Affinity For Opiate Receptors Research Articles

The influence of non-opiate analogue of leu-enkephalin to the cardiac consequences of intrauterine hypoxia of albino rats

Objective ― Our study aimed to evaluate the possibility of correcting cardiac consequences of intrauterine hypoxia (IUH) by injecting leu-enkephalin analog, lacking affinity for opiate receptors, in the early postnatal period. Material and Methods ― To model IUH, we placed pregnant Wistar rats in a hypobaric chamber with an oxygen partial pressure of 52 mmHg. The procedure was repeated for 4 h daily over the 15th-19th days of gestation. From the 2nd through the 6th days of their lives, the offspring were injected intraperitoneally with non-opiate leu-enkephalin analog at a dose of 100 μg/kg (NALE: Phe-D-Ala-Gly-Phe-Leu-Arg). This analog did not have affinity for opiate receptors. The 7- and 60-day old offspring of female rats subjected to IUH were investigated. The control group included the descendants of intact animals. We investigated gravimetric indicators, DNA-synthetic activity of cardiomyocytes (CMC) by tritium-labeled thymidine autoradiography method, the size of the CMC nuclei, as well as size and amount of nucleoli in the CMC nuclei. The activity of free radical oxidation was evaluated in cardiac homogenates by chemiluminescence. Results ― In 7-day old rats subjected to IUH vs. control animals, we observed decreases in body mass by 32.6%, in heart mass by 27.3%; in the proportion of 3Н-thymidine labeled CMC nuclei by 32.7% in the left ventricle and by 30.4% in the right ventricle; in the number of nucleoli in the CMC nuclei (in the left ventricle: control – 2.384±0.027, IUH – 2.282±0.027*, p<0.05; in the right ventricle: control – 2.409±0.038; IUH – 2.240±0.012*, p<0, 05). Increase in CML indices of cardiac homogenates was revealed, indicating the activation of free radical oxidation. In 7-day old rats subjected to IUH and administration of the NALE peptide from the 2nd through the 6th days of their lives, the proportion of 3H-thymidine labeled nuclei in the CMC did not differ from the control (in the left ventricle: control – 12.79±0.89%, IUH + NALE – 10.98±0.95%, p>0.05; in the right ventricle: control – 11.61±0.78%; IUH + NALE – 11.26±0.58%, p>0.05). The number of nucleoli in the CMC nuclei of the left and right ventricles in the heart of 7-day old animals in the IUH + NALE group did not differ from the control too. The CML indices of heart homogenates in the IUH + NALE group were significantly lower than those in the IUH group. In 60-day old male rats exposed to IUH, there was a decrease in heart mass by 18.5%, sizes of CMC nuclei by 7.5% and 16.1% in the left and right ventricles, respectively, and in the total nucleoli area in the CMC nuclei of the left ventricle (control – 3.953±0.085; IUH – 3.372±0.078*; p<0.05). In 60-day old male rats subjected to IUH and injections of the NALE peptide from the 2nd to the 6th days of their lives, heart mass (control – 692.73±26.81 mg; IUH + NALE – 631.0±29.79 mg; p>0.05) and the size of the CMC nuclei of the right ventricle (control – 54.25±0.84; IUH + NALE – 55.24±0.94; p>0.05) did not differ significantly from the control. The size of the nuclei, the number and size of the nucleoli in the CMC of the left ventricle, as well as the area of the nucleoli in the CMC of the right ventricle in 60-day old male rats of the IUH + NALE group significantly exceeded control group values. Conclusion ― Administration of the NALE peptide to albino rats subjected to IUH normalized DNA-synthetic activity and the number of nucleoli in the nuclei of CMC in 7-day old animals, and also reduced the severity of oxidative stress in the heart tissue. In 60-day old albino male rats exposed to IUH, injecting NALE from the 2nd to the 6th days of their lives eliminated declines in heart mass and sizes of the CMC nuclei and nucleoli, and also led to an increase in the values of the nucleus-and-nucleolus complex indices compared with the control.

Opioid receptors mediate the acquisition, but not the expression of mitragynine-induced conditioned place preference in rats.

