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At least 685 records · Page 38Linked to original sources
PubMed1978

New in vivo evidence for narcotic agonistic property of leucine-enkephalin.

Administration of leucine-enkephalin or morphine to mice rendered dependent on morphine by pellet implantation inhibited the naloxone-precipitated abstinence syndrome. The withdrawal jumping response was inhibited by morphine or leucine-enkephalin; however, both failed to inhibit withdrawal defecation and rearing behavior. On a molar basis, leucine-enkephalin was half as potent as morphine in inhibiting the abstinence syndrome. New in vivo pharmacological evidence for narcotic agonist-like activity of leucine-enkephalin is provided.

Animals↗
PubMed1983

Ethanol and tetrahydroisoquinoline alkaloids do not produce narcotic discriminative stimulus effects.

Male Sprague-Dawley rats were trained in a two lever food-reinforced procedure to discriminate between the effects of saline and the synthetic narcotic analgesic fentanyl (0.04 mg/kg). After acquisition of this discrimination, generalization tests with morphine, ethanol and some tetrahydroisoquinoline alkaloids were conducted. The rats dose-dependently generalized the effect of morphine but did not generalize the effects of either ethanol, tetrahydropapaveroline, salsolinol or 3-carboxysalsolinol to the fentanyl discriminative stimulus. Thus, these date do not support a biochemical link between ethanol and opiates.

Alkaloids↗
PubMed1982

The influence of chronic preoperative propranolol therapy on cardiovascular dynamics and narcotic requirements during operation in patients with coronary artery disease.

We measured the dose of sufentanil required for unconsciousness as well as the entire operation in 44 patients (22 taking propranolol and 22 not taking propranolol) undergoing coronary artery bypass grafting (CABG) operations. The incidence of hypertension during operation, requirements for supplements to treat hypertension and recovery times were also determined. The data indicate that patients undergoing CABG operations taking propranolol require significantly less sufentanil for unconsciousness and the entire operation than patients not taking this drug. In spite of requiring less sufentanil, patients taking propranolol had less hypertension during operation and thus required less supplements. However recovery times in both groups were the same. The results of this study may partially explain the varying incidence of hypertension reported during high dose fentanyl and other narcotic-oxygen anaesthetic techniques.

Anesthesia, General↗
PubMed1975

Rates of onset and offset of action of narcotic analgesics in isolated preparations.

In isolated preparations of the myenteric plexus--longitudinal muscle of the guinea-pig ileum and the mouse vas deferens, the rates of onset and offset of action of narcotic analgesics are inversely related to lipid solubility; this effect is probably due to drug binding at secondary lipid-rich binding sites. These findings are in contrast to observations in vivo by A. Herz and his colleagues, who showed that the rates of onset of action and of recovery are directly related to lipid solubility because of the presence of lipid-rich barriers. In view of the opposite effects, an optimum may be expected when a drug has a degree of lipid solubility which ensures rapid penetration of the blood--brain barrier without seriously slowing down of receptor association and dissociation. From the interaction of rapidly acting quaternary antagonists, e.g. N-methylnalorphinium, with slowly acting agonists, e.g. methadone, it is concluded that at least a part of the receptor site is on the surface of the cell membrane, and the possibility of an allosteric agonist--antagonist interaction is considered.

Analgesics, Opioid↗
PubMed1979

Enhanced naloxone potency and the development of narcotic tolerance.

When various biogenic amine modifying drugs were administered to mice which were pretreated with morphine, none of the drugs except atropine and haloperidol altered the usual doubling of the naloxone efficacy which is observed in morphine-pretreated mice. Atropine appeared to decrease the potency of naloxone. Haloperidol, which did not alter naloxone potency in normal mice, further increased the naloxone potency in morphine-pretreated mice. When the biogenic amine modifiers were injected chronically to mice during the development of morphine tolerance, again none of the drugs, except haloperidol and atropine altered the development of tolerance. Haloperidol appeared to enhance and atropine to inhibit the degree of tolerance. These results indicate that it is the alteration in the narcotic-induced enhancement of naloxone potency and not the mere alteration of noloxone potency by various drugs, which can be used as an indicator of the alterations in the development of tolerance.

Animals↗
PubMed1980

Lack of effect of choline and narcotic antagonists upon apomorphine discrimination.

