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Biomedical subjects

H Kalant

Publications and source records attributed to H Kalant.

At least 127 records · Page 7Linked to original sources
PubMed1981

Different sites of action for morphine, ethanol, barbital and pentobarbital within the guinea-pig ileum longitudinal muscle/myenteric plexus preparation.

Morphine, ethanol, barbital and pentobarbital reversibly inhibited in a dose-dependent manner, the electrically evoked contractions of the guinea-pig ileum longitudinal muscle/myenteric plexus (LM/MP) preparation, in vitro. The ED50s for inhibition were 0.2 microM for morphine and 120, 8 and 0.3 mM for ethanol, barbital and pentobarbital respectively. To determine whether the site of inhibition was pre- or postjunctioal we studied the effects of graded concentrations of these drugs on the contractions evoked by exogenous acetylcholine (ACh). A correlation between the inhibition of the electrically and ACh-evoked muscle contractions suggests that morphine acts primarily prejunctionally while ethanol acts both pre-and postjunctionally. The inhibition by barbital and pentobarbital, however, can be accounted completely by a postjunctional depression. These results may explain our previous observation of cross-tolerance between morphine and ethanol in this preparation, and the lack of cross-tolerance between these drugs and barbital.

Acetylcholine↗
PubMed1981

Effect of chronic morphine treatment on beta-endorphin biosynthesis by the rat neurointermediate lobe.

The effect of chronic morphine treatment on the in vitro biosynthesis of beta-endorphin by rat pars intermedia was investigated. Tolerance and physical dependence were induced in 200 g rats by the subcutaneous implantation of 75 mg morphine pellets for either 3 days or 15 days. Immediately following sacrifice of the animals the neurointermediate lobes were removed and incubated with [3H] phenylalanine. The protein extracts of the lobes were analyzed for the incorporation of the labelled amino acid into total protein, pro-opiomelanocortin, beta-lipotropin (beta-LPH) and beta-endorphin. the biosynthesized products were purified by immunoprecipitation with an antiserum to beta-endorphin. The identity and purity of beta-endorphin were verified by polyacrylamide disc gel electrophoresis with sodium dodecyl sulfate, and microsequencing. The identity of pro-opiomelanocortin (POMC) was verified by peptide mapping of its tryptic digestion products. The results showed that morphine treatment induced a decrease in the incorporation of the radioactive amino acid into total protein, pro-opiomelanocortin, beta-LPH and beta-endorphin. The decrease was more pronounced for the incorporation into beta-LPH and beta-endorphin than into pro-opiomelanocortin and total proteins, suggesting an effect of morphine treatment on the processing of the pro-opiomelanocortin to its final maturation products.

Amino Acids↗
PubMed1981

Interaction of catecholamines and ethanol on the kinetics of rat brain (Na+ + K+)-ATPase.

The effects of catecholamines (CA) and ethanol (EtOH), singly and in combination, on the kinetics of rat brain (Na+ + K+)-ATPase were studied. Addition of 0.05 M EtOH alone did not change Vmax or Km for K+, Na+, Mg2+ and ATP. Addition of 0.1 mM dopamine (DA) or noradrenaline (NA) alone stimulated the enzyme activity in presence of vanadium-containing ATP as substrate, but not with vanadium-free ATP except in the presence of high Mg2+ : ATP ratios. CA alone decreased the Km slightly for K+ and by about 50% for ATP, increased it for Mg2+ and did not change it for Na+. However, the combination of DA or NA + EtOH produced a marked inhibition which was competitive for K+, and uncompetitive or mixed for Mg2+, Na+ and ATP. The inhibitory effect of NA + EtOH was abolished in 20 mM K+. These findings suggest that NA sensitizes the enzyme to EtOH inhibition at physiological K+ concentrations, by conformational change away from the outwardly facing K+-binding E2P for to the inwardly facing Na+-binding E1P form.

Adenosine Triphosphate↗
PubMed1981

Naloxone prevention of morphine LDR curve flattening associated with high-dose tolerance.