Mitragynine is the main psychoactive ingredient of the herbal drug preparation Kratom (Ketum), derived from the plant Mitragyna speciosa. Kratom is a widely abused drug in Southeast Asian and has a psychostimulant profile at low-medium doses, while high doses have opioidergic effects. Mitragynine was shown to possess opiate receptor affinity. However, its role in the behavioural effects of mitragynine is unclear. Here we asked whether the reinforcing effects of mitragynine are mediated by opiate receptors using a conditioned place preference (CPP) paradigm in rats. In the first experiment we tested the effects of the opiate receptor antagonist naloxone (0.1, 0.3 and 1.0mg/kg) on the acquisition of mitragynine (10mg/kg)-induced CPP. In the second experiment, we tested the involvement of opiate receptors in the expression of mitragynine-induced CPP in rats. We found that naloxone suppresses the acquisition of mitragynine-induced CPP. This effect was already evident at a dose of naloxone (0.1mg/kg) which, by itself, had no conditioned place aversion (CPA) effect. Higher doses of naloxone induced a CPA and blocked mitragynine-induced CPP. In contrast, naloxone had no effect on the expression of mitragynine-induced CPP. These findings suggest that the acquisition, but not the expression of the reinforcing effects of mitragynine is mediated by opiate receptors.

EphB2 reverse signaling regulates learned opiate tolerance via hippocampal function

Despite significant progress, many uncertainties remain regarding molecular and cellular mechanisms governing opiate tolerance. We report that loss of EphB2 receptor reverse signaling results in a marked acceleration of morphine tolerance in vivo. EphB2 null mice exhibited no significant difference in brain or blood morphine metabolism, mu opiate receptor affinity or binding capacity. Motor and sensory performance for EphB2 null mice was also comparable to controls for both morphine naïve or tolerized states. Regional distributions of mu opioid receptor, CGRP and substance P were also unaltered in EphB2 null mice. However EphB2 null mice, but not animals homozygous for kinase dead version of EphB2, exhibited significant modification of context-dependent anti-nociceptive responses following chronic morphine treatment. To verify the changes seen in EphB2 null mice arise from impairment of hippocampal learning, discreet bilateral lesions of the dorsal hippocampus were produced in wildtype mice demonstrating striking similarities to that seen in EphB2 null mice for opiate-dependent behavior. The results demonstrate that EphB2 reverse signaling plays a unique and requisite role in inhibiting the development of opiate-dependent tolerance in vivo.

A high throughput gold nanoparticles chemiluminescence detection of opioid receptor antagonist naloxone hydrochloride

BackgroundThe opioid antagonist agent naloxone hydrochloride (NLX) is a drug that has high affinity for opiate receptors but do not activate these receptors. Owing to the role of this drug to block the effects of exogenous administered opioids and endogenous released endorphians we can deduce the importance of developing sensitive analytical methods for detection of such drug. In the present study gold nanoparticles (AuNPs) was employed for enhancing the chemiluminescence (CL) signals arising from luminol-ferricyanide reaction in the presence of naloxone hydrochloride using sequential injection chemiluminescence analysis (SIA).MethodIn the present study gold nanoparticles (AuNPs) was employed for enhancing the chemiluminescence (CL) signals arising from luminol-ferricyanide reaction in the presence of naloxone hydrochloride using sequential injection chemiluminescence analysis (SIA).ResultsThe developed method was examined under optimum experimental conditions and the obtained results revealed a linear relationship between the relative CL intensity and the investigated drug at a concentration range of 1.0×10−9-1.0×10−2 mol L−1, (r = 0.9993, n=9) with detection and quantification limits of 1.6×10−11 and 1.0×10−9 mol L−1, respectively. The relative standard deviation was 0.9%.ConclusionThe proposed method was employed for the determination of the investigated drug in bulk powder, its pharmaceutical dosage forms and biological fluids. The interference of some metals and amino acids on the CL intensity was investigated. Also the interference of some related pharmacological action drugs was tested. The obtained results of the developed method were statistically treated and compared with those obtained from other reported methods.Graphical Utility of gold nanparticles in luminol-potassium ferricyanide chemiluminescence system for determination of naloxone hydrochloride.

