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PubMedDate not supplied

[The receptor organization of the reinforcing and analgetic opiate systems in the rat].

Comparative study of topographic and receptor selectivity of emotionally positive (place preference test) and analgetic (electrical and pressure nociceptive stimulation of the tail) effects of opioids was performed in rats. Morphine and selective agonists of mu-, kappa-, delta- and sigma-opiate receptors were administered through cannulae implanted into the periaqueductal grey and ventral tegmental area (VTA). Reinforcing effects of opioids in VTA was shown to be mediated mainly by mu-, delta- and sigma-receptors, while analgetic effect was realised with the aid of mu- and delta-opioid receptors.

Animals↗
PubMed1989

Kappa-opioid agonists do not inhibit adenylate cyclase.

Morphine, levorphanol and D-Ala2, Met enkephalin, but not bremazocine, pentazocine, U-50 488H and U-69 593, were found to inhibit adenylate cyclase activity dose-dependently in bullfrog brain membranes. The inhibition of the enzyme activity was abolished by naloxone. These results suggest that the signalling transduction of mu- and delta-agonists is partially mediated by the adenylate cyclase system coupled with opioid receptors, but that kappa-receptors may not be associated with adenylate cyclase.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1989

Central and peripheral opioid modulation of gastric relaxation induced by feeding in dogs.

The influence of i.v. vs. i.c.v. administration of [( D-Ala2, MetPhe4, Gly-ol5]enkephalin (DAMGO) and morphine), kappa U 50488 and ethylketocyclazocine and delta ([D-Pen2, D-Pen5]enkephalin (DPDPE)] opioid agonists on gastric relaxation induced by a standard meal was evaluated in conscious dogs with strain-gauge transducers implanted on the gastric fundus and antrum. Under control conditions, the amplitude of the gastric relaxation in response to feeding was 2.46 +/- 0.23 g. Given i.v. 10 min before feeding, both U 50488 (10 micrograms/kg) and ethylketocyclazocine (10 micrograms/kg) significantly (P less than .01) reduced the amplitude of the gastric relaxation by 57 and 68%, respectively, whereas DAMGO and morphine (10 micrograms/kg i.v.) increased markedly the response to feeding by 67 and 51%, respectively. In contrast, DPDPE had no effect on the gastric relaxation induced by feeding. Previous administration of naloxone (0.3 mg/kg i.v.) or MR 2266 (0.3 mg/kg i.v.) blocked the effect of U 50488 on gastric relaxation with no effect per se on the amplitude of response; naloxone also blocked the increase in gastric relaxation induced by DAMGO. When administered i.c.v. (0.1 microgram/kg) DAMGO induced a significant (P less than .05) increase in the amplitude of gastric relaxation whereas U 50488 and DPDPE (0.1 and 1 microgram/kg i.c.v.) had no effect. The effect of i.c.v. DAMGO on gastric relaxation was unaffected by a previous i.v. administration of SR 58002C (1 mg/kg). Truncal vagotomy blocked the increase in gastric relaxation induced by DAMGO (10 micrograms/kg i.v.), but did not change the effect of U 50488 (10 micrograms/kg i.v.) on gastric relaxation.(ABSTRACT TRUNCATED AT 250 WORDS)

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1989

Pharmacological characterization of supersensitivity to naltrexone in squirrel monkeys.

