Mu-opioid Receptor Antagonist Naltrexone Research Articles

Effects of selective dopamine D3 receptor partial agonist/antagonists on oxycodone self-administration and antinociception in monkeys.

Recent studies suggest that dopamine D3 receptors (D3R) may be a therapeutic target for opioid use disorders (OUD). This study examined the effects of the D3Rpartial agonist (±)VK4-40 and the D3R-selective antagonist (±)VK4-116, compared to the mu-opioid receptor antagonist naltrexone (NTX), in nonhuman primate models of OUD and antinociception. Adult male and female (N = 4/sex) cynomolgus monkeys were trained to self-administer oxycodone (0.003-0.1 mg/kg/injection) first under a fixed-ratio (FR) and then a progressive-ratio (PR) schedule of reinforcement during daily 1- and 4-hr sessions, respectively. Under the FR schedule, intravenous NTX (0.01-0.1 mg/kg), (±)VK4-116 (1.0-10 mg/kg), and (±)VK4-40 (1.0-10 mg/kg) were studied in combination with the peak oxycodone dose and a dose on the descending limb of the dose-effect curve; NTX and (±)VK4-40 were also studied at the peak of the PR dose-response curve (N = 4). Following saline extinction, each compound was examined on oxycodone-induced reinstatement. Finally, these compounds were assessed in adult male rhesus monkeys (N = 3) in a warm-water (38 °C, 50 °C, 54 °C) tail withdrawal assay. NTX decreased responding on the peak of the FR oxycodone dose-response curve, but increased responding on the descending limb. (±)VK4-40, but not (±)VK4-116, significantly decreased peak oxycodone self-administration; (±)VK4-40 did not increase responding on the descending limb. NTX and (±)VK4-40, but not (±)VK4-116, attenuated oxycodone-induced reinstatement. Under PR responding, NTX and (±)VK4-40 decreased breakpoints. Oxycodone-induced antinociception was attenuated by NTX, but not by (±)VK4-40 or (±)VK4-116. Together, these results suggest that further research evaluating the effects of (±)VK4-40 as a novel pharmacotherapy for OUD is warranted.

481 Interactions between buprenorphine and norbuprenorphine in neonatal opioid withdrawal syndrome

OBJECTIVES/GOALS: Buprenorphine (BUP) is used for opioid use disorder during pregnancy but causes neonatal opioid withdrawal syndrome (NOWS). The goal of this study was to determine the contribution of the active metabolite, norbuprenorphine (NorBUP), to the development of NOWS when the parent drug, BUP, is administered during pregnancy. METHODS/STUDY POPULATION: Subcutaneously implanted osmotic minipumps delivered BUP (0, 0.01, 0.1 or 1 mg/kg/day) ± NorBUP (1 mg/kg/day) to pregnant Long-Evans rats from gestation day 9 until after delivery. NOWS was measured between 3 and 12 hours after delivery. Withdrawal was precipitated by an intraperitoneal injection of a mu opioid receptor antagonist naltrexone (NTX; 0, 1 or 10 mg/kg), and movement duration (MD; a validated proxy for NOWS) was measured using Noldus Ethovision. Concentrations of BUP, NorBUP, and their glucuronide conjugates in the brains of neonatal littermates not undergoing withdrawal testing were determined using LC/MS/MS. Two-way ANOVA and multiple linear regression analyses tested for interactions between BUP and NorBUP on MD and related brain concentrations to MD, respectively. RESULTS/ANTICIPATED RESULTS: There was no interaction effect between BUP and NorBUP on MD for either sex or at any dose of naltrexone. In females, but not males, BUP (1 mg/kg/day) significantly increased NorBUP-induced MD by 58% following an injection with 1 mg/kg NTX. A multiple linear regression model that included BUP and NorBUP brain concentrations as predictors of MD was significant and well-fitting [FEMALES: F (2, 40) = 23.97, P < .0001, adj R2 = 0.52; MALES: F (2, 40) = 5.84, P = .0059, adj R2 = 0.19]. There was a differential contribution of NorBUP brain concentrations to MD based on sex. The partial regression coefficient for NorBUP was 51.34 (p < .0001) for females and 19.21 (p = 0.093) for males. The partial regression coefficient for BUP was similar for females and males (FEMALES:βBUP = 10.62, p = .0017; MALES:βBUP = 11.38, p = .009). DISCUSSION/SIGNIFICANCE: We show for the first time a differential contribution of NorBUP to BUP-associated NOWS in each sex, suggesting sex differences in NorBUP susceptibility and implicating that treatment strategies reducing prenatal NorBUP exposure may be more effective for females than males.