The effect of mirthful laughter on the human cardiovascular system

It has become increasingly recognized and more widely acknowledged during the past several decades, that a complex relationship exists between behavior associated with emotion and the human cardiovascular (CV) system. Early studies focused on the interplay between negative emotions and elevated CV risk, an effect that has in large part been attributed to increased adrenergic activity. Thus, a variety of adverse CV effects ranging from sudden cardiac death triggered by natural disasters such as earthquakes to transient myocardial stunning resulting from heightened sympathetic overload have been identified in response to acute emotional distress. In fact, the biologic interplay between emotion and CV health has been greatly enhanced through studies of the vascular endothelium. As the largest organ in humans, the inner blood vessel lining serves as a conduit for the transfer of blood cells, lipids and various nutrients across the lumen to neighboring tissues. Healthy endothelial cells secrete vasoactive chemicals, most notably endothelial-derived relaxing factor or nitric oxide (NO), that effects smooth muscle relaxation and vessel dilation via a cyclic guanosine monophosphate (cGMP) dependent protein kinase signaling pathway. In addition, endothelial derived NO may reduce vascular inflammation by attenuating or inhibiting leukocyte adhesion and subendothelial transmigration as well as decreasing platelet activation via cGMP mediated pathways. Taken together, studying the endothelium provides an exceptional opportunity to advance our understanding of the potentially important interrelationship between emotions and the vasculature. Premised on the identification of physiological and biochemical correlates, the former was demonstrated after intracoronary administration of acetylcholine yielded paradoxical endothelial vasoconstriction in response to mental stress exercises. More recently, the brachial artery reactivity test (BART) has permitted endothelial function to be assessed in a non-invasive manner. In addition to traditional CV risk factors, exposure to negative emotions including mental stress and depression have been associated with reduced endothelial vasoreactivity as measured by BART. Whether mirthful laughter has the opposite effect garnered consideration following the discovery that mu3 opiate receptors were expressed in the vascular endothelium. Because mirthful laughter induces the release of beta-endorphins which in turn have high affinity for mu3 opiate receptors, we hypothesize that such positive emotions lead to the direct release of NO and associated biological consequences. Indeed, our studies have demonstrated opposing effects on endothelial vasoreactivity between those previously established (e.g., mental stress induced by negative visual and/or auditory stimuli) and those induced after mirthful laughter, thereby providing a potential mechanistic link between positive emotions and beneficial effects on the vasculature. This article reviews the relevant physiology and comments on the potentially wider clinical implications in the integration of this process to improve vascular health.

Effects of the Immunostimulant, Levamisole, on Opiate Withdrawal and Levels of Endogenous Opiate Alkaloids and Monoamine Neurotransmitters in Rat Brain

This report presents evidence that the immunostimulant drug levamisole, (−)-(S)-2,3,5,6-tetrahydro-6-phenylimidazo[2,1-b] thiazole monohydrochloride, produced a significant elevation of endogeneous morphine and codeine levels in brain regions and peripheral organs and attenuated the effects of naltrexone-induced withdrawal in morphine-addicted rats. Levamisole also significantly altered the metabolism of norepinephrine, dopamine, and serotonin in specific brain regions. These results suggest that levamisole’s attenuation of opiate withdrawal may be related to its ability to increase endogeneous opiate alkaloid levels and/or to alter central monoaminergic function. Levamisole does not have significant affinity for opiate receptors. These results raise the intriguing possibility that agents such as levamisole, which elevate the levels of the endogenous opiate alkaloids, might be useful for treating narcotic withdrawal. The mechanism for the immunostimulatory properties of agents such as levamisole and muramyl dipeptide (MDP) have not been established. We suggest that the ability of MDP and levamisole to increase endogenous opiate alkaloids may be related to their immunostimulatory properties.

The Effect of an Acute Ethanol Exposure on the Rat Brain POMC Opiopeptide System

Endogenous peptides with a high affinity for opiate receptors located in the central nervous system have been postulated to play a role in the etiology of alcoholism or in other addictive diseases. Effects of different doses of ethanol (EtOH) at different time points post-EtOH administration on hypothalamic and hindbrain beta-endorphin–like peptide (β-EPLP) content in male rats were measured by radioimmunoassay (RIA). A single EtOH exposure resulted in an increase in hypothalamic and a decrease in the hindbrain β-EPLP levels. In another set of experiments, proopiomelanocortin (POMC) synthesis in the hypothalamus was measured by assaying both POMC primary transcript and mature mRNA. No changes in primary transcript or mature POMC hypothalamic mRNA were detected. Based on the results from this experiment we conclude that an acute EtOH exposure affects the rat hypothalamic POMC opiopeptide system by increasing levels of β-EPLP and this increase in levels is not related to an increase in synthesis.