Effects of naltrexone and of other drugs in decreasing rates of schedule-controlled responding were studied in squirrel monkeys treated weekly with naltrexone while responding under fixed-ratio schedules of either food presentation (FP) or stimulus-shock termination (SST). By the 5th week of treatment, sensitivity to the rate-decreasing effects of naltrexone had increased 32-fold in FP monkeys (supersensitivity) but had not changed in SST monkeys; continued weekly injections of naltrexone did not change the effects of naltrexone further in either group. FP monkeys were more sensitive than SST monkeys to the rate-decreasing effects of other opioid antagonists and mixed agonist-antagonists; however, for some compounds (e.g., MR 2266) differences between groups did not exceed differences reported in nonsensitized monkeys responding under similar schedule conditions. Differences in sensitivity between FP and SST monkeys appeared to be stereospecific; FP monkeys were 28 times more sensitive than SST monkeys to (-)-cyclazocine, but equally sensitive to (+)-cyclazocine. Sensitivity to opioid agonists and to some nonopioids varied by less than 3-fold between groups and doses of lithium that decreased responding in FP monkeys had no effect in SST monkeys. Neither acute nor repeated injections of morphine altered the sensitivity of FP or SST monkeys to naltrexone; however, morphine attenuated the rate-decreasing effects of naltrexone in FP monkeys, and naltrexone reversed the rate-decreasing effects of morphine in all monkeys. Super-sensitivity to opioid antagonists in squirrel monkeys is behaviorally and pharmacologically selective as well as stereospecific. Although other effects of antagonists might contribute to supersensitivity, opioid antagonistic action appears to be one important component of supersensitivity and cross-supersensitivity among opioid antagonists.

Animals↗
PubMed1989

Diuretic effect of bremazocine, a kappa-opioid with central and peripheral sites of action.

Intracerebroventricular or i.p. injections of bremazocine produced a dose-dependent diuretic response and increased glomerular filtration rate in hydrated as well as in nonhydrated rats. The potency and magnitude of the bremazocine-induced diuresis were more pronounced in the nonhydrated group of rats. That bremazocine has a central component of action is deduced from the fact that 0.1 microgram of the opioid administered centrally caused a significant increase in urine output; proportionally, larger doses of bremazocine were required to produce the same diuretic effect when the drug was administered parenterally. Bremazocine did not change the total amount of urinary Na+ and K+ as compared to the saline controls; it increased significantly the free water clearance. The bremazocine-induced diuresis was antagonized in a competitive fashion by 10 mg/kg of naloxone giving further support to the notion that the mechanism of action of bremazocine involves activation of kappa-opioid receptors. Bremazocine injected i.v. to nonanesthetized rats increased mean systemic blood pressure in a dose-dependent manner; the pressor action of the opiate was blocked and prevented by 1 mg/kg of naloxone. In contrast, i.c.v. administration of bremazocine did not change mean systemic blood pressure but produced a dose-related increase in urine output. To determine whether in addition to a central site bremazocine also activates a renal mechanism, experiments were performed in the isolated perfused rat kidney. Bremazocine (0.15-2.5 microM) caused a dose-dependent diuretic response and a significant rise in perfusion pressure as well as in glomerular filtration rate.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

[Effects of kappa-opiate receptor antagonist MR-2266-BS on ACTH and prolactin release].

The effect of intravenous injection of different doses of MR-2266-BS, a selective antagonist of kappa-opiate receptor, on plasma adrenocorticotropin (ACTH) and prolactin (PRL) in conscious male rats bearing an intrajugular cannulae was assessed. The results revealed that the MR-2266-BS of 3 mg/kg completely blocked the restraint stress-induced increase in plasma ACTH levels, and further elevated plasma PRL levels in these animals, while there were no effects on the resting levels of ACTH and PRL. MR-2266-BS of 6 mg/kg significantly increased the resting levels of plasma ACTH and also further elevated the restraint stress-induced increase of plasma ACTH and PRL. The present data suggest that kappa-opiate receptor and its endogenous ligand may be involved in the regulation of the resting and restraint stress-induced release of ACTH, and their action appears to be both stimulatory and inhibitory. Furthermore, kappa-opiate receptor and its endogenous ligand may only inhibit the stress-induced release of PRL.

Adrenocorticotropic Hormone↗
PubMed1989

Discriminative stimulus effects of mu and kappa opioids in the pigeon: analysis of the effects of full and partial mu and kappa agonists.

