norbinaltorphimine and Morphine-Dependence

Much data suggest that the binding of dynorphin-like peptides to kappa-opioid receptors (KORs) during the administration of and withdrawal from a variety of addictive drugs is aversive and serves to limit the reinforcing properties of those drugs and to enhance tolerance, withdrawal, and the probability of stress-induced relapse. In this study, we examined the role of KORs in mediating opioid withdrawal and its aversive consequences in rats. We found that selective blockade of KORs by i.p. administration of 20mg/kg nor-binaltorphimine (nor-BNI) 5h prior to naltrexone-precipitated withdrawal in morphine-dependent rats decreased feces excreted during a 30-min withdrawal session. More critically, this injection of nor-BNI decreased the subsequent conditioned place aversion (CPA) for the withdrawal chamber 2 days later. The subsequent finding that administration of nor-BNI 2h following withdrawal did not affect the CPA 2 days later suggested that nor-BNI reduced the CPA in the prior experiment because it reduced the aversive effects of withdrawal, not because it reduced the aversive/anxiogenic effects of the withdrawal chamber at the time of CPA testing. These data indicate that the binding of dynorphin-like peptides to KORs during opioid withdrawal serves to enhance withdrawal and its aversive consequences and suggest that selective KOR antagonists may be useful in reducing these aversive effects and consequent relapse.

Topics: Animals; Conditioning, Psychological; Defecation; Dynorphins; Male; Morphine; Morphine Dependence; Motor Activity; Naltrexone; Narcotic Antagonists; Narcotics; Neurotransmitter Agents; Random Allocation; Rats, Long-Evans; Receptors, Opioid, kappa; Spatial Behavior; Substance Withdrawal Syndrome

Our previous studies indicated that processed Aconiti tuber (PAT), a traditional Chinese herbal medicine, had antinociceptive effects and inhibitory effects on morphine tolerance by activation of kappa-opioid receptor (KOR). Preclinical studies also demonstrated that KOR agonists functionally attenuate addictive behaviors of morphine, such as conditioned place preference (CPP). Therefore, we hypothesize that PAT may inhibit morphine-induced CPP in rats.. (1) Five groups of rats (n=8 for each group) were alternately subcutaneous (s.c.) injected with morphine 10mg/kg (one group receive normal saline as a control) and normal saline for 8 days and oral co-administrated with distilled water or PAT 0.3, 1.0, or 3.0 g/kg daily on days 2-9 during CPP training, respectively. (2) Other four groups of rats were randomly s.c. injected with nor-binaltorphimine (nor-BNI; 5mg/kg) or normal saline (as a control) 120 min before alternately s.c. with morphine and normal saline and oral co-administrated with distilled water or PAT 3.0 g/kg daily. Each rat was acquired pre-conditioning and post-conditioning CPP data and assayed dynorphin concentrations by radioimmunoassay in rat's nucleus accumbens (NAc) after CPP training.. (1) PAT 1.0 or 3.0 g/kg dose-dependently decreased the morphine-induced increase of CPP scores. (2) Nor-BNI completely antagonized the inhibition of PAT on morphine-induced CPP. (3) PAT dose-dependently increased dynorphin content in rats' NAc after CPP training.. (1) PAT dose-dependently inhibited morphine-induced CPP. (2) The inhibition of PAT on morphine-induced CPP was probably due to activation of KOR by increasing dynorphin release in rats' NAc.