The Effects of Estradiol and Progesterone on Pain Sensitivity and Brain Opioid Receptors in Ovariectomized Rats

Previous studies in our laboratory have shown that estradiol and progesterone affect β-endorphin and Met-enkephalin levels in specific brain regions and that these effects are diurnally controlled. The present investigation was conducted to evaluate the effects of estradiol and progesterone on pain latency and brain opioid receptors of ovariectomized rats. Female Sprague–Dawley rats (100–120 g) adapted to a 12 hr light:12 hr dark illumination cycle were used in these studies. Animals were ovariectomized under pentobarbital anesthesia. After a recovery period of 10–14 days, estradiol (50 μg/kg/day in 0.2 ml olive oil) and progesterone (5 mg/kg/day in 0.1 ml olive oil) were administered subcutaneously in the dorsal neck region alone and in combination at 16:00 hr for 7 days. Control animals received 0.2 ml olive oil. Control and treated groups were evaluated daily for pain latency postinjection using the tailflick and hotplate methods. On Day 7 of drug treatment, animals were sacrificed by decapitiation after pain latency evaluations. Whole brains were removed and immediately frozen at −70°C. Binding and affinity of brain opiate receptors were determined for each treatment group. Results obtained indicate that estradiol and progesterone treatment alone or in combination significantly alter pain latency. This alteration in pain was not accompanied by any change in affinity or number of mu opioid receptors. However, an increase inKdof kappa opiate receptors was observed following treatment with estradiol, progesterone, or their combination. This increase inKdof kappa opiate receptors may in part explain the increased hotplate sensitivity following estrogen administration. The present findings suggest that the decrease in pain sensitivity induced by estradiol or progesterone could not be explained by their effects on opioid receptors. The previously reported effects of estradiol and progesterone on brain levels of β-endorphin and Met-enkephalin may contribute to the analgesic effects of these steroids.

Abecarnil in Generalised Anxiety Disorder

Abecarnil is a β-carboline partial benzodiazepine agonist which may be selective for certain subpopulations of benzodiazepine receptors. It has greater affinity for central benzodiazepine receptor sites than diazepam, but low affinity for peripheral benzodiazepine, adrenergic, dopaminergic, opiate and serotonergic receptors. At present, virtually all published pharmacodynamic data for abecarnil are derived from animals studies. Abecarnil is active in a number of animal models of anxiety and is generally more effective than diazepam. It also attenuated some, but not all, chemically- or electrically-induced seizures in animals (diazepam antagonised most types of induced seizures) and was protective in genetic models of epilepsy. In most instances, its anticonvulsant activity did not appear to be attenuated during long term administration. Although some sedation occurs with abecarnil administration to animals, the drug is associated with less sedation, muscle relaxation, ataxia and impairment of memory than are several benzodiazepines. It also produces less potentiation of the effects of ethanol and hexobarbital than diazepam. In animals, the withdrawal syndrome after abecarnil discontinuation or administration of the benzodiazepine antagonist flumazenil is generally reduced or absent compared with benzodiazepines, suggesting that abecarnil has a low dependence potential. Abecarnil appears to have less propensity to induce tolerance than diazepam; it may also have a reduced abuse liability compared with benzodiazepines, as suggested by limited evidence in animals. The pharmacokinetic profile of abecarnil has yet to be investigated in patients with generalised anxiety disorder. Although pharmacokinetic parameters showed great intra- and interindividual variability in volunteers, the mean oral bioavailability of abecarnil 5 or lOmg was 39% in older volunteers and 55 to 65% in younger volunteers, and maximum plasma concentrations and AUC values after a single dose or at steady-state were dose-proportional. Abecarnil is predominantly metabolised, with less than about 10% of the drug being excreted unchanged. The main metabolite is the glucuronide conjugate of abecarnil, although 4 metabolites have been identified. Only one clinical trial assessing the efficacy of abecarnil in the treatment of generalised anxiety disorder has been published in full. Low dosages of the drug (3 to 9 mg/day) were significantly more effective than placebo and produced few serious adverse effects with no significant withdrawal syndrome upon discontinuation of 3 weeks of treatment. However, higher dosages of abecarnil (15 to 30 mg/day, and to a lesser extent 7.5 to 15 mg/day) produced a high incidence of adverse CNS effects [including drowsiness (71 and 51%), a loss of equilibrium (26 and 11 %), confusion (24 and 3%), amnesia (15 and 3%), fatigue (15 and 17%), lethargy (18 and 3%), insomnia (15 and 6%) and dizziness (18 and 11%)] which caused discontinuation of treatment in 29% of patients receiving abecarnil 15 to 30 mg/day. Higher drug dosages were also associated with some withdrawal signs upon discontinuation of therapy. In addition, there appeared to be some loss of efficacy with all tested dosages of abecarnil in comparison with placebo during the third week of treatment. Other trials of abecarnil, published collectively in abstract form with little detail, have suggested that 4 to 6 weeks of treatment with the drug had efficacy similar to benzodiazepines and produced a similar number of adverse effects or withdrawal symptoms as placebo when discontinued in a tapered fashion. In conclusion, experimental evidence to date suggests that abecarnil may be a valuable alternative to currently used agents for the treatment of generalised anxiety disorder, particularly if efficacy is maintained at lower dosages. However, clinical trials, including comparisons with benzodiazepines, will first need to demonstrate the potential advantages (reduced adverse effects, dependence and abuse potential) observed with abecarnil in animal models.

