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At least 415 records · Page 23Linked to original sources
PubMed1991

Effects of diazepam on nociception in rats.

Acute i.p. injection of diazepam (1 mg/kg) resulted in a moderate increase in the tail-flick latency in rats. Tolerance to this diazepam effect developed after 10 days of diazepam treatment (1 mg kg-1 day-1). The benzodiazepine antagonist Ro 15-3505 only partially reversed the effect of diazepam on nociception. Naloxone (5 mg/kg i.p.) failed to affect the effect of diazepam on nociception, while the kappa antagonist MR 2266 fully antagonized the diazepam-induced increase of the tail-flick latency. Diazepam injected intracerebroventricularly (1, 5, 20 micrograms/rat) did not alter basal nociceptive threshold, however, diazepam injected intrathecally (20 micrograms/rat) prolonged the tail-flick latency. Furthermore, intracerebroventricular injection of muscimol partially antagonized the i.p. diazepam-induced increase of the tail-flick latency. These results suggest that benzodiazepine receptor sites are partially involved in the effect of diazepam on nociception and indicate that an indirect kappa-opioid-receptor-mediated mechanism may be involved. The anatomical site of diazepam action on tail-flick latency seems to be at the spinal level. Descending axons to the spinal cord from brain areas reached by intracerebroventricular injection of muscimol seem to modulate the effect of diazepam effect on nociception.

Animals↗
PubMed1993

In vitro study of the interaction of salmon calcitonin with mu, delta and kappa opioid agonists.

A possible interaction of salmon-calcitonin with opioid systems was studied in isolated tissues. Neurogenic contractions were elicited by electrical stimulation in guinea-pig ileum myenteric plexus-longitudinal muscle strips, rabbit vas deferens and mouse vas deferens. Bremazocine inhibited neurogenic contractions in all three tissues (presumably through kappa-receptors) [D-Pen2, D-Pen5]enkephalin and [Met5]enkephalin inhibited contractions in mouse vas deferens (presumably through delta-receptors), and [D-Ala2, N-Me-Phe4, Gly5-ol]enkephalin (DAMGO) inhibited contractions in guinea-pig ileum and mouse vas deferens (presumably through mu-receptors). All inhibitory effects were concentration-dependent. Salmon-calcitonin 0.1 IU/ml increased the effect of bremazocine in guinea-pig ileum and rabbit vas deferens and also increased the effects of [D-Pen2, D-Pen5]enkephalin and [Met5]enkephalin in mouse vas deferens. In contrast, salmon-calcitonin up to 0.4 IU/ml did not change the effect of bremazocine in mouse vas deferens and the effect of DAMGO in guinea-pig ileum and mouse vas deferens. It is concluded that salmon-calcitonin enhances agonist effects at opioid kappa- and delta- but not at opioid mu-receptors. The level of this interaction remains to be elucidated. The interaction may be the basis of the analgesic effect of salmon-calcitonin in vivo.

Animals↗
PubMed1988

Observational analysis of the effects of kappa opioid agonists an open field behaviour in the rat.

An observational analysis of the effects of four kappa-opioid agonists on forward locomotion, rearing and grooming displayed by rats in a novel open field was undertaken. The doses of agonists used corresponded to those previously found to produce changes in food consumption. Ethylketocyclazocine (0.1 and 1 mg/kg), bremazocine (0.01 and 0.1 mg/kg) and tifluadom (0.3 and 3 mg/kg) exerted suppressant effects on all the activities monitored. Grooming behaviour appeared to be particularly sensitive to this action, being virtually abolished by the larger doses of these compounds. In contrast, the selective kappa agonist U-50,488H (0.1-3 mg/kg) only attenuated grooming at the two highest doses tested (1 and 3 mg/kg). None of the agonists tested produced stimulation of open field activity during the 1-h study. Reductions in activity occurred at doses previously found to increase and decrease food intake. It was therefore concluded that the hyperphagia induced by kappa agonists was not part of a more general behavioural activation, whilst reductions in food consumption probably result from a non-specific behavioural depression.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1987

The effect of kappa-opioid agonist U-50, 488H on wet-dog shaking behavior induced by hippocampal stimulation in rats.