Rats were trained to discriminate between the stimulus properties of intraperitoneal 0.16 mg/kg apomorphine and saline in a two-lever, food-motivated operant task. Subjects were then injected with either 79 mg choline chloride, 0.02 mg/kg haloperidol, 10 mg/kg naloxone or 10 mg/kg naltrexone prior to apomorphine or saline discriminative testing. Only haloperidol pretreatment was observed to significantly alter the rats' ability to discriminate apomorphine. The results are discussed in relation to the possible mechanism(s) of action of narcotic antagonist and cholinomimetic drug effects upon dopaminergically mediated behaviors.

Animals↗
PubMed1983

Quaternary derivatives of narcotic antagonists: stereochemical requirements at the chiral nitrogen for in vitro and in vivo activity.

We have studied three pairs of diastereoisomers of quaternary narcotic antagonists and their parent tertiary amines, levallorphan, nalorphine and naloxone, to see how configuration about the chiral nitrogen affects in vitro and in vivo activity. In each series only the diastereoisomer obtained by methylation of the N-allyl substituted tertiary amine (N-methyl diast.) was potent in displacing 3H-naltrexone from rat brain membranes (Ki 10(-8) - 10(-7)M) and as pure morphine antagonist in the guinea-pig ileum (Ki 10(-8)-10(-7)M). Conversely, diastereoisomers obtained by reacting N-methyl substituted tertiary amines with allyl halide (N-allyl diast.) did not displace 3H-naltrexone, up to 10(-6)M, and had negligible antagonist activity and slight agonist action in the guinea-pig ileum. In vivo findings (charcoal meal transit test in mice) were generally consistent with those in vitro. Thus only the N-methyl but not the N-allyl diast. inhibited morphine constipation and behaved as pure antagonists.

Animals↗
PubMed1983

Reversal of morphine-induced catalepsy in the rat by narcotic antagonists and their quaternary derivatives.

The effects of the pure narcotic antagonists, naloxone and naltrexone, and their quaternary derivatives, methylnaloxone and methylnaltrexone, were examined in reversing the catalepsy induced by morphine in rats. Morphine, 20 mg/kg, induced rigid catalepsy which attained a peak effect (as manifested by duration of catalepsy) at 60-120 min and progressively declined thereafter. Both naloxone and naltrexone, administered subcutaneously 40 min after the injection of morphine, dose-dependently reduced the duration of the catalepsy at doses of 10-30 micrograms/kg. Methylnaloxone also completely reversed the catalepsy at doses of 1-10 mg/kg, when given subcutaneously. In contrast, the subcutaneous administration of methylnaltrexone only partially reversed the catalepsy at doses up to 56 mg/kg 60-90 min post-morphine. The extent of the reversal of catalepsy produced by methylnaltrexone tended to increase with time. Methylnaltrexone, administered into the cerebral ventricles 70 min after the injection of morphine, completely suppressed the catalepsy with an ED50 of approx. 1 microgram/kg when tested at 90 min after morphine. These results indicate that opiate-induced catalepsy is predominantly mediated at sites within the central nervous system. Methylnaltrexone is about 10,000 times more potent in reversing catalepsy when administered centrally than when administered peripherally. Thus, methylnaltrexone may be useful in defining sites of opiate action and in therapeutically blocking undesirable peripheral effects of opiate analgesics.

Animals↗
PubMed1983

Effects of chronic antenatal and postnatal administration of narcotics on naloxone-induced anorexia in preweanling rats.

Previous studies have reported age-related changes in opiate receptors and in their response to narcotics during the process of normal growth of the brain. By inducing alterations in this developmental sequence, the present study attempted to provide correlates of the opiate receptor system with naloxone-induced anorexia. Offspring of mothers treated with morphine (7.5 mg/kg twice daily, s.c.) or saline during pregnancy, and infants from untreated mothers given morphine (5 mg/kg), naltrexone (10 mg/kg) or saline subcutaneously on postnatal days 1-5, were tested at days 10, 12 and 14 for deprivation-induced milk consumption following an acute dose of naloxone (1 or 5 mg/kg, i.p.). Naloxone reduced the food intake of 10- and 12-day old infants chronically treated with morphine postnatally. At age 14, naloxone reduced the food consumed by all the pretreatment groups, and pretreatment with morphine altered the dose-response curves for feeding modulation induced by naloxone. Naloxone had no effect on the food consumed by 10- or 12-day old offspring of mothers treated with morphine or saline, or on those age-groups that received naltrexone chronically or saline pretreatments postnatally. The observed changes occurred in the absence of gross malformations, drug-withdrawal symptoms and differences in activity. These results demonstrate that opiate receptors may participate in feeding.

Aging↗
PubMed1976

Interactions between naloxone and narcotic analgesics under three schedules that induce polydipsia.