A comparison of (−)-deoxybenzomorphans devoid of opiate activity with their dextrorotatory phenolic counterparts suggests role of σ2 receptors in motor function

Three novel benzomorphans, (+)-N-benzylnormetazocine, (−)-deoxy-N-benzylnormetazocine, and (−)-deoxypentazocine were tested for their ability to produce circling behavior in rats following intranigral microinjections. Dose studies revealed the following rank order of potency: (−)-deoxypentazocine > (−)-deoxy-N-benzylnormetazocine > (+)-N-benzylnormetazocine. This rank order approximates that for affinities for σ 2 receptors but not σ 1 receptors. It is very unlikely that the effects of the (−)-deoxybenzomorphans were mediated by opiate receptors for the following reasons: (1) consistent with the known requirement for the phenolic hydroxyl group for opiate activity, both (−)-deoxy compounds showed very low affinity for opiate receptors; (2) naloxone (4 μg) co-administered with (−)-deoxy-N-benzylnormetazocine failed to reduce its efficacy; (3) both (−)-deoxy compounds failed to produce marked analgesic effects in the tail flick test following systemic injections of 20 mg/kg s.c. These findings suggest that σ 2 receptors mediated the motor effects of σ ligands in rats.

Erratum

Quantification of Human Opiate Receptor Concentration and Affinity Using High and Low Specific Activity [11C]Diprenorphine and Positron Emission Tomography Bernard Sadzot, Julie C. Price, Helen S. Mayberg, Kenneth H. Douglass, Robert F. Dannals, John R. Lever, Hayden T. Ravert, Alan A. Wilson, Henry N. Wagner, Jr., Marc A. Feldman, and J. James Frost [originally published in Journal of Cerebral Blood Flow and Metabolism 1991;11(2):204–219] Due to errors in the PET calibration factors, the published values of some of the parameter estimates are inaccurate. The correct values of Bmax and KD are 1.4 times and 0.4 times the published value, respectively. The correct values of Kl and Ktfk2 are 3.2 times the published value. Accordingly, the values of konf2 and f2 are 0.7 and 0.3 times the published value, respectively. The values of k2′ k3′ and k4 are correct. These quantitative errors in the parameter estimates do not affect the overall strategy for the application of tracer kinetic modeling nor the identification of the optimal fitting strategy. The authors regret these errors.

Mechanisms of action of ibogaine and harmaline congeners based on radioligand binding studies.

Assays using radioligands were used to assess the actions of ibogaine and harmaline on various receptor types. Ibogaine congeners showed affinity for opiate receptors whereas harmaline and harmine did not. The Ki for coronaridine was 2.0 microM at mu-opiate receptors. The Kis for coronaridine and tabernanthine at the delta-opiate receptors were 8.1 and 3.1 microM, respectively. Ibogaine, ibogamine, coronaridine and tabernanthine had Ki values of 2.08, 2.6, 4.3 and 0.15 microM, respectively, for kappa-opiate receptors. Long-lasting, dose-dependent behavioral effects of ibogaine have been reported. The possibility that these effects were due to irreversible binding properties of ibogaine at kappa-receptors was considered; however, radioligand wash experiments showed a rapid recovery of radioligand binding after one wash. A voltage-dependent sodium channel radioligand demonstrated Ki values in the microM range for all drugs tested. Using radioligand binding assays and/or 36Cl- uptake studies, no interaction of ibogaine or harmaline with the GABA receptor-ionophore was found. The kappa-activity of ibogaine (or an active metabolite) may be responsible for its putative anti-addictive properties whereas the tremorigenic properties of ibogaine and harmaline may be due to their effects on sodium channels.

