κ-opioid receptors are implicated in the increased potency of intra-accumbens nalmefene in ethanol-dependent rats

Previously, it was shown that ethanol-dependent animals display increased sensitivity to the general opioid receptor antagonist nalmefene compared to naltrexone. It was hypothesized that the dissociable effects of the two antagonists were attributable to a κ-opioid receptor mechanism. Nucleus accumbens dynorphin is upregulated following chronic ethanol exposure and such neuroadaptations could contribute to nalmefene's increased potency in ethanol-dependent animals. To test this hypothesis, male Wistar rats were trained to self-administer ethanol using an operant conditioning procedure. Animals were then implanted with bilateral intra-accumbens shell guide cannulae and assigned to either a chronic intermittent ethanol vapor-exposure condition (to induce dependence) or an air-exposed control group. Following a one-month exposure period, nalmefene, nor-binaltorphimine (nor-BNI; selective for κ-opioid receptors) or a combination of the selective opioid receptor antagonists CTOP and naltrindole (selective for the μ- and δ-opioid receptors, respectively) were site-specifically infused into the nucleus accumbens shell prior to ethanol self-administration sessions during acute withdrawal. Nalmefene and CTOP/naltrindole dose-dependently reduced ethanol self-administration in nondependent and dependent animals, whereas nor-BNI selectively attenuated ethanol self-administration in ethanol-dependent animals without affecting the self-administration of nondependent animals. Further analysis indentified that intra-accumbens shell nalmefene was more potent in ethanol-dependent animals and that the increased potency was attributable to a κ-opioid receptor mechanism. These data support the concept that dysregulation of DYN/κ-opioid receptor systems contributes to the excessive self-administration observed in dependent animals and suggest that pharmacotherapeutics for ethanol dependence that target κ-opioid receptors, in addition to μ- and δ-opioid receptors, are preferable to those that target μ- and δ-opioid receptor mechanisms alone.     

Effects of intracerebroventricular injection of opioid peptides selective for μ, δ and κ receptors on discriminative stimulus properties of pentazocine in the rat

The present study was designed to investigate the effects of centrally administered morphine and opioid peptides on the discriminative stimulus properties of pentazocine in the rat. Rats were trained to discriminate 3 mg/kg (s.c.) of pentazocine from vehicle in a shock avoidance paradigm. A 3 mg/kg (s.c.) dose of pentazocine produced stimulus effects in common with those induced by a training dose (3 mg/kg, s.c.) of pentazocine. Morphine (0·1–3 μg, i.c.v.) produced a dose-dependent increase in responding appropriate for pentazocine lever. The μ-selective opioid receptor agonist [D-Ala²,NMePhe⁴,Gly-ol] enkephalin (DAMGO) (0·0003–0·03 μg, i.c.v.) generalized to pentazocine cue. d -Pen², l -Pen⁵] enkephalin (DPLPE) (3 and 10 μg, i.c.v.), a δ-selective opioid receptor agonist, produced partial generalization to pentazocine cue. However, the κ-selective opioid receptor agonist dynorphin A-(1–13) (3 and 10 μg, i.c.v.) did not generalize to pentazocine cue. The pentazocine-like discriminative stimulus effects of morphine (3 μg, i.c.v.) and DAMGO (0·03 μg, i.c.v.) were fully reversed by intracerebroventricular injection of the μ-selective opioid receptor antagonist β-funaltrexamine (5 μg, i.c.v.). These results suggest that μ-opioid receptors play a major role in the discriminative stimulus effects of pentazocine, while δ-opioid receptors only partially contribute to them. © 1998 John Wiley & Sons, Ltd.     