The effect of a selective kappa-opioid agonist, U-50, 488H, on wet-dog shaking (WDS) induced by hippocampal stimulation was investigated and compared with that produced by morphine. U-50, 488H, as well as morphine, inhibited the appearance of WDS in a dose-dependent manner. U-50, 488H was approximately three times more potent than morphine in this effect. Neither drug showed any effect on hippocampal afterdischarge. The inhibition of WDS produced by U-50, 488H was blocked significantly by a kappa-opioid antagonist, MR-2266, but not by naloxone. On the other hand, the inhibitory effect of morphine was completely antagonized by both MR-2266 and naloxone. The present results strongly suggest that not only mu-but also kappa-opioid receptors are involved in the appearance of WDS induced by hippocampal stimulation.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1992

Intracellular calcium and hormone release from nerve endings of the neurohypophysis in the presence of opioid agonists and antagonists.

Rat neural lobes and isolated nerve terminals from the neurohypophysis were stimulated in the presence of different opioid agonists and antagonists. The secretion of arginine vasopressin and oxytocin and rise in cytoplasmic calcium induced by depolarization were analyzed by radioimmunoassay and the fluorescent probe fura-2, respectively. The kappa-agonists dynorphin A(1-13) and dynorphin A(1-8) did not affect electrically evoked release of vasopressin, although oxytocin release was slightly reduced. U-50 488, a relatively specific kappa-receptor agonist, had no effect on the amount of vasopressin or oxytocin secreted, although it significantly reduced K(+)-evoked changes in [Ca2+]i in isolated nerve endings. Two kappa-receptor antagonists, MR 2266 and diprenorphin, alone had no effect on vasopressin and oxytocin secretion from isolated nerve endings depolarized with potassium. Opioid agonists less selective for the kappa receptors, etorphin and ethylketocyclazocin, were found to inhibit the release of both vasopressin and oxytocin significantly. Naloxone, a nonselective opiate receptor antagonist, alone had no effect on vasopressin release but potentiated the electrically evoked release of oxytocin. Naloxone also could overcome the inhibitory effect of etorphin on oxytocin and vasopressin release observed after electrical stimulation of the neural lobe. A number of inconsistencies therefore exist between the effects of opioid agonists and antagonists on neuropeptide release and on the evoked changes in [Ca2+]i. In view of these inconsistencies and the high concentrations of opioid agonists and antagonists necessary to modify release, we conclude that it is doubtful that opioid molecules have a physiological role in controlling neurohypophysial secretion.

Animals↗
PubMed1986

Possible mediation of catecholaminergic pathways in the antinociceptive effect of an extract of Cannabis sativa L.

An extract of cannabis (5 and 15 mg/kg expressed as delta 9-THC) orally administered to rats caused an elevation of the nociceptive threshold (tail-flick latency and vocalization tests). Naloxone and naltrexone (blockers of mu-type opiate receptors) as well as MR 1452 (blocker of kappa opiate receptors) did not prevent the antinociceptive effect of cannabis when used at the dose of 2 mg/kg SC; only a high dose (10 mg/kg SC) of these narcotic antagonists partially blocked cannabis antinociception. ICI 154, 129, an antagonist of delta-type opiate receptors, failed to prevent the cannabis-induced rise in nociceptive threshold when used at a dose of 2 mg/kg SC but produced a significant effect at 10 mg/kg SC. While the role of opiate receptors does not seem fundamental to cannabis antinociception, the clear-cut effectiveness shown by 6-hydroxydopamine (a neurotoxin which causes a degeneration of catecholamine-containing terminals) in reducing cannabis antinociception is indicative of a participation of catecholamines in the phenomenon.

Analgesics↗
PubMed1989

Kappa antagonist properties of buprenorphine in non-tolerant and morphine-tolerant rats.

Buprenorphine was evaluated for its ability to act as a kappa opioid antagonist in rats responding under a fixed-ratio 30 schedule of food presentation both before and after the induction of morphine tolerance. Before the induction of morphine tolerance, both buprenorphine and the selective kappa agonist bremazocine decreased rates of responding in a dose-dependent manner, and buprenorphine (0.03 and 0.3 mg/kg) failed to antagonize bremazocine's rate-decreasing effects. Following the induction of morphine tolerance, the bremazocine dose-effect curve was unaffected, but a profound cross-tolerance developed to buprenorphine. Furthermore, buprenorphine (0.03, 0.3 and 1.0 mg/kg) produced a dose-dependent antagonism of the rate-decreasing effects of bremazocine in the morphine-tolerant rats. These results support the hypothesis that buprenorphine has antagonist activity at kappa opioid receptors.