Male wistar rats, previously made tolerant to morphine by at least 3 weeks of daily intraperitoneal (IP) injections of 20 mg/kg morphine-SO4 (MS), were then given 200 mg/kg MS daily for 4 or 5 days. Tail immersion tests of antinociception, carried out before and after the 200 mg/kg MS treatment, indicated that the additional morphine treatment, was followed by a large further decrease in opiate sensitivity, characterized by decreased slope of the log-dose/response curve (LDR curve flattening). The further decrease in opiate sensitivity was substantially reduced by naloxone-HCl (IP) in a dose of 10 mg/kg given 30 min before and 8 h after the 200 mg/kg MS injections, or a dose of 4 mg/kg given 45 min after the MS. It was concluded that LDR curve flattening produced by high doses of MS is mediated by specific opiate receptors, and is a true expression of a high degree of opiate tolerance in the intact rat.

Animals↗
PubMed1981

Effect of modification of brain serotonin (5-HT), norepinephrine (NE) and dopamine (DA) on ethanol tolerance.

Rats were permanently depleted of brain dopamine (DA), serotonin (5-HT), 5-HT + norepinephrine (NE), or NE + DA by intraventricular injection of either 5,7-dihydroxytryptamine (5,7-DHT) or 6-hydroxydopamine (6-OHDA) with or without pretreatment with desmethylimipramine (DMI). Following 1 week of recovery from surgery, daily treatment with ethanol (5 g/kg, PO) or isocaloric sucrose was carried out for a period of 20-25 days. Testing at 5-day intervals showed that chronic ethanol treatment produced tolerance to the hypothermic and motor impairing effects of ethanol. Depletion of 5-HT alone retarded tolerance, while depletion of NE or DA alone produced no effect. Combined depletion of both NE and 5-HT, however, completely inhibited tolerance development. The inhibition of tolerance development by combined depletion of both NE and 5-HT is discussed in terms of a reciprocal relationship between these two systems.

5,7-Dihydroxytryptamine↗
PubMed1981

Conditioned increases in locomotor activity produced with morphine as an unconditioned stimulus, and the relation of conditioning to acute morphine effect and tolerance.

Rats administered 5 mg/kg morphine SO4, through subcutaneously implanted catheters, during each of several daily sessions in an open field showed a progressive increase in locomotor activity measured in the open field prior to each morphine administration. Since the increases in activity were not observed in rats given morphine in a different environment (home cage) and saline in the open field, it is concluded that the increases were due to conditioning. In addition, the increases in activity were retained over a 7-day rest period; they were also produced when a second opiate (5 microgram/kg etorphine HCl) was substituted for morphine, were not seen when 2 mg/kg naloxone HCl (ip) was administered during treatment, and were present in rats showing tolerance to opiate-produced hypoactivity. Morphine's direct effect on activity is believed to have a biphasic dose-response curve; therefore, the relation of dose to conditioning was also studied. Increases in activity were the only conditioned behaviors observed; they were present only at the higher doses (16, 4, and 1 vs. .25, .065, and 0 mg/kg), and they occurred whether or not the dose was associated with unconditioned hypoactivity. The discussion deals with the relation of conditioning and morphine tolerance, the question of whether the unconditioned stimulus of morphine conditioning is a compensatory or a direct effect of morphine, and the similarity of conditioned increases in activity produced by morphine and by other stimuli that are reinforcing.

Animals↗
PubMed1981

The effect of lesions in the dorsal, median and magnus raphe nuclei on the development of tolerance to ethanol.

Electrolytic lesions were made in the median, the dorsal, the dorsal + median or magnus raphe nuclei of rats. Sham-control animals were also prepared through the same procedure with the exception that no current was delivered. After 1 week of recovery from surgery, a dose-response curve to the hypothermic and motor-impairment effects (moving belt test) was carried out to assess the initial response to ethanol. The maximal fall in temperature and maximum motor impairment were used to quantify the ethanol effects. Two days after the dose-response study, hypothermia and motor impairment were again determined in all animals after a test dose of ethanol. The animals in each main treatment group were than divided into two subgroups matched on the basis of their maximum hypothermic or motor impairment response. The subgroups received daily treatment with either ethanol (5 g/kg p.o.) or calorically equivalent amounts of sucrose. Tolerance to the ethanol-induced hypothermia or motor impairment was assessed at intervals of 5 days for 25 days. Lesions of the dorsal and magnus raphe nuclei produced a negligible effect on the development of ethanol tolerance. Lesions of the median raphe nucleus delayed the development of tolerance. Combined lesions of the median + dorsal raphe nuclei did not significantly increase the effect produced by the lesions of the median raphe nuclei alone. Biochemical analysis confirmed the differential depletion of 5-hydroxytryptamine by the various lesions. These results indicate that the 5-hydroxytryptamine pathway from the median raphe nucleus to the dorsal hippocampus is important in the development of tolerance to ethanol.