Kappa-opioid receptors mediate the antidepressant-like activity of hesperidin in the mouse forced swimming test

The opioid system has been implicated as a contributing factor for major depression and is thought to play a role in the mechanism of action of antidepressants. This study investigated the involvement of the opioid system in the antidepressant-like effect of hesperidin in the mouse forced swimming test. Our results demonstrate that hesperidin (0.1, 0.3 and 1 mg/kg; intraperitoneal) decreased the immobility time in the forced swimming test without affecting locomotor activity in the open field test. The antidepressant-like effect of hesperidin (0.3 mg/kg) in the forced swimming test was prevented by pretreating mice with naloxone (1 mg/kg, a nonselective opioid receptor antagonist) and 2-(3,4-dichlorophenyl)-Nmethyl-N-[(1S)-1-(3-isothiocyanatophenyl)-2-(1-pyrrolidinyl)ethyl] acetamide (DIPPA (1 mg/kg), a selective κ-opioid receptor antagonist), but not with naloxone methiodide (1 mg/kg, a peripherally acting opioid receptor antagonist), naltrindole (3 mg/kg, a selective δ-opioid receptor antagonist), clocinnamox (1 mg/kg, a selective μ-opioid receptor antagonist) or caffeine (3 mg/kg, a nonselective adenosine receptor antagonist). In addition, a sub-effective dose of hesperidin (0.01 mg/kg) produced a synergistic antidepressant-like effect in the forced swimming test when combined with a sub-effective dose of morphine (1 mg/kg). The antidepressant-like effect of hesperidin in the forced swimming test on mice was dependent on its interaction with the κ-opioid receptor, but not with the δ-opioid, μ-opioid or adenosinergic receptors. Taken together, these results suggest that hesperidin possesses antidepressant-like properties and may be of interest as a therapeutic agent for the treatment of depressive disorders.     

Role of central opioid on the antinociceptive effect of sulfated polysaccharide from the red seaweed Solieria filiformis in induced temporomandibular joint pain

This study aimed to investigate the effect of sulfated polysaccharide from red seaweed Solieria filiformis (Fraction F II) in the inflammatory hypernociception in the temporomandibular joint (TMJ) of rats. Male Wistar rats were pretreated (30 min) with a subcutaneous injection (s.c.) of vehicle or FII (0.03, 0.3 or 3.0 mg/kg) followed by intra-TMJ injection of 1.5% Formalin or 5-hydroxytryptamine (5-HT, 225 μg/TMJ). In other set of experiments rats were pretreated (15 min) with an intrathecal injection of the non-selective opioid receptors Naloxone, or μ-opioid receptor antagonist CTOP, or δ-opioid receptor Naltridole hydrochloride, or κ-opioid receptor antagonist Nor-Binaltorphimine (Nor-BNI) followed by injection of FII (s.c.). After 30 min, the animals were treated with an intra-TMJ injection of 1.5% formalin. After TMJ treatment, behavioral nociception response was evaluated for a 45-min observation period, animals were terminally anesthetized and periarticular tissue, trigeminal ganglion and subnucleus caudalis (SC) were collected plasma extravasation and ELISA analysis. Pretreatment with F II significantly reduced formalin- and serotonin-induced TMJ nociception, inhibit the plasma extravasation and inflammatory cytokines release induced by 1.5% formalin in the TMJ. Pretreatment with intrathecal injection of Naloxone, CTOP, Naltridole or Nor-BNI blocked the antinociceptive effect of F II in the 1.5% formalin-induced TMJ nociception. In addition, F II was able to significantly increase the β-endorphin release in the subnucleus caudalis. The results suggest that F II has a potential antinociceptive and anti-inflammatory effect in the TMJ mediated by activation of opioid receptors in the subnucleus caudalis and inhibition of the release of inflammatory mediators in the periarticular tissue.     

The role of opioid receptor sub-types in tifluadom-induced feeding

There is now considerable evidence that opioid agonists and benzodiazepines increase food and water intake in a variety of animal species. The appetitive effects of the novel opioid-benzodiazepine tifluadom have been investigated. (±)-Tifluadom significantly increased food intake in freely-feeding rats. This stimulation of appetite was attributable principally to the activity of the (+)-isomer. Furthermore tifluadom-induced feeding was blocked by the opioid antagonists naloxone, naltrexone, Mr 1452 and Mr 2266 but not by the δ-opioid receptor antagonist ICI 154, 129, or by the benzodiazepine antagonist Ro 15–1788. These results suggest that tifluadom exerts its effect on food intake by interaction with opioid as opposed to benzodiazepine receptors and that this activity is mediated by κ and/or μ- rather than δ-opioid receptor sub-types.     