Pre-training naltrexone increases conditioned fear learning independent of adolescent alcohol consumption history

Our previous research has shown a relationship between low voluntary alcohol consumption and high conditioned fear in male Long Evans rats. Here, we examined whether differences in the endogenous opioid systems might be responsible for these differences. Rats received 6 weeks of chronic intermittent to 20% alcohol (v/v) or water-only from PND 26–66. Based on their consumption during the last 2 weeks of alcohol access, the alcohol-access rats were divided into high drinking (>2.5 g/kg/24-h) or low drinking (<2 g/kg/24-h). Rats were then given injections of the preferential mu opioid receptor antagonist naltrexone (1 mg/kg, s.c.) or the selective kappa opioid receptor antagonist LY2456302 (10 mg/kg, s.c.) prior to fear conditioning and were then tested for conditioned fear 2 days later. Pre-training naltrexone increased conditioned suppression of lever-pressing during training and testing, with no differences between high versus low alcohol drinkers or between water-only versus alcohol access groups (averaged across drinking levels). There was no effect of LY2456302 on conditioned fear in any comparison. We also found no differences between high and low alcohol drinkers and no reliable effect of prior alcohol access (averaged across drinking levels) on conditioned fear. Our experiment replicates and extends previous demonstrations that a preferential MOR antagonist can increase fear learning using conditioned suppression of lever-pressing as a fear measure. However, additional research is needed to determine the cause of the differences in conditioned fear that we previously observed (as they were not observed in the current experiments).

Abstract 3006: A novel strategy of targeting opioidergic receptors to potentially reduce human breast cancer cell proliferation, colony formation, invasion, and migration

Abstract Breast cancer is the second most prevalent cancer after lung cancer among American women. The efficacy of current antitumor therapies is still quite limited. Endogenous opioid peptides, such as endorphin, which is involved in body stress controlling mechanisms, have been shown to enhance immune function and prevent cancer growth and progression in various animal models of cancers. Therefore, targeting the endogenous opioid peptides receptors in the regulation of cancer chemoprevention may offer new promise for the design of therapeutic strategies. Our previous studies have shown differential actions of mu-opioid receptor (MOR) and delta opioid receptor (DOR) on various cell types. In this study we tested the effects of a MOR antagonist naltrexone (NTX) and a DOR agonist (D-Ala2-,N-Me-Phe4,Gly-ol Enkephalin; DPDPE) on proliferation and invasion of human breast cancer cells of different molecular subtype such as T47D (Luminal A), MDA-MB-231 (triple negative, Claudin-Low) and MDA-MB- 468 (triple negative, basal A) in cultures. We used cytotoxicity, clonogenic, cell migration and cell invasion assays to identify effects of these drugs on cancer cells. We found that both NTX and DPDPE have significant cytotoxic effects on these breast cancer cells. Our work from clonogenic, cell migration and cell invasion assays showed that both NTX and DPDPE inhibit the formation of colony, migration and invasion of cancer cells in a concentration-dependent manner. These data suggest that naltrexone and DPDPE have anticancer efficacy in subtypes of human breast cancer cells. The anticancer effects varied depending on the concentration of the drugs and the subtype of breast cancer cells. (Supported by NIH grant R01 CA20863201). Citation Format: Sengottuvelan Murugan, Vanisha Patel, Dipak K. Sarkar. A novel strategy of targeting opioidergic receptors to potentially reduce human breast cancer cell proliferation, colony formation, invasion, and migration [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3006.