A pattern of schedule-induced polydipsia was maintained in rats by a fixed-time schedule where food pellets were presented every 90 sec, a fixed-interval schedule where licking the drinking tube produced pellets every 90 sec, or a fixed-interval schedule where lever presses produced pellets every 90 sec. Under all 3 schedules, injections of morphine, methadone, etonitazene and meperidine generally decreased licking rates and amounts of water consumed, as well as rates of lever-pressing under the schedules where lever presses were required. Naloxone (1 mg/kg) almost completely blocked the effects of morphine and etonitazene, but the effects of methadone sometimes were blocked to a lesser degree. Small increases in the rate of licking and amount of water consumed after the lowest dose of meperidine under the schedule requiring lever-presses were blocked by naloxone, but the higher doses of meperidine that decreased licking, lever-pressing and amount of water consumed under the three schedules were not blocked by naloxone. These data suggest that there are important differences in the ability of naloxone to antagonize the behavioral effects of different narcotic analgesics.

Animals↗
PubMed1979

Detection of antagonist activity for narcotic analgesics in mouse hot-plate test.

On the assumption that by the use of the hot-plate procedure the antagonist properties of narcotic analgesics could be detected, the effect of morphine, pentazocine, nalorphine and naloxone were investigated. The latency of paw-licking and jumping-off were determined and compared. The agonist, morphine, at doses of 0.025, 0.05 and 0.1 mmole/kg injected IP significantly increased paw-lick and jump-off latency above that seen in saline controls. The mixed agonist-antagonist, pentazocine, at doses of 0.048, 0.096 and 0.192 mmole/kg and nalorphine, an antagonist with some agonist activity, at doses of 0.032, 0.064 and 0.128 mmole/kg significantly increased the latency of paw-licking, but did not significantly change the jump-off latency. At a dose of 0.016 mmole/kg naloxone treated mice jumped from the hot-plate significantly sooner than controls but no effects of naloxone on paw-licking latency were observed. These results suggest that agonist properties are involved in the paw-lick response and that antagonistic properties determine jumping-off behavior.

Animals↗
PubMed1982

Motility response of rats to chronic constant-dose treatment with narcotics.

The changes in effects on motor activity of rats upon repeated (48 day) dosing with four narcotic analgesics were determined. The following were administered IP once daily in a.m.: morphine sulfate (MOR), 20 mg/kg: dl-methadone HCl (MET), 5 mg/kg: meperidine HCl (MEP), 10 mg/kg; and pentazocine lactate (PEN), 20 mg/kg. Motility was measured in photocell actometers every 4 days for 6 hr after dosing. Activity was elevated after the initial dose as follows: for MOR at hours 3-5, for MET at hours 2-5, for MEP and PEN at hours 2-3. Time of peak response showed no systematic change over days. For all 4 drugs there occurred, upon repeated dosing, a considerable increase in motility over the initial acute response. For MOR the greatest increment occurred between days 12 and 16, but regression analysis showed a strong linear trend of increasing activity from day 1 through day 48. For MET and MEP, activity rose considerably between days 4 and 12 to a maximum, after which the activity trended downward for MET, but showed no continuing fall or climb for MEP. For PEN the greatest increases were from days 4 to 8 and 44 to 48, with an intervening period of relative stability. These results seem to be more readily explainable in terms of increasing sensitivity to the motor excitatory actions of these agents than merely by a development of tolerance to motor-inhibitory actions.

Animals↗
PubMed1985

Relative affinities of the quaternary narcotic antagonist, N-methyl levallorphan (SR 58002), for different types of opioid receptors.

The relative affinities for different subtypes of opioid receptors (mu, kappa and delta) of the peripheral narcotic antagonist N-methyl levallorphan (SR 58002) have been studied in two in vitro smooth muscle systems (guinea-pig ileum and rabbit vas deferens) and by binding studies (guinea-pig brain and cerebellum membranes) using selective tritiated ligands. All the evidence obtained indicates that SR 58002 is a pure antagonist with relative affinity for mu receptors vs kappa and delta superior to that of the parent tertiary compound, levallorphan.

Animals↗
PubMed1985

Use of gut cyclic motor activity to evaluate a stimulant (narcotic) and inhibitor (anticholinergic) of gastrointestinal-tract activity in the unanesthetized dog.