Role of Opioidergic and Serotonergic Mechanisms in Cough and Antitussives

This paper provides an overview of our current understanding of the serotonergic and opioidergic mechanisms of cough and antitussives. Systemic administration of 8-OH-DPAT, at doses of 0.1 and 0.3 mg/kg, ip, markedly reduced the number of coughs in rats in a dose-dependent manner. The antitussive effects of 8-OH-DPAT, dihydrocodeine and dextromethorphan were significantly reduced by pretreatment with methysergide, but not with ketanserin. Therefore it is possible to speculate that 5-HT₁receptors, in particular the 5-HT_1Areceptors, may be more important than others with respect to the effect of antitussive drugs. DAMGO, a selective μ-opioid receptor agonist, and U-50,488H, a highly selective κ-opioid receptor agonist, have potent antitussive effects when administered either icv or ip. However, we did not observe a cough-depressant effect of DPDPE, a selective δ-opioid receptor agonist. These results indicate that the antitussive effects of opioids are mediated predominantly by μ- and κ-opioid receptors. On the other hand, naloxonazine, a selective μ₁-opioid receptor antagonist, had no effect on the antitussive effects associated with icv DAMGO. These results indicate that μ₂- rather than μ₁-opioid receptors are involved in μ-opioid receptor-induced antitussive effects. Antitussive effects of dextromethorphan and noscapine were significantly and dose-dependently reduced by pretreatment with rimcazole, a specific antagonist of sites. However, rimcazole did not have a significant effect on the antitussive effect of morphine. These results suggest that sites may be involved in the antitussive mechanism of non-narcotic antitussive drugs.     

Nicotine and endogenous opioids: neurochemical and pharmacological evidence

Although the mesolimbic dopamine hypothesis is the most influential theory of nicotine reward and reinforcement, there has been a consensus that other neurotransmitter systems contribute to the addictive properties of nicotine as well. In this regard, the brain opioidergic system is of interest. Striatum is rich in opioid peptides and opioid receptors, and striatal opioidergic neurons are engaged in a bidirectional communication with midbrain dopaminergic neurons, closely regulating each other's activity. Enkephalins and dynorphins exert opposing actions on dopaminergic neurons, increasing and decreasing dopamine release respectively, and are components of circuits promoting positive or negative motivational and affective states. Moreover, dopamine controls the synthesis of striatal enkephalins and dynorphins. Evidence suggests that opioidergic function is altered after nicotine and endogenous opioids are involved in nicotine's behavioral effects. 1) The synthesis and release of β-endorphin, met-enkephalin and dynorphin in brain, especially nucleus accumbens (NAc), are altered after acute or chronic nicotine treatment and during nicotine withdrawal. 2) Although opioid receptor binding and mRNA do not appear to change in the striatum during nicotine withdrawal, the activity of κ-opioid (KOPr) and δ-opioid (DOPr) receptors is attenuated in NAc. 3) The nicotine withdrawal syndrome reminisces that of opiates, and naloxone precipitates some of its somatic, motivational, and affective signs. 4) Genetic and pharmacological studies indicate that μ-opioid (MOPr) receptors are mainly involved in nicotine reward, while DOPrs contribute to the emotional and KOPrs to the aversive responses of nicotine. 5) Finally, MOPrs and enkephalin, but not β-endorphin or dynorphin, are necessary for the physical manifestations of nicotine withdrawal. This article is part of a Special Issue entitled 'Trends in neuropharmacology: in memory of Erminio Costa'.     

Antinociceptive evaluation of 14β-(bromoacetamido)- 7,8-dihydro-N(cyclopropylmethyl)-normorphinone in mice

This study evaluated the supraspinal opioid effects of 14β-(bromoacetamido)-7,8-dihydro-N(cyclopropylmethyl)-normorphinone (N-CPM-H₂BAMO) in the mouse acetic acid-induced writhing and tail-flick assays. In the writhing test, N-CPM-H₂BAMO produced a time- and dose-dependent antinociception after i.c.v. administration, with a 50% antinociceptive response being obtained with 0.28 (0.19–0.39) nmol when given 10 min before testing. The antinociceptive effect of N-CPM-H₂BAMO was antagonized in a dose-dependent manner by the κ-selective opioid receptor antagonist, nor-binaltorphimine. In the mouse tail-flick assay, N-CPM-H₂BAMO failed to produce any antinociception after i.c.v. administration. N-CPM-H₂BAMO produced a dose-dependent antagonism of morphine-induced antinociception but not antinociception induced by the δ-opioid receptor agonist [D-Pen²,D-Pen⁵]enkephalin. Nor-binaltorphimine (0.3 nmol) at dose that completely antagonized N-CPM-H₂BAMO-induced antinociception in the writhing assay did not prevent the antagonistic effect of N-CPM-H₂BAMO on morphine-induced antinociception. Therefore, these data indicate that N-CPM-H₂BAMO produces antinociception by acting at supraspinal κ-opioid receptors in the writhing assay, and also acts as a μ-opioid receptor antagonist.     