Pigeons were trained to discriminate a dose of either 0.01 mg/kg of bremazocine or 0.05 mg/kg of fentanyl from water using a two-key drug discrimination procedure. During tests of substitution, the selective kappa-opioid agonists bremazocine, U50, 488 and tifluadom substituted for the bremazocine stimulus, whereas the less selective kappa-opioid agonists ethylketocyclazocine, levallorphan, proxorphan and nalorphine substituted for the fentanyl stimulus. The full mu-opioid agonists fentanyl, morphine, I-methadone and levorphanol, as well as the partial agonists nalbuphine, butorphanol and buprenorphine, substituted for the fentanyl stimulus. Compounds with partial-opioid agonist effects, namely nalbuphine, butorphanol, buprenorphine, proxorphan, levallorphan and nalorphine, produced 50% fentanyl-appropriate responding at doses 25 to 369.2 times smaller than the doses required to decrease response rates to 50% of control values. In contrast, the full mu-opioid agonists fentanyl, morphine, I-methadone and levorphanol produced 50% fentanyl-appropriate responding at doses only 1.3 to 10.9 times smaller than those required to decrease response rates by 50%. During tests of antagonism, both naloxone and Mr2266 produced a dose-dependent attenuation of the stimulus effects of bremazocine and fentanyl, whereas beta-funaltrexamine antagonized the stimulus effects of fentanyl but not bremazocine. Although bremazocine has been reported to have mu-opioid antagonist effects, it failed to antagonize the stimulus effects of the training dose of fentanyl. The present investigation establishes further that pigeons can discriminate selective kappa-opioid agonists from mu-opioid agonists and that in pigeons the classification of numerous opioid compounds on the basis of their kappa-like or mu-like stimulus effects differ from those in rat and monkey. In addition, under the drug discrimination procedure the actions of compounds classified as partial-opioid agonists can be differentiated from those of full mu-opioid agonists on the basis of the ratio of the dose required to engender fentanyl-like stimulus effects to the dose required to reduce response rates.(ABSTRACT TRUNCATED AT 250 WORDS)

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMedDate not supplied

Immunohistochemical evidence for different opioid systems in the rat superior cervical ganglion as revealed by imipramine treatment and receptor blockade.

The distribution pattern of opioid-immunoreactive nerve cell bodies and varicose fibres in the rat superior cervical ganglion after chronic administration of the tricyclic antidepressant imipramine, various receptor blockades (muscarinic antagonist, atropine sulphate; opiate antagonist, naloxone; kappa-antagonist, MR2266BS), and denervation was investigated immunohistochemically using a biotin-streptavidin-peroxydase complex method. Antisera to four peptides derived from two different precursors of the opioid family were used. In control superior cervical ganglia sparsely scattered nerve fibres and no neuronal cell bodies were immunoreactive when antisera to dynorphin A (1-17) or alpha-neo-endorphin (cleavage products of prodynorphin) were applied. A moderate number of nerve fibres and neuronal perikarya were immunoreactive to antisera directed against met-enkephalin-arg-phe (cleavage product of proenkephalin) and leu-enkephalin (cleavage product of prodynorphin and proenkephalin); non-identical cell bodies contained met-enkephalin-arg-phe- or leu-enkephalin-immunoreactivity. After drug treatment specific changes in the immunoreactivity of the investigated peptides in the superior cervical ganglion were demonstrated. (a) Treatment with imipramine resulted in an increase of nerve fibres demonstrating immunoreactivity to antisera against dynorphin A and alpha-neoendorphin. In contrast, no alteration in the numbers of nerve fibers but a numerical increase of postganglionic cell bodies immunoreactive to either met-enkephalin-arg-phe or leu-enkephalin antisera was demonstrated. Moreover, some perikarya exhibited immunoreactivity to both these opioids. (b) Receptor blockade with the muscarinic antagonist atropine sulphate or the general opiate antagonist naloxone had no effect on the number and distribution of dynorphin A or alpha-neoendorphin immunoreactive fibres, whereas both met-enkephalin-arg-phe and leu-enkephalin-immunoreactive fibres and postganglionic perikarya were increased in number. (c) After the kappa antagonist (MR2266BS), an increase of fibres with prodynorphin-derived opioid immunoreactivity as well as those with met-enkephalin-arg-phe- or leu-enkephalin-immunolabelling was visible and the met-enkephalin-arg-phe and leu-enkephalin-immunoreactive cell bodies were increased in number. The preganglionic origin of the investigated fibres with prodynorphin cleavage products was concluded from the complete disappearance of such fibres after preganglionic denervation. Denervation also resulted in an increase of met-enkephalin-arg-phe- and leu-enkephalin-immunoreactive perikarya. Small intensely fluorescent (SIF) cells, which in controls were nonrea