Animals↗
PubMed1980

A role for calcium in the acute and chronic actions of ethanol in vitro.

Ethanol, in a concentration of 40--160 mM, depressed the electrically evoked contractions of the guinea-pig ileum longitudinal muscle/myenteric plexus (LM/MP) preparation in a dose-dependent manner. The acute ethanol inhibition in vitro was partially reversed by raising the extracellular calcium concentration. Following a 4 week ethanol treatment in vivo, by means of daily i.p. injections, the LM/MP preparation was rendered tolerant to ethanol and at the same time calcium was more effective in reversing the inhibitory effect of ethanol. It appears that calcium plays a role in the acute action of, and development of tolerance to, ethanol.

Animals↗
PubMed1980

Cross-tolerance between ethanol and morphine in the guinea-pig ileum longitudinal-muscle/myenteric-plexus preparation.

Morphinization of guinea pigs with s.c. implanted pellets (4 X 75 mg morphine base) has resulted in tolerance, within the isolated longitudinal muscle/myenteric plexus preparation, to the in vitro inhibitory effects of morphine on the electrically induced contractions, and in cross-tolerance to the inhibitory effects of ethanol. Similar results were observed with opiate-naive preparations that were incubated for 18 h in Krebs-Ringer solution containing 40 muM morphine. Daily ethanol injections (6 g/kg) resulted in tolerance to ethanol and cross-tolerance to morphine. These results suggest a commonality between ethanol and morphine actions on the myenteric plexus preparation.

Animals↗
PubMed1980

Role of serotonin (5-HT) in tolerance to ethanol and barbiturates.

Previously it has been shown that chronic administration of p-chlorophenylalanine (p-CPA), slowed the development of tolerance to ethanol, pentobarbital and cross-tolerance development to ethanol in rats chronically treated with pentobarbital. These findings have been extended by the following observations: (1) p-CPA slowed the development of tolerance to barbital as measured by motor impairment on the moving belt test, without altering the acute response. (2) p-CPA also reduced the tolerance to barbital as measured by sleeping time, in animals chronically treated with pentobarbital. (3) Administration of L-tryptophan increased the rate of tolerance development to ethanol as measured by motor impairment and hypothermia. These results further confirm and extend the generality of our observations that 5-HT may be involved in the development of tolerance and cross-tolerance to sedatives.

Animals↗
PubMed1980

Cross-tolerance between ethanol and morphine.

Adult male Wistar rats were fed chronically a liquid diet providing 35% of the calories as ethanol (10-12 g/kg ethanol daily), while pair-fed controls received the corresponding diet with alcohol replaced by an equicaloric concentration of sucrose. Rectal temperatures, after test doses of ethanol or morphine, were measured in several groups of rats at various times during chronic ethanol treatment. The fall in rectal temperature after a challenge dose of ethanol (3.0 g/kg) was significantly lower in the chronic alcohol group than in controls, indicating tolerance to ethanol-induced hypothermia. The same animals also developed cross-tolerance to the hypothermic effect of morphine (15 and 30 mg/kg), but not to the hyperthermic effect of morphine (5 mg/kg). Administration of morphine (30 mg/kg i.p.) for 3 days resulted in tolerance to morphine hypothermia, and cross-tolerance to ethanol-induced hypothermia. These studies fit with out hypothesis that tolerance and cross-tolerance among drugs develop to drug effects rather than to drug per se. Therefore drugs sharing a common effect, even by different mechanisms, might show cross-tolerance for that effect.

Animals↗
PubMed1980

Reversal of ethanol tolerance and cross-tolerance to pentobarbital in the rat.

Adult male Wistar rats were fed nutritionally adequate liquid diets providing 35% of the total calories as ethanol, while pair-fed controls received the corresponding diet with ethanol replaced by an equicaloric concentration of sucrose. After 2, 4, 6, 8, 10 and 14 weeks of chronic ethanol treatment, separate groups of rats were injected with a test dose of either ethanol (3 g/kg) or pentobarbital (40 mg/kg). Rectal temperatures were determined prior to and at 30, 60, 90 and 120 min after injection. The fall in rectal temperature after a test dose of ethanol or pentobarbital was significantly lower at 2 and 4 weeks in ethanol-treated rats than in pair-fed controls. After 6 and 8 weeks of chronic ethanol treatment, the fall in temperature after the same test doses was still less in ethanol-treated rats than in controls. However, at 10 and 14 weeks the fall in temperature was virtually identical in the two groups. A similar pattern of results was obtained when ethanol-induced sleep was compared in ethanol-treated rats and control rats. These intriguing results challenge the generally believed concept that tolerance and cross-tolerance, once produced, are sustained with chronic treatment, and may raise the possibility that such processes are reversible even during chronic treatment, at least under certain regimens.