Lack of involvement of δ-opioid receptor in mediating physical dependence at the hypothalamus-pituitary-adrenocortical (HPA) axis in the rat

1. In previous studies, we have demonstrated that δ-opioid receptors are involved both in the acute control of hypothalamus-pituitary-adrenocortical (HPA) axis activity and in the development of neuroendocrine opioid tolerance. In the present work we studied whether central δ-opioid receptors play a role in the development of neuroendocrine physical dependence to opioids in the rat.2. Intracerebroventricular (i.c.v.) administration of the δ-selective agonist DPDPE ([D-Pen²,D-Pen²]enkephalin) produced stimulation of HPA activity, as shown by an increase in corticosterone release. This effect was antagonized by i.c.v. co-administration of ICI 174,864, a selective δ-receptor antagonist, which provide direct evidence that the activation of the HPA axis produced by DPDPE is mediated by central δ-opioid receptor.3. Chronic pretreatment with i.c.v. DPDPE resulted in tolerance to its neuroendocrine effect. Intracerebroventricular injection of ICI 174,864 to DPDPE-tolerant rats produced neither alteration in corticosterone release nor behaviour signs of dependence.4. It was concluded that δ-opioid receptors do not play a role in the development of opioid neuroendocrine physical dependence at the HPA axis.     

Acute effects of morphine on distinct forms of impulsive behavior in rats

Rationale  Disturbances in impulse control are key features of substance abuse disorders, and conversely, many drugs of abuse are known to elicit impulsive behavior both clinically and preclinically. To date, little is known with respect to the involvement of the opioid system in impulsive behavior, although recent findings have demonstrated its involvement in delay discounting processes. The aim of the present study was to further investigate the role of the opioid system in varieties of impulsivity. Materials and methods  To this end, groups of rats were trained in the five-choice serial reaction time task (5-CSRTT) and stop-signal task (SST), operant paradigms that provide measures of inhibitory control and response inhibition, respectively. In addition, another group of rats was trained in the delayed reward paradigm, which measures the sensitivity towards delay of gratification and as such assesses impulsive choice. Results and discussion  Results demonstrated that morphine, a selective μ-opioid receptor agonist, primarily impaired inhibitory control in the 5-CSRTT by increasing premature responding. In addition, in keeping with previous data, morphine decreased the preference for the large over small reward in the delayed reward paradigm. The effects of morphine on measures of impulsivity in both the 5-CSRTT and delayed reward paradigm were blocked by naloxone, a μ-opioid receptor antagonist. Naloxone by itself did not alter impulsive behavior, suggesting limited involvement of an endogenous opioid tone in impulsivity. Response inhibition measured in the SST was neither altered by morphine nor naloxone, although some baseline-dependent effects of morphine on response inhibition were observed. Conclusion  In conclusion, the present data demonstrate that acute challenges with morphine modulate distinct forms of impulsive behavior, thereby suggesting a role for the opioid system in impulsivity.     