Animals↗
PubMed1982

Discriminative stimulus properties of narcotic and non-narcotic drugs in rats trained to discriminate opiate kappa-receptor agonists.

The purpose of this study was to evaluate the discriminative stimulus properties of some narcotic and non-narcotic drugs in rats trained to discriminate the effect of the proposed opiate kappa-receptor agonists ethylketocyclazocine and bremazocine. Male Sprague-Dawley rats were trained in a two-lever food-reinforced paradigm to discriminate between the effect of ethylketocyclazocine (0.32 mg/kg) or bremazocine (0.04 mg/kg) and saline. Both groups of trained rats showed dose-dependent generalization to the effect of the proposed kappa-agonist MRZ-2033 and some animals generalized the effect of nalorphine and pentazocine. Some ethylketocyclazocine - but no bremazocine - trained rats generalized the effect of buprenorphine. The effect of dextrorphan, phencyclidine, and ketamine was generalized by some bremazocine -, but no ethylketocyclazocine-trained rats. Neither group of rats generalized the effect of etorphine, haloperidol, diazepam, or pentobarbital. These data suggest the usefulness of this procedure to evaluate the kappa-like properties of opioid drugs.

Animals↗
PubMed1986

Withdrawal responses of guinea-pig isolated ileum following brief exposure to opiates and opioid peptides.

Withdrawal contractures following brief exposure of guinea-pig ileum to enkephalin analogues, dynorphin A-(1-13) and beta-endorphin and the opiate drugs morphine, ketocyclazocine, buprenorphine and MR2034 were investigated. Following 2 min contact with the ileum a withdrawal contracture was induced by washout of (Met5)- and (Leu5)-enkephalin and by several enkephalin analogues but not by washout of (D-Ala2,D-Leu5)-enkephalinamide or any of the other drugs tested. Addition of naloxone precipitated withdrawal to all opioids tested except the kappa receptor preferential drugs ketocyclazocine and MR2034 and the mu receptor partial agonist, buprenorphine. The heights of the withdrawal contractures to enkephalin analogues were found to be dependent on the concentration of agonist and of naloxone, and on the duration of the contact period of opioid with the ileum. The naloxone-precipitated withdrawal responses to morphine, dynorphin A-(1-13) and the washout withdrawal response to (Met5)-enkephalin were inhibited by substance P antagonists thus supporting the previous proposal that substance P mediates the opiate withdrawal response. This study has shown that mu receptor agonists produced dependence in the guinea-pig ileum revealed by a withdrawal contracture on addition of naloxone, whereas dependence on kappa receptor agonists could not be revealed with naloxone. Since the guinea-pig ileum preparation has millimicron and kappa receptors it was concluded that the endogenous opioid peptides, enkephalins, beta-endorphin and dynorphin A-(1-13), all induced dependence by acting on mu receptors in this preparation.

Animals↗
PubMed1986

On the opioid receptor subtype inhibiting the evoked release of 3H-noradrenaline from guinea-pig atria in vitro.

