated in acute and chronic pain responses. Little is known, however, about which neurons express opioid receptors in their dendrites and axon terminals. The present studies employed experimental techniques to remove afferent axons or classes of projection neurons from rat ACC area 24 followed by coverslip autoradiography to localize changes in binding of [3H]Tyr-D-Ala-Gly-MePhe-Gly-ol (DAMGO) to mu receptors and 2-[3H]D-penicillamine-5-D-penicillamine-enkephalin (DPDPE) to delta receptors. Removal of all afferents to area 24 with undercut lesions did not alter DPDPE binding, but significantly reduced binding of DAMGO in layers I, III, and V. In contrast, removal of all cortical neurons with the excitotoxin ibotenic acid almost abolished DPDPE binding in all layers. The same lesions reduced DAMGO binding in most layers; however, there was a postlesion bimodal distribution in binding with high levels of binding in layer I and moderate levels in layer VI. These data suggest that delta receptors are expressed by cortical neurons, while mu receptors are expressed by both cortical neurons and afferent axons. To explore the distribution of postsynaptic receptors, immunotoxin lesions were made in area 24 by injection of OX7-saporin into the caudate and/or thalamic nuclei. Almost complete removal of projection neurons to these targets in layers Vb and VIa did not alter DPDPE binding, while the lesions reduced DAMGO binding in all but layer II. Removal of layer Vb corticostriatal projection neurons with caudate OX7-saporin injections reduced binding only in this layer. It is proposed that opioidergic circuits in area 24 are organized according to an input/output model for mu opioid regulation. In this model mu receptors regulate axon terminal activity from the thalamus in layer Ia and the locus coeruleus in layers Ic and II, whereas cortical outputs to the thalamus are modulated via postsynaptic receptors expressed in all layers by thalamocortical projection neurons with somata in layer VI. These opioidergic circuits in ACC are of particular importance because they may regulate responses to chronic nociceptive activity and associated pain perceptions.
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PMID:Localization of Mu and delta opioid receptors to anterior cingulate afferents and projection neurons and input/output model of Mu regulation. 758 27

We investigated the effects of opioid agonists on the capsaicin-evoked release of glutamate from nociceptive primary afferent fibers of the rat (6-8 weeks) using a fluorometric on-line continuous monitoring system for glutamate. In the presence of 0.3 microM tetrodotoxin, the application of 3 microM capsaicin to spinal dorsal horn slices produced an evoked glutamate release (55.9 +/- 4.02 pmol.mg-1 protein, n = 15). DAMGO ([D-Ala2,N-Me-Phe4,Gly5-ol]enkephalin; 0.3-10 microM) and morphine (1-30 microM), mu-opioid agonists, produced a concentration-dependent reduction (approximately 85 and approximately 77% reduction, respectively) in the capsaicin (3 microM)-evoked release of glutamate. These inhibitory effects were significantly antagonized by naloxone (1 microM). DPDPE ([D-Pen2,5]enkephalin; 1-10 microM), a delta-opioid agonist, also reduced the capsaicin-evoked release in a concentration-dependent manner (approximately 59% reduction). Naltrindole (1 microM), a selective delta-antagonist, significantly antagonized the inhibitory effect of DPDPE (10 microM). In contrast, neither U-50,488H (1-10 microM) nor U-69,593 (10 microM), kappa-opioid agonists, had any effects on the evoked release of glutamate. These results suggest that mu-, and delta-opioid agonists modulate pain transmission in the spinal dorsal horn, at least in part, by inhibiting the release of glutamate from capsaicin-sensitive primary afferents.
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PMID:Opioidergic inhibition of capsaicin-evoked release of glutamate from rat spinal dorsal horn slices. 763 Apr 85


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