Effects of Selective Opioid Receptor Antagonists on Morphine-Induced Changes in Striatal and Limbic Dopamine Metabolism

Abstract: The effects of selective opioid receptor antagonists, β-funaltrexamine (selective for μ receptor), naloxonazine (μl) and naltrindole (δ) on morphine-induced changes in striatal and limbic dopamine (DA) metabolism were studied in rats. β-Funaltrexamine (20 μg intracerebroventricularly) and naloxonazine (15 mg/kg intraperitoneally) were given 24 hr before morphine (15 mg/kg subcutaneously), and the rats were decapitated 60 min. after morphine. Naltrindole (1 mg/kg intraperitoneally) was given twice, 15 min. before and after morphine. Morphine significantly increased the concentrations of DA metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA). This effect was significantly antagonized by pretreatment with β-funaltrexamine but not by naloxonazine or naltrindole. However, naloxonazine attenuated the antinociceptive effect of morphine in the hot-plate test. The concentration of DA was not significantly altered by any of the drugs studied. These results show that selective blockade of μ-opioid receptors totally blocks the increase of striatal and limbic DA metabolism induced by morphine. It seems that μ2-subtype of μ-opioid receptor predominantly mediates this effect. Blockade of δ-opioid receptor did not alter these effects of morphine.     

The peripheral L-arginine-nitric oxide-cyclic GMP pathway and ATP-sensitive K⁺ channels are involved in the antinociceptive effect of crotalphine on neuropathic pain in rats

Crotalphine, a 14 amino acid peptide first isolated from the venom of the South American rattlesnake Crotalus durissus terrificus, induces a peripheral long-lasting and opioid receptor-mediated antinociceptive effect in a rat model of neuropathic pain induced by chronic constriction of the sciatic nerve. In the present study, we further characterized the molecular mechanisms involved in this effect, determining the type of opioid receptor responsible for this effect and the involvement of the nitric oxide-cyclic GMP pathway and of K? channels. Crotalphine (0.2 or 5 μg/kg, orally; 0.0006 μg/paw), administered on day 14 after nerve constriction, inhibited mechanical hyperalgesia and low-threshold mechanical allodynia. The effect of the peptide was antagonized by intraplantar administration of naltrindole, an antagonist of δ-opioid receptors, and partially reversed by norbinaltorphimine, an antagonist of κ-opioid receptors. The effect of crotalphine was also blocked by 7-nitroindazole, an inhibitor of the neuronal nitric oxide synthase; by 1H-(1,2,4) oxadiazolo[4,3-a]quinoxaline-1-one, an inhibitor of guanylate cyclase activation; and by glibenclamide, an ATP-sensitive K? channel blocker. The results suggest that peripheral δ-opioid and κ-opioid receptors, the nitric oxide-cyclic GMP pathway, and ATP-sensitive K? channels are involved in the antinociceptive effect of crotalphine. The present data point to the therapeutic potential of this peptide for the treatment of chronic neuropathic pain.     

Peripheral antinociception induced by δ-opioid receptors activation, but not μ- or κ-, is mediated by Ca²⁺-activated Cl⁻ channels

Studies have demonstrated that the L-arginine/NO/cGMP pathway and the potassium and calcium channels are involved in the mechanisms underlying opioid receptor activation. As additional pathways may participate in the observed antinociceptive effects following opioid exposure, the aim of our study was to determine whether Ca(2+)-activated Cl(-) channels (CaCCs) are involved in peripheral antinociception induced by μ-, δ- and κ-opioid receptor activation. Hyperalgesia was induced by intraplantar injection of prostaglandin E(2) (PGE(2), 2 μg). Nociceptive thresholds to pressure (grams) were measured using an algesimetric apparatus 3h following injection. The μ-opioid receptor agonist morphine (200 μg), δ-opioid receptor agonist (+)-4-[(alphaR)-alpha-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide (SNC80, 80 μg), κ-opioid receptor agonist bremazocine (50 μg), CaCCs blocker niflumic acid (8-64 μg), CaCCs blocker 5-Nitro-2-(3-phenylpropylamino) benzoic acid (NPPB, 32-128 μg), nitric oxide donor sodium nitroprusside (SNP, 500 μg) and cGMP exogenous analogs dibutyryl cGMP (db-cGMP, 100 μg) were also administered into the paw. The CaCCs blocker niflumic acid and NPPB partially reversed the peripheral antinociception induced by exposure to the SNC80 in a dose-dependent manner. In contrast, niflumic acid did not modify the antinociceptive effect observed following exposure to morphine or bremazocine. Additionally, the peripheral antinociception induced by the NO donor SNP or by db-cGMP was not inhibited by niflumic acid. These results provide evidence for the involvement of CaCCs in the peripheral antinociception induced by SNC80. CaCCs activation does not appear to be involved when μ- and κ-opioid receptors are activated. In addition, we did not observe a link between CaCCs and the L-arginine/NO/GMPc pathway.     