Interactions between cannabinoid receptor agonists and mu opioid receptor agonists in rhesus monkeys discriminating fentanyl

Cannabinoid receptor agonists such as delta-9-tetrahydrocannabinol (Δ9-THC) enhance some (antinociceptive) but not other (positive reinforcing) effects of mu opioid receptor agonists, suggesting that cannabinoids might be combined with opioids to treat pain without increasing, and possibly decreasing, abuse. The degree to which cannabinoids enhance antinociceptive effects of opioids varies across drugs insofar as Δ9-THC and the synthetic cannabinoid receptor agonist CP55940 increase the potency of some mu opioid receptor agonists (e.g., fentanyl) more than others (e.g., nalbuphine). It is not known whether interactions between cannabinoids and opioids vary similarly for other (abuse-related) effects. This study examined whether Δ9-THC and CP55940 differentially impact the discriminative stimulus effects of fentanyl and nalbuphine in monkeys (n=4) discriminating 0.01mg/kg of fentanyl (s.c.) from saline. Fentanyl (0.00178–0.0178mg/kg) and nalbuphine (0.01–0.32mg/kg) dose-dependently increased drug-lever responding. Neither Δ9-THC (0.032–1.0mg/kg) nor CP55940 (0.0032–0.032mg/kg) enhanced the discriminative stimulus effects of fentanyl or nalbuphine; however, doses of Δ9-THC and CP55940 that shifted the nalbuphine dose-effect curve markedly to the right and/or down were less effective or ineffective in shifting the fentanyl dose-effect curve. The mu opioid receptor antagonist naltrexone (0.032mg/kg) attenuated the discriminative stimulus effects of fentanyl and nalbuphine similarly. These data indicate that the discriminative stimulus effects of nalbuphine are more sensitive to attenuation by cannabinoids than those of fentanyl. That the discriminative stimulus effects of some opioids are more susceptible to modification by drugs from other classes has implications for developing maximally effective therapeutic drug mixtures with reduced abuse liability.

Effects of the NOP agonist SCH221510 on producing and attenuating reinforcing effects as measured by drug self-administration in rats

Nociceptin/orphanin FQ peptide (NOP) receptor agonists attenuate morphine-induced conditioned place preference in rodents. However, it is not known whether NOP agonists have reinforcing properties or can inhibit mu opioid receptor (MOP)-mediated reinforcement as measured by drug self-administration in rodents. Further understanding the behavioral effects of NOP agonists could suggest them as having potential in attenuating reinforcing effects of opioids. In the first part of the study, reinforcing properties of selective NOP agonist SCH221510 were determined and compared with the full MOP agonist remifentanil under fixed-ratio 5 (FR5) and progressive-ratio (PR) schedules of drug self-administration. In the second part, effects of systemic and intracisternal pretreatment of SCH221510 were determined and compared with MOP antagonist naltrexone in attenuating reinforcing effects of remifentanil and a non-drug reinforcer (sucrose pellets). Remifentanil self-administration (0.3–10µg/kg/infusion) generated a biphasic dose-response curve, characteristic of drugs with reinforcing properties. SCH221510 (3–300µg/kg/infusion) self-administration resulted in flat dose-response curves and early break-points under the PR, indicative of drugs lacking reinforcing value. Intracisternally, but not systemically, administered SCH221510 (0.3–3µg) attenuated remifentanil self-administration, comparable with systemic naltrexone (0.03–0.3mg/kg). SCH221510 (1–3µg), unlike naltrexone (0.03–1mg/kg), attenuated responding for sucrose pellets. Both effects of SCH221510 were reversed by the NOP antagonist J-113397 (0.3–3µg). These results suggest that SCH221510 does not function as a reinforcer in rats, and that it can attenuate the reinforcing value of MOP agonists; therefore, the potential utility of NOP agonists for the treatment of drug addiction warrants further evaluation.