Topics: Aconitum; Animals; Behavior, Addictive; Behavior, Animal; Conditioning, Operant; Dose-Response Relationship, Drug; Drug Tolerance; Drugs, Chinese Herbal; Dynorphins; Male; Morphine Dependence; Naltrexone; Narcotic Antagonists; Nucleus Accumbens; Phytotherapy; Plant Tubers; Random Allocation; Rats; Rats, Sprague-Dawley; Receptors, Opioid, kappa

Vulnerability to drug abuse disorders is determined not only by environmental but also by genetic factors. A body of evidence suggests that endogenous opioid peptide systems may influence rewarding effects of addictive substances, and thus, their individual expression levels may contribute to drug abuse liability.. The aim of our study was to assess whether basal genotype-dependent brain expression of opioid propeptides genes can influence sensitivity to morphine reward.. Experiments were performed on inbred mouse strains C57BL/6J, DBA/2J, and SWR/J, which differ markedly in responses to morphine administration: DBA/2J and SWR/J show low and C57BL/6J high sensitivity to opioid reward. Proenkephalin (PENK) and prodynorphin (PDYN) gene expression was measured by in situ hybridization in brain regions implicated in addiction. The influence of the kappa opioid receptor antagonist nor-binaltorphimine (nor-BNI), which attenuates effects of endogenous PDYN-derived peptides, on rewarding actions of morphine was studied using the conditioned place preference (CPP) paradigm.. DBA/2J and SWR/J mice showed higher levels of PDYN and lower levels of PENK messenger RNA in the nucleus accumbens than the C57BL/6J strain. Pretreatment with nor-BNI enhanced morphine-induced CPP in the opioid-insensitive DBA/2J and SWR/J strains.. Our results demonstrate that inter-strain differences in PENK and PDYN genes expression in the nucleus accumbens parallel sensitivity of the selected mouse strains to rewarding effects of morphine. They suggest that high expression of PDYN may protect against drug abuse by limiting drug-produced reward, which may be due to dynorphin-mediated modulation of dopamine release in the nucleus accumbens.

Topics: Animals; Behavior, Addictive; Behavior, Animal; Conditioning, Psychological; Cues; Enkephalins; Gene Expression Regulation; Genotype; In Situ Hybridization; Male; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Morphine Dependence; Naltrexone; Narcotic Antagonists; Nucleus Accumbens; Phenotype; Protein Precursors; Receptors, Opioid, kappa; Reward; RNA, Messenger; Species Specificity

Low-dose naloxone-precipitated withdrawal hyperalgesia is a reliable indicator of physical dependence after chronic morphine treatment. A remarkably similar long-lasting (>3-4 h) hyperalgesia is evoked by injection of a low dose of naloxone (10 microg/kg, s.c.) in naïve mice after acute pretreatment with the glycolipid, GM1 ganglioside (1 mg/kg) (measured by warm-water-immersion tail-flick assays). GM1 treatment markedly increases the efficacy of excitatory Gs-coupled opioid receptor signaling in nociceptive neurons. Co-treatment with an ultra-low-dose (0.1 ng/kg, s.c.) of the broad-spectrum opioid receptor antagonist, naltrexone or the selective kappa opioid receptor antagonist, nor-binaltorphimine, blocks naloxone-evoked hyperalgesia in GM1-pretreated naïve mice and unmasks prominent, long-lasting (>4 h) inhibitory opioid receptor-mediated analgesia. This unmasked analgesia can be rapidly blocked by injection after 1-2 h of a high dose of naltrexone (10 mg/kg) or nor-binaltorphimine (0.1 mg/kg). Because no exogenous opioid is administered to GM1-treated mice, we suggest that naloxone may evoke hyperalgesia by inducing release of endogenous bimodally acting opioid agonists from neurons in nociceptive networks by antagonizing putative presynaptic inhibitory opioid autoreceptors that "gate" the release of endogenous opioids. In the absence of exogenous opioids, the specific pharmacological manipulations utilized in our tail-flick assays on GM1-treated mice provide a novel bioassay to detect the release of endogenous bimodally acting (excitatory/inhibitory) opioid agonists. Because mu excitatory opioid receptor signaling is blocked by ultra-low doses of naloxone, the higher doses of naloxone that evoke hyperalgesia in GM1-treated mice cannot be mediated by activation of mu opioid receptors. Co-treatment with ultra-low-dose naltrexone or nor-binaltorphimine may selectively block signaling by endogenous GM1-sensitized excitatory kappa opioid receptors, unmasking inhibitory kappa opioid receptor signaling, and converting endogenous opioid receptor-mediated hyperalgesia to analgesia. Co-treatment with kelatorphan stabilizes putative endogenous opioid peptide agonists released by naloxone in GM1-treated mice, so that analgesia is evoked rather than hyperalgesia. Acute treatment of chronic morphine-dependent mice with ultra-low-dose naltrexone (0.1 ng/kg) results in remarkably similar rapid blocking of naloxone (10 microg/kg)-precipitated withdrawal hyperalgesia