Guinea-pig isolated atria were incubated and loaded with 3H-(-)-noradrenaline. The intrinsic nerves were stimulated with trains of 5 or 35 field pulses (4 Hz), and the evoked efflux of 3H-noradrenaline and of total tritium was determined in the presence of atropine, corticosterone, desipramine, and phentolamine by liquid scintillation spectrometry. Ethylketocyclazocine (1.4 nmol/l, IC50), MR 2033 (9.1 nmol/l), dynorphin A (1-13) (25 nmol/l, peptidase inhibitors present), etorphine (71 nmol/l), and [D-Ala2, D-Leu5]-enkephalin (greater than 10 mumol/l, peptidase inhibitors present) inhibited the stimulation-evoked efflux of 3H-noradrenaline in a concentration-dependent manner, but not morphine up to 10 mumol/l. The inhibition by ethylketocyclazocine, MR 2033, and etorphine was antagonized by naloxone 1 mumol/l. Similarly, the MR 2033 effect was antagonized by SKF 10047 1 mumol/l. All antagonists investigated failed to affect the evoked 3H-noradrenaline efflux when present in the absence of exogenous agonists. Arunlakshana-Schild plots were calculated for the antagonism between ethylketocyclazocine and a pair of stereoisomers, (-)-MR 2266 (20 nmol/l-5 mumol/l) and (+)-MR 2267 (0.3-10 mumol/l) at the presynaptic opioid receptor, and pA2 values were estimated. The isomeric affinity ratio was 60, with pA2 values of (-)-MR 2266, 9.06, and (+)-MR 2267, 7.28, respectively. The results show that the 3H-noradrenaline release can be inhibited via activation of presynaptic opioid receptors. Under the conditions presently investigated endogenous opioids do not modulate the evoked transmitter release. The results favour the idea that a single population (presumably of the kappa-subtype) of opioid receptors is present at guinea-pig atrial noradrenergic nerves.

Animals↗
PubMed1985

Locomotor activity of rats after injection of various opioids into the nucleus accumbens and the septum mediale.

The possible role of the nucleus accumbens (ACB) and, in some experiments, the septum mediale (SM) in mediating alterations in locomotor activity, produced by various opioids, was evaluated in the rat, the drug being injected either into the left central part of the ACB or into the left SM. Morphine, predominantly acting at the mu-type receptors, given in larger doses (13 or 40 nmol into the ACB) produced depression of locomotor activity and catalepsy, whereas 2.5 nmol were ineffective. Co-administration of naloxone into the ACB suppressed the effects of morphine. D-ala2, D-leu5-enkephalin (DADL), a preferential delta-type receptor agonist, produced a biphasic effect on locomotor activity, namely an inhibition of it and a catalepsy, followed by a locomotor activation. This effect was observed after 4 or 13 nmol; 1 nmol produced a delayed locomotor activation without any previous inhibition, whereas 0.4 or 0.1 nmol were ineffective. Equimolar doses of naloxone, when co-administered with DADL, only partially antagonized these effects of DADL. In contrast, co-administration of a small dose of DADL and an excess dose of naloxone into the ACB produced an immediate increase in locomotor activity. Injections of a predominant kappa type receptor agonist, MR 2033-Cl, were ineffective. Injection of DADL, either alone or combined with naloxone into the SM (1 nmol) produced an immediate stimulation of locomotor activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Localization of kappa opioid receptor binding sites in human forebrain using [3H]U69,593: comparison with [3H]bremazocine.

1. The autoradiographic distribution of kappa opioid receptor binding sites in human brain was examined using two radiolabeled probes, namely [3H]U69,593 and [3H]bremazocine. 2. [3H]U69,593 binding was performed in the absence of blockers for other sites, while [3H]bremazocine binding was investigated in the presence of saturating concentrations of mu and delta blockers to ensure selective labeling of kappa opioid receptors. 3. Our results show that the autoradiographic distribution of [3H]U69,593 and [3H]bremazocine (plus blockers) binding sites is identical, with high densities of sites found in deep cortical layers and claustrum. 4. This indicates that [3H]U69,593 is a highly selective ligand of the kappa opioid receptor type.

Autoradiography↗
PubMed1988

[Ability of the opiate kappa-agonist bremazocine to facilitate the flexor reflex of the right hindlimb in spinal rats].

It has been found that bremazocine predominantly enhances the flexor reflex of the right hind limb, without affecting the left limb. The similarity of the visual data measuring the asymmetry of the pose and the asymmetry of EMG responses to painful stimulation has a high probability. No correlation between the asymmetry of the pose and EMG extensor activity has been found.

Analgesics↗
PubMedDate not supplied

Opioids stimulate sarcolemmal NAD(P)H-vanadate dehydrogenase activity.