Acamprosate: An Alcoholism Treatment That May Not Be What We Thought

Acamprosate: An Alcoholism Treatment That May Not Be What We Thought

Nanoscale Effects of Ethanol and Naltrexone on Protein Organization in the Plasma Membrane Studied by Photoactivated Localization Microscopy (PALM)

BackgroundEthanol affects the signaling of several important neurotransmitter and neuromodulator systems in the CNS. It has been recently proposed that ethanol alters the dynamic lateral organization of proteins and lipids in the plasma membrane, thereby affecting surface receptor-mediated cellular signaling. Our aims are to establish whether pharmacologically relevant levels of ethanol can affect the lateral organization of plasma membrane and cytoskeletal proteins at the nanoscopic level, and investigate the relevance of such perturbations for mu-opioid receptor (MOP) function.Methodology/Principal FindingsWe used Photoactivated Localization Microscopy with pair-correlation analysis (pcPALM), a quantitative fluorescence imaging technique with high spatial resolution (15–25 nm) and single-molecule sensitivity, to study ethanol effects on protein organization in the plasma membrane. We observed that short (20 min) exposure to 20 and 40 mM ethanol alters protein organization in the plasma membrane of cells that harbor endogenous MOPs, causing a rearrangement of the lipid raft marker glycosylphosphatidylinositol (GPI). These effects could be largely occluded by pretreating the cells with the MOP antagonist naltrexone (200 nM for 3 hours). In addition, ethanol induced pronounced actin polymerization, leading to its partial co-localization with GPI.Conclusions/SignificancePharmacologically relevant levels of ethanol alter the lateral organization of GPI-linked proteins and induce actin cytoskeleton reorganization. Pretreatment with the MOP antagonist naltrexone is protective against ethanol action and significantly reduces the extent to which ethanol remodels the lateral organization of lipid-rafts-associated proteins in the plasma membrane. Super-resolution pcPALM reveals details of ethanol action at the nanoscale level, giving new mechanistic insight on the cellular and molecular mechanisms of its action.

Hormonal contraceptive use diminishes salivary cortisol response to psychosocial stress and naltrexone in healthy women

The use of hormonal contraception (HC) may affect salivary cortisol levels at rest and in response to a pharmacological or stress challenge. Therefore, the current study used a secondary data analysis to investigate the effect of HC on salivary cortisol levels in response to the mu-opioid receptor antagonist naltrexone and a psychosocial stressor, and also across the diurnal curve. Two hundred and nine women (n=72 using hormonal contraception; HC+) completed a two-session stress response study that consisted of a stress day, in which they were exposed to public speaking and mental arithmetic, and a rest day, in which unstimulated cortisol levels were measured to assess the diurnal rhythm. A subset of seventy women (n=24 HC+) also completed a second study in which they were administered oral naltrexone (50mg) or placebo in a randomized, placebo-controlled, double blind fashion. Women who were HC+ had a significantly reduced salivary cortisol response to both the psychosocial stressor (p<0.001) and naltrexone (p<0.05) compared to HC− women. Additionally, HC+ women had a significantly altered morning diurnal cortisol rhythm (p<0.01), with a delayed peak and higher overall levels. The results of the current study confirm that HC attenuates salivary cortisol response to a psychosocial stressor and mu-opioid receptor antagonism, and also alters the morning diurnal cortisol curve.