Aripiprazole blocks reinstatement but not expression of morphine conditioned place preference in rats

Aripiprazole is an atypical antipsychotic drug primarily characterized by partial agonist activity at dopamine (DA) D₂ receptors and serotonin-1A (5-hydroxytryptamine, 5-HT_1A) receptors and minimal side effects. Based on its pharmacological profile, including stabilization of mesocorticolimbic DA activity (a pathway implicated in drug addiction), we investigated the effects of aripiprazole on relapse to morphine seeking in rats. In experiment 1, rats underwent morphine-induced conditioned place preference (CPP) training with alternate injections of morphine (5 mg/kg, s.c.) and saline (1 ml/kg, s.c.) for 8 consecutive days. To examine the effect of aripiprazole on the expression of morphine-induced CPP, rats received aripiprazole (0, 0.03, 0.1, and 0.3 mg/kg, i.p.) 30 min before testing for the expression of CPP. In experiment 2, rats underwent the same CPP training as in experiment 1 and subsequent extinction training. To examine the effect of aripiprazole on reinstatement of morphine-induced CPP, rats received aripiprazole 30 min before testing for reinstatement of CPP. In experiment 3, to assess the effects of aripiprazole on locomotor activity, aripiprazole was administered 30 min before testing for locomotor activity. Aripiprazole significantly decreased the reinstatement of CPP induced by a priming injection of morphine but had no effect on the expression of morphine-induced CPP or locomotor activity. The D₂ and 5-HT_1A partial agonist and 5-HT_2A antagonist properties of aripiprazole likely account for the blockade of relapse to drug seeking. These findings suggest that aripiprazole may have therapeutic value for reducing craving and preventing relapse to drug seeking.     

Dihydroetorphine is a μ-Receptor-selective Ligand

The selectivity to opioid receptors of dihydroetorphine, a potent analgesic with only mild physical dependence, was investigated using radioligand binding assay and its analgesic activity in mice determined. The relative affinity ratio of dihydroetorphine to μ-, δ- and κ- opioid receptors was 333:1:1. The analgesic effect of intracerebro-ventricular injection in mice could be antagonized by the μ-antagonist β-funaltrexamine but could not be antagonized by δ- and κ-selective antagonists naltrindole and nor-binaltorphimine. We conclude that dihydroetorphine is a selective ligand for the μ-opioid receptor.     

κ1-Opioid binding sites are the dominant opioid binding sites in surgical specimens of human pheochromocytomas and in a human pheochromocytoma (KAT45) cell line

The adrenal medulla produces opioids which exert paracrine effects on adrenal cortical and chromaffin cells and on adrenal splanchnic nerves, via specific binding sites. The opioid binding sites in the adrenals are detectable mainly in the medullary part of it and differ in type between species. Thus, the bovine adrenal medulla contains mostly κ-opioid binding sites and fewer δ- and μ-opioid binding sites while primate adrenals contain mainly δ sites and few κ-opioid binding sites. Most chromaffin cell tumors, the pheochromocytomas, produce opioids which suppress catecholamine production by the tumor. The aim of the present work was to identify the types of opioid binding sites in human pheochromocytomas. For this purpose, we characterized the opioid binding sites on crude membrane fractions prepared from 14 surgically excised pheohromocytomas and on whole KAT45 cells, a recently characterized human pheochromocytoma cell line. Our data showed that human pheohromocytomas are heterogeneous, as expected, with regard to the production of catecholamines and the distribution and profile of their opioid binding sites. Indeed, only one out of the 14 pheochromocytomas expressed exclusively δ and μ opioid sites, while in the remaining 13 tumors κ-type binding sites were dominant. The KAT45 cell line possessed a significant number of κ₁ binding sites, fewer κ₂-opioid binding sites and κ₃-opioid binding sites, and minimal binding capacity for δ- and μ-opioid receptor agonists sites. More specifically, the κ₁ sites/cell were approximately 18,000, the κ₂ 4500/cell and the κ₃ sites 2000/cell. Our findings for the surgical specimens and the cell line combined with previously published pharmacological data obtained from KAT45 cells suggest that κ sites appear to be the most prevalent opioid binding sites in pheochromocytomas. Finally, in normal bovine adrenals the profile of opioid binding sites differs in adrenaline and noradrenaline producing chromaffin cells. To test the hypothesis that the type of catecholamine produced by a pheochromocytoma depends on its cell of origin, we compared our binding data with the catecholamine content of each pheochromocytoma examined. We found no correlation between the type of the predominant catecholamine produced and the opioid binding profile of each tumor suggesting that this hypothesis may not be valid.     