Animals↗
PubMed1980

Effect of 5,7-dihydroxytryptamine on the development of tolerance to ethanol.

5,7-Dihydroxytryptamine (5,7-DHT) or the vehicle was administered once into both lateral ventricles of the rat. Desmethylimipramine (DMI) was administered IP prior to the intraventricular injection of 5,7-DHT to prevent the destruction of norepinephrine (NE) terminals. Following recovery from surgery, ethanol (5 g/kg, PO) or isocaloric sucrose was given daily for 25 days. Tests at 5-day intervals showed that chronic ethanol treatment produced tolerance to the motor impairment on the moving belt test and to hypothermic effects of ethanol. The 5,7-DHT treatment did not alter either the motor impairment or hypothermia produced by the initial dose of ethanol. However, 5,7-DHT treatment produced a 75% depletion of brain serotonin (5-HT) without altering NE concentration and retarded the development of tolerance to ethanol in both measurements. This study with a specific central depletor of 5-HT, without alteration in NE concentration, extends and supports our hypothesis that brain 5-HT modulates the development of tolerance to ethanol.

5,7-Dihydroxytryptamine↗
PubMed1980

Log dose/response curve flattening in rats after daily injection of opiates.

Rats injected (IP) daily with 0, 20, and 200 mg/kg morphine-SO4 for 25-49 days experienced log dose/response (LDR) curve flattening (decrease in slope and/or maximum response) for analgesia (tail immersion test) produced by etorphine-HCl injected IP or intracerebroventricularly (ICV), and for latency to maximum rectal temperature increase produced by IP etorphine. Rats treated similarly with 0, 50, and 500 micrograms/kg etorphine-HCl for 32 days exhibited LDR-curve flattening for analgesia produced by etorphine and morphine (IP). In addition, a profound body weight loss produced by high-dose morphine treatment (200 mg/kg) was found not to be involved in flattening, since similar body weight decreases produced by food restriction in 0 and 20 mg/kg rats did not have this effect. Flattening, however, may be due to a rapidly acquired and rapidly lost within-session (acute) tolerance. When flattening was not seen at short intervals after IP or ICV test etorphine doses, flattening was seen when rats were retested at longer test intervals. Forty-eight hours after cessation of chronic etorphine treatment, flattening of the etorphine analgesia LDR curve was lost, but parallel shift was unaffected. Similarly, 200 mg/kg morphine-treated rats lost morphine tolerance more rapidly than 20 mg/kg-treated rats during the first 12 days after the last treatment injection. Subsequently, however, levels of the analgesia and the amounts of tolerance loss were comparable in both chronically treated groups. The data support the notion that chronic tolerance reflects an enhancement or prolongation of acute tolerance.

Analgesics↗
PubMed1980

Acute and chronic catecholamine-ethanol interactions on rat brain (Na+ + K+)-ATPase.

Noradrenaline (N) sensitizes rat brain (Na+ + K+)-ATPase to inhibition by low concentrations of ethanol (E). Only 1-N and not d-N was effective. The sensitization is also produced by other alpha-adrenergic agonists (adrenaline, phenylephrine), but not by isoproterenol, and is prevented by phentolamine but not by propranolol. The sensitization is greater with partially purified enzyme than with crude homogenates. N + E, like much higher concentrations of E alone, produced competitive inhibition with respect to K+ but uncompetitive or mixed inhibition with respect to Na+, Mg++ and ATP, and a reduced "physiological efficiency" of ATP utilization. All these changes were abolished by increasing K+ to 20 mM. After 3-week E treatment, with or without withdrawal, the N + E interaction was markedly reduced, though basal ATPase activity was increased only after withdrawal. Temperature-dependence studies (Arrhenius plots) indicated that sensitization occurs by alteration of activation energy only above the transition temperature. These findings suggest that alpha-agonists fluidize membrane lipids and thus facilitate conformational change of the enzyme by E, resulting in inhibition.

Animals↗