Elevated Liver Enzymes with Naltrexone Might Not Indicate Toxicity

The mu-opioid receptor antagonist naltrexone, which is approved for the treatment of alcohol and opiate dependence, has a black-box warning for

Morphine/Naltrexone

Oral morphine/naltrexone extended release capsules comprise the selective mu-opioid receptor agonist morphine in a sustained-release formulation combined with a sequestered core of the mu-opioid receptor antagonist naltrexone for use in the management of moderate to severe pain. When morphine/naltrexone is taken as intended, naltrexone exerts no clinically significant effect. However, when the capsule contents are taken after being tampered with by crushing, chewing or dissolution, naltrexone is rapidly released and absorbed, thereby mitigating the effects of morphine. Morphine/naltrexone was effective in the treatment and management of moderate to severe chronic pain in patients with pain due to osteoarthritis of the hip or knee participating in a randomized, double-blind, placebo-controlled, phase III study (n = 344). Changes in mean Brief Pain Inventory (BPI) average scores from baseline of the double-blind maintenance phase to 12 weeks were significantly better with morphine/naltrexone (20 mg/0.8 mg to 80 mg/3.2 mg twice daily) than with placebo. In a 12-month, open-label safety study, morphine/naltrexone also provided effective pain relief and sustained pain control in patients with chronic, moderate to severe, nonmalignant pain (n = 465 at baseline; 162 at study end). Furthermore, significant mean changes from baseline in BPI worst, least, average and current pain scores were seen from week 1 onwards. Morphine/naltrexone treatment was generally well tolerated in adult patients with chronic moderate to severe nonmalignant pain in clinical trials of up to 1-year duration.

Leukotriene B4 Mediates Sphingosylphosphorylcholine-Induced Itch-Associated Responses in Mouse Skin

In atopic dermatitis, the concentration in the skin of sphingosylphosphorylcholine (SPC), which is produced from sphingomyelin by sphingomyelin deacylase, is increased. In the present study, we investigated the itch-eliciting activity of SPC and related substances and the mechanisms of SPC action in mice. An intradermal injection of SPC, but not sphingomyelin and sphingosine, induced scratching, an itch-associated response, which was not suppressed by a deficiency in mast cells or the H(1) histamine receptor antagonist terfenadine. The action of SPC was inhibited by the mu-opioid receptor antagonist naltrexone. SPC action also was inhibited by the 5-lipoxygenase inhibitor zileuton and the leukotriene B(4) antagonist ONO-4057, but not by the cyclooxygenase inhibitor indomethacin. Moreover, SPC action was inhibited by the antiallergic agent azelastine, which suppresses the action and production of leukotriene B(4). Administration of SPC to the skin and to primary cultures of keratinocytes increased leukotriene B(4) production. SPC increased intracellular Ca(2+) ion concentration in primary cultures of dorsal root ganglion neurons and keratinocytes. These results suggest that SPC induces itching through a direct action on primary afferents and leukotriene B(4) production of keratinocytes. Sphingomyelin deacylase and SPC receptors may be previously unreported targets for antipruritic drugs.

Non-opioid induction of morphine-6-glucuronide synthesis is elicited by prolonged exposure of rat hepatocytes to heroin

Background Liver metabolism of morphine leads to the formation of morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G), the latter possessing strong opioid activity that however differs from that of the parent compound. In previous studies conducted in rats we have shown that repeated in vivo exposure to phenanthrene class of mu opioid receptor (MOR) agonists or antagonists (heroin, morphine, and naltrexone), but not to non-phenanthrene class of MOR agonist methadone, affects morphine glucuronidation by liver microsomes. Methods In the present study, we measured the in vitro formation of M3G and M6G by rat hepatocytes incubated for 120 min with morphine (0.1–1.0 mM) after 72 h pre-incubation with one of the following MOR agonists: heroin (3.3 or 6.6 μM), morphine (7.8 μM), or methadone (12 μM). The MOR antagonist naltrexone (10 or 25 μM) was also tested, alone or in combination with heroin. The amount of M3G and M6G synthesized was then measured by HPLC method. Results Heroin inhibited M3G synthesis and induced the formation of M6G, which under basal conditions is not synthesized in rats. Heroin effects were not blocked by naltrexone. Morphine, but not methadone, produced effects similar to those of heroin but more modest in intensity. Pre-incubation with naltrexone alone slightly increased M3G synthesis, but had no effect on M6G formation. Conclusions These results are in agreement with those of previous ex vivo studies and indicate that exposure to heroin or, to a lesser extent, morphine, can affect morphine glucuronidation via direct non-opioid actions on the hepatocytes.