14,17-Ethano-norcodeinone

A new codeinone derivative was synthesized starting with northebaine which might be of interest with regard to the question of opiate-receptor affinity in the sense of its rigidity near the anionic side of the alkaloid.

Quantification of Human Opiate Receptor Concentration and Affinity Using High and Low Specific Activity [11C]Diprenorphine and Positron Emission Tomography

[11C]Diprenorphine, a weak partial opiate agonist, and positron emission tomography were used to obtain noninvasive regional estimates of opiate receptor concentration (Bmax) and affinity (Kd) in human brain. Different compartmental models and fitting strategies were compared statistically to establish the most reliable method of parameter estimation. Paired studies were performed in six normal subjects using high (769-5,920 Ci/mmol) and low (27-80 Ci/mmol) specific activity (SA) [11C]diprenorphine. Two subjects were studied a third time using high SA [11C]diprenorphine after a pretreatment with 1-1.5 mg/kg of the opiate antagonist naloxone. After the plasma radioactivity was corrected for metabolites, the brain data were analyzed using a three-compartment model and nonlinear least-squares curve fitting. Linear differential equations were used to describe the high SA (low receptor occupancy) kinetics. The k3/k4 ratio varied from 1.0 +/- 0.2 (occipital cortex) to 8.6 +/- 1.6 (thalamus). Nonlinear differential equations were used to describe the low SA (high receptor occupancy) kinetics and the curve fits provided the konf2 product. The measured free fraction of [11C]diprenorphine in plasma (f1) was 0.30 +/- 0.03, the average K1/k2 ratio from the two naloxone studies was 1.1 +/- 0.2, and the calculated free fraction of [11C]diprenorphine in the brain (f2) was 0.3. Using the paired SA studies, the estimated kinetic parameters, and f2, separate estimates of Bmax and Kd were obtained. Bmax varied from 2.3 +/- 0.5 (occipital cortex) to 20.6 +/- 7.3 (cingulate cortex) nM. The average Kd (eight brain regions) was 0.85 +/- 0.17 nM.

Effects of Fedotozine on Gastrointestinal Motility in Dogs: Mechanism of Action and Related Pharmacokinetics

The effects of fedotozine, (+)-(1R)-1-phenyl-1-[(3,4,5-trimethoxy)benzyloxymethyl]-N,N-dim eth yl- n-propylamine, on motility of the antrum and small intestine were investigated in dog. In fasted dogs, following i.v. administration, fedotozine at 1 and 2 mg kg-1 stimulated and at 5 mg kg-1 inhibited antral motility. Between 1 to 5 mg kg-1, fedotozine exhibited a sustained and potent stimulatory effect on the small intestine inducing 1 to 4 phases III of the migrating motor complex (MMC) lasting up to 32 min in the duodenum and migrating to the jejunum. Following oral administration, fedotozine at 2.5 and 5 mg kg-1 constantly stimulated both antrum and small intestinal motility. In fed dogs, fedotozine i.v. (2 mg kg-1) increased antral motility and induced phase III of MMC in the place of postprandial pattern. Naloxone (0.3 mg kg-1 i.v.) and naloxone methylbromide (2 mg kg-1 i.v.) inhibited the stimulatory effects of fedotozine on gastrointestinal motility indicating a peripheral opiate site of action of the drug whereas phentolamine, hexamethonium, propranolol and methysergide were inactive. In-vitro fedotozine showed submicromolar affinity for opiate receptors with a weak specificity for the mu-receptors in guinea-pig brain and myenteric plexus preparations. Plasma concentrations in dogs receiving fedotozine administered orally at 2.5 mg kg-1 (and in all dogs except one at 5 mg kg-1) were below the detection limit (less than 20 ng g-1). In contrast, tissue concentrations in the muscle and mucosal layers of the gut were above 1 microgram g-1.(ABSTRACT TRUNCATED AT 250 WORDS)

Stereoselectivity and subtype of the opiate receptor involved in stress-induced hypertension

Naloxone enantiomorphs were given intracerebroventricularly (i.c.v.) to rats socially deprived for a brief period of time (7–14 days) in order to ascertain the mediation of central opiate receptors in the reversal effect of opiate antagonists on the high systolic blood pressure induced by this type of stress. While the active enantiomorph ((−)-naloxone, 20 nmol per rat) lowered the elevated blood pressure, the (+)-enantiomorph (which shows a 10 000-fold lower affinity for opiate receptors) had no effect. Additionally, the antihypertensive effect induced by i.c.v. administration of an antagonist of the μ-opiate receptor (β-funaltrexamine, 20 nmol per rat), but not of the δ-opiate receptor (ICI 174, 864, 15 nmol per rat) pointed to the involvement of μ-opiate receptors as the endogenous component of the hypertensive response of rats to stress.