Amino Acid Sequence↗
PubMed1989

The effect of naloxone and the kappa antagonist MR 1452 MS on myocardial infarction in rats.

The intravenous infusion of naloxone (Nal) (0.17 mg/kg/min) and of the selective kappa antagonist MR 1452 MS (0.07 mg/kg/min) on rats with left coronary artery occlusion was studied. The results demonstrated significant improvement of cardio-circulatory parameters, i.e., mean arterial pressure (MAP), heart rate (HR) and cardiac output (CO). The action of Nal is peripheral and central with prevalence of central effect, since its hypertensive effect is due to a rise in total peripheral resistance (TPR) (by 12%), rather than to an increase of CO (by 3% compared to saline-treated rats 20 min postinfarction). The effect of MR 1452 MS is mainly peripheral, since MAP increased due to increased CO (by 5% and by 8% compared to saline-treated animals 20 min and 2 h postinfarction). As a result of increased MAP and CO a reduction of myocardial oxygen deficiency was evident, and the development of cardiogenic shock in Nal- and MR 1452 MS-treated animals decreased by 7% and by 17% 2 and 24 h postinfarction. Reduction of the incidence of early arrhythmias (20 min-2 h postinfarction) by 25% and 16%, respectively, was found. Mortality was significantly reduced in both groups by 8% 2 h postinfarction and by 17% 24 h postinfarction, which suggested a comparable effect of both drugs in cardiogenic shock.

Acid-Base Equilibrium↗
PubMedDate not supplied

Possible role for endogenous opiates in the regulation of food intake in the newborn rat.

The possible role of endogenous opiates in the regulation of food intake was investigated by studying their influence on body weight of rat pups. Subcutaneous injection of the opiate antagonist Mr 1452 to non-deprived 1 day old rats (1-4 mg/kg) and 1.5 hr deprived 5 day old rats (2-8 mg/kg) inhibited feeding. Its stereoisomer Mr 1453 increased intake when injected to nondeprived 1 day old rats (1-4 mg/kg), but was ineffective in altering feeding behavior in 1.5 hr deprived 5 day old rats (2-8 mg/kg). Subcutaneous injection of another opiate antagonist, levallorphan (6 and 9 mg/kg), to 3 hr deprived rats also decreased intake, while its stereoisomer dextrallorphan (3-9 mg/kg) was inactive in the same experimental conditions. Subcutaneous injection of the opiate agonist met5enkephalin (16 and 32 mg/kg) to 1.5 hr deprived 5 day old rats increased feeding but leu5enkephalin (8 and 16 mg/kg) did not alter feeding behavior in the same condition. Taken together, these findings suggest a role for endogenous opiates in the facilitation of feeding in the newborn rat.

Animals↗
PubMed1987

Effects of kappa agonists and dexoxadrol on the acquisition of conditional discriminations in monkeys.