NIH 11082 produces anti-depressant-like activity in the mouse tail-suspension test through a delta-opioid receptor mechanism of action

The present study examined the effects of NIH 11082 ((−)-(1 R,5 R,9 R)-5,9-dimethyl-2′-hydroxy-2-(6-hydroxyhexyl)-6,7-benzomorphan hydrochloride), a benzomorphan analogue, in the mouse tail-suspension, an assay used to detect anti-depressant agents. NIH 11082 significantly decreased immobility time during tail-suspension, with a comparable magnitude as the tricyclic anti-depressant desipramine. Importantly, NIH 11082 failed to elicit convulsions or other overt behavioral signs of toxicity. The delta-opioid receptor antagonist naltrindole (AD 50 = 2.0 mg/kg), but not the non-selective mu-opioid receptor antagonist naltrexone or the kappa-opioid receptor antagonist nor-BNI, blocked the effects of NIH 11082 in the tail-suspension test. These results reinforce the notion that delta-opioid receptor agonists can produce significant effects in a behavioral model used to screen anti-depressant drugs.

Tiagabine does not attenuate alcohol-induced activation of the human reward system

The rewarding effects of ethanol and other drugs of abuse are mediated by activation of the mesolimbic dopamine system. Recent neuroimaging studies in primates and humans suggest that cocaine-induced dopamine stimulation might be diminished by drugs augmenting gamma-aminobutyric acid A (GABA-A) receptor function such as the GABA transaminase inhibitor vigabatrin. The objective of this study was to test the property of the selective GABA transporter 1 (GAT1) inhibitor tiagabine to block ethanol-induced activation of the mesolimbic reward system in an i.v. ethanol challenge. Twenty nonaddicted healthy volunteers underwent an i.v. ethanol challenge after 1 week of tiagabine (15 mg/day) administration. Neuronal activation was measured using [(18)F]-fluoro-deoxyglucose positron emission tomography (PET). Tiagabine did not prevent ethanol-induced stimulation of the mesolimbic reward system but augmented ethanol-induced hypometabolism within areas of the visual system and the cerebellum. Tiagabine alone also decreased neuronal metabolism within parts of the right temporal cortex that are highly enriched with GABA-ergic neurons. Our ethanol challenge imaging study does not provide supporting evidence that the GAT1 inhibitor tiagabine diminishes the rewarding effects of ethanol. Further PET imaging studies using established anticraving compounds, such as the mu-opioid receptor antagonist naltrexone and antiepileptic drugs affecting the GABA-ergic system more broadly, will provide additional important insights on the interaction between the GABA-ergic and the brain reward system in vivo and the suitability of GABA-ergic drugs as anticraving compounds.

Association of OPRM1 A118G variant with the relative reinforcing value of nicotine