The present study demonstrates that the bovine cardiac sarcolemma possesses an NAD(P)H dehydrogenase activity which is able to oxidize both NADH and NAD(P)H in the presence of vanadate as an electron acceptor. The NADH dehydrogenase activity was significantly higher than the NAD(P)H dehydrogenase activity and both of them were almost completely inhibited by superoxide dismutase and atebrin and markedly reduced by the addition of the protonophore 2,4-dinitrophenol. The incubation of the sarcolemma in the presence of 10(-10), 10(-9), 10(-8) M methionine-enkephalin, a prevalent delta-opioid receptor agonist, or dynorphin A (1-17), a prevalent kappa-receptor agonist, produced a dose-dependent increase in the NAD(P)H dehydrogenase activity, with 10(-10) and 10(-9) M dynorphin A (1-17) more effective than the corresponding doses of methionine-enkephalin. The preincubation of the sarcolemma in the presence of superoxide-dismutase, atebrin or 2,4-dinitrophenol strongly inhibited the opioid-stimulated dehydrogenase activity. The stimulatory action elicited by 10(-8) M methionine-enkephalin or dynorphin A (1-17) was completely antagonized by 10(-8) M naloxone or Mr 1452, respectively, whilst 10(-8) M naloxone exerted only a partially antagonistic action against the effect produced by 10(-8) M dynorphin A (1-17), significantly more accentuated than the action of 10(-8) M Mr 1452 versus the same dose of methionine-enkephalin.

Animals↗
PubMed1991

Differential cross-tolerance to mu and kappa opioid agonists in morphine-tolerant rats responding under a schedule of food presentation.

If different populations of opioid receptors mediate the actions of mu and kappa opioid agonists, then tolerance induced by the chronic administration of a mu agonist should confer cross-tolerance to other mu agonists but not necessarily to those compounds whose effects are mediated by the kappa receptor. This hypothesis was evaluated in the present investigation by examining the effects of the mu agonists morphine, l-methadone and fentanyl, the kappa agonists U50,488 and bremazocine, and the mixed kappa/mu agonist ethylketocyclazocine in rats responding under a fixed-ratio 30 schedule of food presentation before, during and after exposure to a regimen of chronic morphine administration. For comparison, naloxone was evaluated as a representative mu antagonist and the phenothiazine chlorpromazine as a control drug. During all phases of the experiment, each of these compounds produced dose-related decreases in rate of responding. During the daily administration of 40 mg/kg morphine, tolerance developed to the rate-decreasing effects of morphine, l-methadone and fentanyl, and an enhanced sensitivity to the effects of naloxone. In contrast to the effects obtained with these mu opioids, there was no evidence that chronic morphine administration produced tolerance or enhanced sensitivity to the rate-decreasing effects of U50,488, bremazocine, ethylketocyclazocine and chlorpromazine. The present findings demonstrate that the chronic administration of morphine results in the selective development of tolerance to other mu agonists.(ABSTRACT TRUNCATED AT 250 WORDS)

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1995

Discriminative stimulus effects of the 5HT1A agonist 8-OH-DPAT: attenuation by mu but not by kappa opioids.

The ability of mu and kappa opioids to alter the discriminative-stimulus and rate-decreasing effects of the 5-HT1A receptor agonist 8-OH-DPAT was examined in rats trained to discriminate either a low (0.1 mg/kg) or a high (0.3 mg/kg) dose of 8-OH-DPAT from water using a two-lever food-reinforced drug discrimination procedure. The mu opioids, morphine and fentanyl, and the kappa opioids, U50,488 and bremazocine, failed to substitute for the 8-OH-DPAT stimulus, even when tested up to doses that substantially reduced rates of responding. During antagonism tests, selected doses of the mu opioids, morphine and fentanyl, administered at various pretreatment times, attenuated the stimulus effects of both training doses of 8-OH-DPAT. Moreover, morphine (135-min pretreat) and fentanyl (15-min pretreat) produced rightward shifts in the 8-OH-DPAT dose-effect curve that were partially surmountable and naltrexone-reversible. In contrast to the effects of the mu opioids, the kappa opioids, U50,488 and bremazocine, failed to alter the stimulus effects of the training dose of 8-OH-DPAT, regardless of dose or pretreatment time. The rate-decreasing effects of 8-OH-DPAT were not altered substantially by either the mu or kappa opioids examined. The present study demonstrates that the stimulus effects, but not the rate-decreasing effects, of 5-HT1A receptor agonists can be modulated by mu opioids, whereas neither of these effects are changed by kappa opioids.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