Binding Profile of SM-9018, a Novel Antipsychotic Candidate

The present study employed various receptor-binding assays to clarify the biochemical characteristics of SM-9018. SM-9018 possessed very high affinity for 5-HT2, D2 and 5-HT1A receptors (Ki=0.61, 1.4 and 2.9 nM, respectively), and it had moderate affinity for α1 and D1 receptors (Ki=17 and 41 nM, respectively). However, SM-9018 had only negligible affinity for α2, opiate, glutamate, phencyclidine, benzodiazepine and GABAA receptors. These results suggest that SM-9018 may be a novel antipsychotic agent with binding affinity for 5-HT2 and 5-HT1A receptors.

Behavioural and neurochemical changes produced by lefetamine in two inbred strains of mice.

Lefetamine, a diphenylalkylaminic derivative, is a centrally acting analgesic which seems to possess abuse liability. The analgesic effect and the abuse liability of this compound are both due to its opiate activity. Lefetamine is an opiate agonist with an affinity for opiate receptors 50 times lower than that of morphine (De Montis et al 1985). Since genetic factors play a critical role in modulating some effects of morphine, the purpose of the present study was to investigate the effects of lefetamine on behavioural and neurochemical parameters in two inbred strains of mice (C57 BL/6J and DBA/2J) showing different responses to morphine (Oliverio and Castellano 1974; Cuomo et al 1981, 1981a).KeywordsLocomotor ActivityInbred StrainDopaminergic SystemHomovanillic AcidOpiate ReceptorThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Effects of the desensitization by morphine of the opiate-dependent adenylate cyclase system in the rat striatum on the activity of the inhibitory regulatory G protein

Opiates act through a specific receptor to inhibit the striatal adenylate cyclase [ATP pyrophosphate-lyase (cyclizing), EC 4.6.1.1] and stimulate a high-affinity GTPase (EC 3.6.1). The present study analyzes the functions of the striatal adenylate cyclase complex following chronic morphine treatment in the rat. The inhibitory effects of GTP on basal adenylate cyclase activity, between 10 −6 and 10 −4 M, were reduced. Moreover, the half-maximal inhibitory concentration of the opiate receptor agonist ( d-Ala 2Met 5-enkephalinamide (DAME) on striatal adenylate cyclase activity was increased by about four times, whereas the maximal effect was reduced in membranes from treated rats. In parallel, the half-maximal stimulatory concentration of DAME on GTPase was increased by two times, and the maximal stimulation was reduced from 60 to 25%. Binding studies performed with [3,5- 3] DAME (saturation curves) and with [ 3H]naloxone (competition curves) did not show any change in opiate receptor numbers and affinity. Moreover, the kinetics of the activation of the inhibitory GTP binding protein (G i) which transduces the opiate receptor effect on adenylate cyclase showed a small but significant delay. Therefore, hypofunction of G i can be, at least in part, responsible for the observed desensitization by morphine of the opiate-dependent GTPase and adenylate cyclase.

Pharmacological effects of MDL 11,939: A selective, centrally acting antagonist of 5‐HT2 receptors

AbstractMDL 11,939 (α‐phenyl‐1‐(2‐phenylethyl)‐4‐piperidine methanol) has been shown, through in vitro studies utilizing radioligand binding and isolated tissues as well as through in vivo tests of central and peripheral serotonergic activity, to be a potent, selective antagonist at 5‐hydroxytryptamine receptors of the 5‐HT2 subtype. In particular, MDL 11,939 shows low affinity for the 5‐HT1 and 5‐HT3 subtypes of the serotonin receptor and displays low or negligible affinity for alpha adrenergic, dopaminergic, cholinergic, histamininergic, and opiate receptors. Because the 5‐HT2 subtype of the serotonin receptor has been implicated in the control of both the central nervous and vascular systems of experimental animals, it is likely that a compound with the potency and specificity of MDL 11,939 has interesting therapeutic potential.