Topics: Analgesics, Opioid; Animals; Chronic Disease; Dipeptides; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Synergism; G(M1) Ganglioside; Hyperalgesia; Male; Mice; Morphine; Morphine Dependence; Naloxone; Naltrexone; Narcotic Antagonists; Nociceptors; Opioid Peptides; Receptors, Opioid, kappa; Substance Withdrawal Syndrome

We have recently shown concurrent changes in behavioural responses and c-Fos protein expression in the central nervous system in both naive and morphine-dependent rats after systemic administration of the opioid antagonist naloxone. However, because naloxone acts on the three major types of opioid receptors, the present study aimed at determining, in the same animals, both changes in behaviour and c-Fos-like immunoreactivity after intravenous injection of selective opioid antagonists, such as mu (beta-funaltrexamine, 10 mg/kg), delta (naltrindole, 4 mg/kg) or kappa (nor-binaltorphimine, 5 mg/kg) opioid receptor antagonists, in naive or morphine-dependent rats. In a first experimental series, only beta-funaltrexamine increased c-Fos expression in the eight central nervous system structures examined, whereas no effect was seen after naltrindole or nor-binaltorphimine administration in naive rats. These results suggest a tonic activity in the endogenous opioid peptides acting on mu opioid receptors in normal rats. A second experimental series in morphine-dependent rats showed that beta-funaltrexamine had the highest potency in the induction of classical signs of morphine withdrawal syndrome, as well as the increase in c-Fos expression in the 22 central nervous system structures studied, suggesting a major role of mu opioid receptors in opioid dependence. However, our results also demonstrated that naltrindole and, to a lesser extent, nor-binaltorphimine were able to induce moderate signs of morphine withdrawal and relatively weak c-Fos protein expression in restricted central nervous system structures. Therefore, delta and kappa opioid receptors may also contribute slightly to opioid dependence.

Topics: Animals; Behavior, Animal; Cell Count; Central Nervous System; Gene Expression Regulation; Immunohistochemistry; Male; Morphine; Morphine Dependence; Naltrexone; Narcotic Antagonists; Narcotics; Proto-Oncogene Proteins c-fos; Rats; Rats, Sprague-Dawley; Substance Withdrawal Syndrome

The nucleus paragigantocellularis (PGi) has been hypothesized to play an important role in the development of physical dependence on opioids, including the prototype mu-opioid receptor agonist, morphine, and the mixed agonist/antagonist, butorphanol, which shows selective kappa-opioid receptor agonist activity, in rats. In confirmation of previous work, electrical stimulation of the PGi in opioid-nai;ve rats induced stimulus-intensity-related, withdrawal-like behaviors similar to those observed during naloxone-precipitated withdrawal from dependence upon butorphanol. Novel findings were made in rats surgically implanted with cannulae aimed at the lateral ventricle and the right PGi and made physically dependent by intracerebroventricular infusion of either morphine (26 nmol/microl/h) or butorphanol (26 nmol/microl/h) through an osmotic minipump for 3 days. Two hours following termination of the opioid infusion, microinjections of naloxone (11 nmol/400 nl), a nonselective opioid receptor antagonist, or nor-binaltorphimine (nor-BNI) (3.84 nmol/400 nl), a selective kappa-opioid receptor antagonist, were made into the PGi of morphine-dependent and butorphanol-dependent rats. Discrete PGi injections precipitated withdrawal behaviors, with significant (P<.05) increases noted in the incidence of teeth chattering, wet-dog shakes, and scratching. Composite scores for behavioral withdrawal were significantly higher in nor-BNI-precipitated, butorphanol-dependent rats (score=6.8+/-0.6), in naloxone-precipitated, butorphanol-dependent rats (8.9+/-0.8), and in naloxone-precipitated, morphine-dependent rats (11.5+/-0.9) than in all other groups. Both kappa- and mu-opioid receptor mediated dependence can be demonstrated at the level of a discrete medullary site, the PGi, which further supports a specific role for this nucleus in elicitation of behavioral responses during opioid withdrawal.