The use of gut cyclic motor activity to evaluate both a stimulant and inhibitor of gastrointestinal contractile activity in the unanesthetized dog is described. In the interdigestive (fasted) state, there is a cyclic alternation of intense periods of contractions (burst) with quiescent periods (basal). Codeine phosphate, a narcotic agent, caused a dose-dependent increase in the number and duration of circular muscle contractions when administered in the basal phase. Hyoscine N-butyl-bromide, an anticholinergic drug, caused a dose-dependent reduction in both amplitude and frequency of burst-phase contractions. When a combination of codeine phosphate and hyoscine N-butylbromide was administered simultaneously in the basal or burst phase, the hyoscine N-butylbromide prevailed and had the dominant effect. This is a useful in vivo model to evaluate the effects of drugs on the gastrointestinal tract.

Animals↗
PubMedDate not supplied

Degradation of met-enkephalin by extracts of various regions of the human brain: effects of antipsychotics and narcotics in vitro.

Antischizophrenic drugs, reduced in a concentration-dependent fashion enkephalin degradation by the soluble and particulate fractions of the human cerebral cortex and cerebellum. The order of potency is as follows: thioridazine greater than chlorpromazine greater than fluphenazine greater than haloperidol greater than or equal to promazine with IC50 of 50, 80, 120, 200-250 micro M, respectively. Kinetic studies revealed non-competitive and competitive inhibition by thioridazine and chlorpromizine, respectively. Narcotics, were weak inhibitors of enkephalin degradation. For dl-, d-, l-methadone and l-alpha-acetylmethadol, IC50 was about 500 micro M, and 1000 micro M for heroin and morphine. It is suggested that inhibition of the degradation of endogenous morphinomimetic peptides in the CNS may be a crucial factor governing the pharmacology of some neuroleptics and other psychoactive drugs. Enkephalin-hydrolyzing activity was ubiquitous and exhibited considerable regional differences in the normal human and in Huntington's chorea brains. The rate of enkephalin degradation is generally higher in the subcortical nuclei than in the cortex and cerebellum. The highest hydrolytic activity was found in the substantia nigra, anterior thalamus, septal area, globus pallidus and caudate nucleus, in this decreasing order.

Antipsychotic Agents↗
PubMed1985

Narcotic antagonist potentiation of apomorphine drug effect: a stereospecific, centrally mediated drug action.

Systemic pretreatment with naloxone but not its (+)-enantiomer significantly potentiated apomorphine-induced stereotypic climbing activity in mice. Systemic or central pretreatment with naltrexone also significantly potentiated the apomorphine drug effect. The N-methyl derivative of naltrexone had no influence when administered systemically but significantly potentiated the apomorphine drug effect when administered centrally. These findings suggest that narcotic antagonist potentiation of apomorphine-induced stereotypic climbing in mice is a stereospecific phenomenon that originates in the central nervous system.

Animals↗
PubMed1976

Clinical trial in post-addicts with oxilorphan (levo-BC-2605): a new narcotic antagonist.

Oxilorphan (levo-BC-2605) is a new, long-acting, narcotic antagonist that has agonist properties. Twenty-one (21) heroin addicts in Los Angeles were detoxified and given at least one oral dose of oxilorphan. Only three (14.3%) patients took daily doses for 14 days, which was the maximal time allowed for oxilorphan administration in this study. The remainder discontinued oxilorphan because of subjective side effects or for unknown reasons. Side effects most responsible for dropouts were dysphoria, insomnia, weakness, hallucinations, nausea, drowsiness and anorexia. Oxilorphan provided 24-hour protection with a single, oral dose, but subjective side effects encountered during inductiolinical trials with oxilorphan should be attempted with other addict populations to fully determine its potential therapeutic value.

Adult↗
PubMed1995

Screening and determination of beta-blockers, narcotic analgesics and stimulants in urine by high-performance liquid chromatography with column switching.

A fast method is described for the screening of eleven beta-blockers, two narcotic analgesics and two stimulants in urine by HPLC with column switching. The urine sample (100 microliters), buffered to pH 9-9.5, is injected onto a short extraction column packed with CN stationary phase. The extraction column is flushed with water for 2.5 min to elute polar matrix components to waste. The retained components are then backflushed by means of a six-port valve onto the ODS analytical column where they are separated. Phosphate buffer pH 3.0 and acetonitrile were used as mobile phase. Gradient elution was applied in the screening method to improve separation. Detection was performed with a diode-array detector at 220, 235 and 300 nm. Recoveries were near 100%, precision was excellent and sensitivity about 0.25 micrograms/l. To speed up the quantitative analysis, the same method but with isocratic elution was successfully applied to the determination of acebutolol and metoprolol in urine samples collected 4 h after administration of the compounds as single doses.

Adrenergic beta-Antagonists↗