In each of two components of a multiple schedule, patas monkeys were required to respond on a right or left lever depending upon the stimulus combination (a color and a geometric form) presented. Reinforcement of a response in the presence of one stimulus (the form) was conditional upon the other stimulus (the color). The completion of a two-member chain of discriminations produced a food pellet. Errors produced a brief timeout. One component of the multiple schedule was a repeated-acquisition task in which the discriminative stimuli for left- and right-lever responses changed each session (learning). In the other component, the discriminative stimuli were the same each session (performance). Dose-effect curves were determined for the kappa agonists bremazocine, tifluadom, ethylketocyclazocine and U50488H. Each drug produced dose-related decreases in overall response rate but had little or no effect on accuracy in either learning or performance. The rate-decreasing effects of ethylketocyclazocine and tifluadom were due to a dose-related pause at the start of the session, whereas those of bremazocine and U50488 were due largely to sporadic pausing throughout the session. Naltrexone blocked the effects of each drug whereas quaternary naltrexone had no effect. In contrast to the kappa agonists, dexoxadrol produced a dose-related disruption in accuracy of responding in learning. Dexoxadrol also decreased response rate in both acquisition and performance in a dose-related manner. Naltrexone attenuated the effects of low doses of dexoxadrol on accuracy, but failed to block the disruptive effects of higher doses.(ABSTRACT TRUNCATED AT 250 WORDS)

Analgesics↗
PubMedDate not supplied

Somatosensory-evoked potentials (SEPs) are affected differently by mu- and kappa-selective opioids in the dog.

Alfentanil, a mu-opioid receptor ligand, induced a dose-related suppression of the early N50 peak and an increase in latency of the late N140 peak. The highest dose blocked all potentials. These effects were reversible by naloxone. The kappa-ligand bremazocine, induced a dose-related increase in latency of the late P150 peak which was, however, reversed by the specific kappa-antagonist Mr2266, not by naloxone. Continuous blockade of the mu-receptor with low-dose naloxone topped with cumulative doses of nalbuphine, a mixed narcotic analgesic, resulted in a Mr 2266-reversible increase in latency of the late N100 peak. Influences of the opioids on the SEP may account for their difference in clinical effects.

Alfentanil↗
PubMed1986

Hyperalgesia produced by intrathecal opioid antagonists depends on receptor selectivity and noxious stimulus.

Opioid antagonists selective for delta-, kappa- and mu-receptor subtypes were administered intrathecally in rats prior to determination of response thresholds to noxious heat, pressure and chemical visceral stimulation. All antagonists induced hyperalgesia differentially with two or more stimuli but delta- and mu-blockade failed to alter writhing activity. Thus, the extent of involvement of an opioid receptor subtype in antinociception depends on the type of noxious stimulation.

Analgesia↗
PubMed1986

Kappa opioid binding sites in rat spinal cord.

The spinal cord of the rat is shown to contain only a low level of kappa-binding sites, comparable to rat brain. [3H]Bremazocine appears to label an additional class of sites which do not appear to be of mu, delta, or kappa specificity.

Animals↗
PubMed1986

The direct demonstration of binding of mu, delta and kappa agonists to digitonin-solubilized opioid receptors from bovine striatum.

Active opioid binding sites, that retain the ability to bind tritiated agonists have been obtained in good yield in digitonin/NaCl/Mg2+ extracts of morphine protected bovine striatal membranes. Ligand protection of binding sites and the presence of Mg ions were found to be absolute requirements for agonist binding in this solubilized opioid receptor preparation. Soluble preparations contained a ratio of mu: delta:kappa similar to that in the membranes.

Analgesics↗
PubMedDate not supplied

[Effect of opiate agonists administered intrathecally on the behavioral and hemodynamic manifestations of pain].

An agonist of mu-opiate receptors, D-Ala2-Gly-ol5-enkephalin (DAGO, 0.5 mcg), administered intrathecally, was found to inhibit behavioral and hemodynamic reactions induced by thermal and electrical stimulation of conscious male rats. D-Ala2-D-Leu-enkephalin (DADL, 0.5 mcg), acting on delta-receptors, was shown to potentiate nociceptive shifts of arterial blood pressure. Phencyclidine and bremazocine failed to exert any significant effect on the opioidergic mechanisms of the spinal cord.

Animals↗