Topics: Animals; Basal Ganglia; Butorphanol; Diffusion; Electric Stimulation; Male; Microinjections; Morphine; Morphine Dependence; Naloxone; Naltrexone; Narcotic Antagonists; Narcotics; Rats; Rats, Sprague-Dawley; Receptors, Opioid, kappa; Stereotaxic Techniques; Stereotyped Behavior; Substance Withdrawal Syndrome

Two of the synthesized (-)-(1R,5R,9R)-N-homologues (N-but-3-enyl- and N-but-3-ynyl-5,9-dimethyl-2'-hydroxy-6,7-benzomorphan (9, 13)) were found to be about 20 times more potent than morphine in the mouse tail-flick assay (ED(50) = 0.05 mg/kg), and (-)-(1R,5R, 9R)-N-but-2-ynyl-5,9-dimethyl-2'-hydroxy-6,7-benzomorphan ((-)-(1R, 5R,9R)-N-but-2-ynylnormetazocine, 12) was about as potent as the opioid antagonist N-allylnormetazocine (AD(50) in the tail-flick vs morphine assay = 0.3 mg/kg). All of the homologues examined had higher affinity for the kappa-opioid receptor than the mu-receptor except (-)-N-but-2-ynyl-normetazocine (12), which had a kappa/mu ratio = 7.8 and a delta/mu ratio = 118. The (-)-N-2-cyanoethyl (3), -allyl (8), and -but-3-ynyl (13) analogues had good affinity (<10 nM) for delta-opioid receptors. Two homologues in the (+)-(1S,5S,9S)-normetazocine series, N-pent-4-enyl (24) and N-hex-5-enyl (25), were high-affinity and selective sigma(1)-ligands (K(i) = 2 nM, sigma(2)/sigma(1) = 1250, and 1 nM, sigma(2)/sigma(1) = 750, respectively); in contrast, N-allylnormetazocine (22) had relatively poor affinity at sigma(1), and its sigma(1)/sigma(2) ratio was <100.

Topics: Analgesics; Animals; Benzomorphans; Binding, Competitive; Cerebral Cortex; Ligands; Macaca mulatta; Mice; Morphine; Morphine Dependence; Narcotic Antagonists; Pain Measurement; Radioligand Assay; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu; Stereoisomerism; Structure-Activity Relationship; Substance Withdrawal Syndrome

The relative involvement of kappa opioid receptors in the mediation of behavioral and neurochemical responses to withdrawal from chronic drug treatment with the opioid analgesic butorphanol was studied using in vivo microdialysis to detail extracellular fluid concentrations of glutamate and aspartate within the locus ceruleus. Sprague-Dawley rats were rendered opioid dependent after 3 days of intracerebroventricular (i.c.v.) infusion of butorphanol (26 nmol/microl/hr) or morphine (26 nmol/microl/hr) and after i.c.v. infusion of saline vehicle (1 microl/hr). Acute withdrawal was precipitated by i.c.v. injection of the selective kappa opioid receptor antagonist nor-binaltorphimine (48 nmol/5 microl) after the 3-day period of infusion. Behavioral signs of withdrawal were detected after nor-binaltorphimine only in butorphanol-dependent rats. Basal levels of glutamate and aspartate were not different between treatment groups. Nor-binaltorphimine in the butorphanol-dependent rats increased glutamate to 227% and aspartate to 158% in the initial 15-min sample (P < 0.01). Nor-binaltorphimine did not increase glutamate or aspartate concentrations in the morphine-dependent or saline-treated groups. These results indicate a significantly greater participation of kappa opioid receptors in the development of butorphanol, rather than morphine, dependence and identify a differential neurochemical response to butorphanol withdrawal within a defined brain region, the locus ceruleus.