The endogenous opioid system has been implicated in substance abuse and response to pharmacotherapies for nicotine and alcohol addiction. We examined (1) the association of the functional OPRM1 A118G variant with the relative reinforcing value of nicotine and (2) the main and interacting effects of the mu-opioid receptor antagonist naltrexone on nicotine reinforcement. In a within-subject, double-blind human laboratory study, 30 smokers of each OPRM1 genotype (A/A vs. A/G or G/G) participated in two experimental sessions following 4 days of orally administered naltrexone 50 mg or placebo. Participants completed a validated assessment of the relative reinforcing value of nicotine. This cigarette choice paradigm assesses self-administration of 0.6 mg nicotine vs. 0.05 mg (denicotinized) cigarettes after a brief period of nicotine abstinence. The relative reinforcing value of nicotine (number of nicotine cigarette puffs) was predicted by a significant OPRM1 by gender interaction. Among women, the low-activity G allele (A/G and G/G) was associated with a reduced reinforcing value of nicotine; among male smokers, there was no association with genotype. Smokers carrying a G allele were also significantly less likely to differentiate the nicotine vs. denicotinized cigarettes by subjective ratings of satisfaction and strength. No evidence for an effect of naltrexone on nicotine reinforcement was found in the overall sample or in the genotype or gender subgroups. This study provides initial evidence for an association of the OPRM1 A118G variant with nicotine reinforcement in women.

Involvement of mu-, delta- and kappa-opioid receptor subtypes in the discriminative-stimulus effects of delta-9-tetrahydrocannabinol (THC) in rats

Many behavioral effects of delta-9-tetrahydrocannabinol (THC), including its discriminative-stimulus effects, are modulated by endogenous opioid systems. To investigate opioid receptor subtypes involved in the discriminative effects of THC. Rats trained to discriminate 3 mg/kg i.p. of THC from vehicle using a two-lever operant drug-discrimination procedure, were tested with compounds that bind preferentially or selectively to either mu-, delta- or kappa-opioid receptors. The preferential mu-opioid receptor agonist heroin (0.3-1.0 mg/kg, i.p.), the selective delta-opioid receptor agonist SNC-80 (1-10 mg/kg, i.p.) and the selective kappa-opioid receptor agonist U50488 (1-10 mg/kg, i.p.) did not produce generalization to the discriminative effects of THC when given alone. However, heroin, but not SNC-80 or U50488, significantly shifted the dose-response curve for THC discrimination to the left. Also, the preferential mu-opioid receptor antagonist naltrexone (0.1-1 mg/kg, i.p.), the selective delta-opioid receptor antagonist, naltrindole (1-10 mg/kg, i.p.) and the kappa-opioid receptor antagonist nor-binaltorphimine (n-BNI, 5 mg/kg, s.c.), did not significantly reduce the discriminative effects of the training dose of THC. However, naltrexone, but not naltrindole or n-BNI, significantly shifted the dose-response curve for THC discrimination to the right. Finally, naltrexone, but not naltrindole or n-BNI, blocked the leftward shift in the dose-response curve for THC discrimination produced by heroin. mu- but not delta- or kappa-opioid receptors are involved in the discriminative effects of THC. Given the role that mu-opioid receptors play in THC's rewarding effects, the present findings suggest that discriminative-stimulus effects and rewarding effects of THC involve similar neural mechanisms.

Ratio between the Contents of 11-Dehydrocorticosterone and Corticosterone after Acute and Repeated Stress: Effect of Dehydroepiandrosterone Sulfate

Acute stress was accompanied by reduction of 11-dehydrocorticosterone to corticosterone in male rats. The reverse reaction predominated during repeated stress and increased after administration of dehydroepiandrosterone sulfate. Treatment with mu-opioid receptor antagonist naltrexone in a dose of 0.1 mg/kg 20 min before administration of dehydroepiandrosterone sulfate abolished this effect.

Activation of mu-opioid pathway is associated with the canceling effect of footshock stimulus on the restraint stress-induced inhibition of small intestinal motility in rats.

We previously reported that small intestinal motility was significantly inhibited by restraint stress, but not by footshock stress. In the present study, we found that plasma beta-endorphin levels were more significantly elevated by footshock stress than restraint stress, and that preloading of footshock stimulus canceled the inhibition of small intestinal motility by restraint stress. Pretreatment with the mu-opioid receptor antagonist naltrexone significantly attenuated this canceling effect of footshock stimulus. These results suggest that footshock stimulus may cancel the inhibition of small intestinal motility by restraint stress via activation of mu-opioid receptors.