Involvement of glutamate receptors in the striatal enkephalin-induced dopamine release

In anesthetized rats, the intrastriatal infusion of the δ-opioid receptor agonist, [d-Pen²,d-Pen⁵]enkephalin, increased the extracellular concentration of dopamine. This effect was abolished by the NMDA receptor antagonist, 3-[(±)-2-carboxypiperazine-4-yl] propyl-1-phosphonate, but was unchanged by the AMPA (d,l-α-amino-3-hydroxy-5-methyl-4-isoxazole propionate) and kainate receptor antagonist, 6,7-dinitroquinoxaline-2,3-dione. This suggests that the dopamine release induced by the δ-opioid agonist depends critically on the involvement of glutamatergic transmission via NMDA receptors.     

Effect of the intraperitoneal administration of salmon-calcitonin on the “in vitro” actions of opioid agonists

• 1.1. The interaction of intraperitoneal administration of salmon-calcitonin with opioids was studied. The study was carried out using guinea pig ileum (μ and κ-opioid receptors), rabbit vas deferens (κ-opioid receptors) and mouse vas deferens (δ-opioid receptors), and selective μ, δ and κ agonists were used in the pertinent tissues.
• 2.2. The treatment with salmon-calcitonin increased, in a dose-dependent manner, the effect of U-50,488H in guinea pig ileum and rabbit vas deferens and the effects of [d-Pen², d-Pen⁵]enkephalin in mouse vas deferens.
• 3.3. The treatment with analgesic doses of salmon-calcitonin enhances the in vitro effects of κ- and δ-opioid agonists. The increase of the effectiveness of the opioid agonists may be one of the mechanisms involved on the analgesia induced by salmon-calcitonin.

     

κ受体激动对去甲肾上腺素诱导的心肌肥大的抑制作用

目的　利用体外培养的乳鼠心肌细胞 ,观测κ阿片肽受体激动对去甲肾上腺素 (norepinephrine ,NE)诱导的心肌肥大的抑制作用 ,并探讨作用机制。方法　对培养乳鼠心肌细胞分组给药 48h后 ,用Lowrys法测心肌细胞的蛋白质含量 ;用消化分离法 ,通过目镜标尺测心肌细胞体积 ;用镜下计数法测心肌细胞的搏动频率。结果　κ阿片肽受体激动剂U5 0 ,488H(简称U5 0 ) (0 1～ 10 μmol·L-1)对培养心肌细胞的蛋白质含量具有抑制作用并呈剂量依赖性 ;对NE诱导的心肌细胞蛋白含量增加、体积增大具有抑制作用 ;同时观察到U5 0 ,488H(1μmol·L-1)具有抑制心肌细胞搏动频率的作用。U5 0 ,488H的上述作用均可被κ阿片肽受体拮抗剂Nor BNI(1μmol·L-1)拮抗。结论　U5 0 ,488H对NE诱导的心肌肥大具有抑制作用 ,这种作用是通过激动κ阿片肽受体发挥的。     

An attempt to structurally convert μ-selective morphine toward δ-receptor binding: dimerization based on enkephalin conformation

In order to elucidate the substrate specificities for μ- and δ-opioid receptors, dimerization of the μ-specific morphine molecule was attempted, based on the hypothesis of the possible relationship between the molecular conformation of endogenous enkephalin and its selectivity for each opioid receptor. The NOR2 ([normorphine]NCH₂CH₂N[normorphine]) thus synthesized exhibited agonist activity showing a preference for binding with the δ-opioid receptor, compared with the parent morphine molecule. Antagonist activity was also observed for NOR3 ([normorphine]NCH₂CH₂CH₂N[normorphine]).