Topics: Animals; Butorphanol; Excitatory Amino Acids; Locus Coeruleus; Male; Microdialysis; Morphine Dependence; Naltrexone; Narcotic Antagonists; Rats; Rats, Sprague-Dawley; Receptors, Opioid, kappa; Substance Withdrawal Syndrome

The kappa-opioid receptor antagonist nor-binaltorphimine (nor-BNI) was recently shown to potentiate certain overt withdrawal signs in morphine-dependent rats. The present study sought to further assess this phenomenon by examining the influence of nor-BNI treatment upon the conditioned place aversion associated with the naloxone-precipitated withdrawal syndrome. In addition, in vivo microdialysis studies were conducted in morphine-dependent rats to determine whether nor-BNI treatment can modify withdrawal-induced changes in basal dopamine (DA) release within the mesolimbic system. Rats were pretreated with either saline or a single dose of nor-BNI and then received ascending doses of morphine for 10 days. A withdrawal syndrome was then precipitated by the administration of naloxone (1 mg/kg SC). In rats which received chronic morphine injections, administration of naloxone produced a characteristic withdrawal syndrome and a marked aversion for an environment previously associated with naloxone-precipitated withdrawal. Nor-BNI treatment potentiated most overt signs of physical dependence. This treatment also resulted in a greater withdrawal-induced place aversion. Morphine-dependent rats exhibited a marked reduction in basal mesolimbic DA release. An even greater decrease in basal DA release was observed in nor-BNI treated rats. These results suggest that endogenous kappa-systems are important in the modulation of mesolimbic DA release and the accompanying place aversion which occurs during opiate withdrawal.

Topics: Animals; Behavior, Animal; Biogenic Monoamines; Conditioning, Operant; Dopamine; Injections, Intraventricular; Limbic System; Male; Microdialysis; Morphine Dependence; Naloxone; Naltrexone; Nucleus Accumbens; Rats; Rats, Sprague-Dawley; Receptors, Opioid, kappa; Reinforcement, Psychology; Substance Withdrawal Syndrome

The effects of a highly selective kappa antagonist, nor-binaltorphimine (nor-BNI), on the development of tolerance to morphine analgesia and physical dependence on morphine were examined. Pretreatment with nor-BNI (5 mg/kg s.c.) 2 h prior to injection of morphine or a selective kappa agonist, U-50,488H, significantly antagonized the analgesic effect of U-50,488H, but not morphine analgesia in mice. The development of tolerance to morphine analgesia was significantly potentiated by pretreatment of mice with nor-BNI 2 h prior to morphine treatment during chronic morphine treatment for 5 days. Additionally, the pretreatment with nor-BNI during chronic treatment with the high dose of morphine for 5 days significantly potentiated the naloxone-induced body weight loss in morphine-dependent mice and rats. These findings suggest that inactivation of the kappa opioid system may potentiate the development of tolerance to morphine analgesia in mice and may aggravate the naloxone-precipitated body weight loss in morphine-dependent mice and rats.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesia; Analgesics; Analysis of Variance; Animals; Behavior, Animal; Body Weight; Drug Tolerance; Male; Mice; Morphine; Morphine Dependence; Naltrexone; Pyrrolidines; Rats

Topics: Analgesics; Animals; Indoles; Male; Morphinans; Morphine Dependence; Naloxone; Naltrexone; Narcotic Antagonists; Rats; Rats, Inbred Strains; Receptors, Opioid; Weight Loss