naltrindole and Morphine-Dependence

Functional interactions between mu- and delta-opioid receptors (MOPr and DOPr, respectively) are implicated in morphine tolerance and dependence. The contribution of DOPr to the conditioned rewarding effects of morphine and the enhanced conditioned response that occurs after repeated morphine administration is unknown. This issue was addressed with the conditioned place preference procedure (CPP).. Rats received home cage injections of saline or morphine (5.0 mg/kg/day x 5 days) before conditioning. For sensitization studies, DOPr antagonists (DOPr1/2: naltrindole, DOPr2: naltriben, DOPr1: 7-benzylidenenaltrexone) were administered before morphine injections. Conditioning sessions (2 morphine; 2 saline) commenced 3 days later. To assess the influence of acute DOPr blockade on the conditioning of morphine reward in naïve animals, 3 morphine and 3 saline conditioning sessions were employed. Antagonists were administered before morphine conditioning sessions.. Morphine was ineffective as a conditioning stimulus after two conditioning sessions in naïve rats. However, doses > or = 3.0 mg/kg produced significant CPP in morphine pre-exposed rats, confirming that sensitization develops to the conditioned rewarding effects of morphine. In animals that received morphine pre-exposure with naltrindole or naltriben but not 7-benzylidenenaltrexone, sensitization was prevented. No attenuation of morphine CPP was observed in animals that received DOPr antagonists acutely, before conditioning sessions.. These data indicate a critical role of DOPr systems in mediating sensitization to the conditioned rewarding effects of morphine. The efficacy of naltrindole and naltriben in preventing the enhanced response to morphine suggest the specific involvement of DOPr2 in the sensitization process.

Topics: Analysis of Variance; Animals; Association Learning; Behavior, Animal; Benzylidene Compounds; Conditioning, Classical; Disease Models, Animal; Male; Morphine Dependence; Naltrexone; Narcotic Antagonists; Rats; Rats, Sprague-Dawley; Receptor Cross-Talk; Receptors, Opioid, delta; Receptors, Opioid, mu; Reinforcement, Psychology; Statistics, Nonparametric

In the search for a selective delta-opioid receptor agonist, (-)-(1R,5R,9R)-5,9-dimethyl-2'-hydroxy-2-(6-hydroxyhexyl)-6,7-benzomorphan hydrochloride ((-)-NIH 11082) and the (+)-enantiomer were synthesized and tested. (-)-NIH 11082 displayed antinociceptive activity in the paraphenylquinone test (PPQ test) in male ICR mice [ED50=1.9 (0.7-5.3) mg/kg, s.c.] and showed little, if any, activity in the tail-flick and hot-plate assays. The (+)-enantiomer was essentially inactive indicating stereoselectivity. Opioid receptor subtype characterization studies indicated that naltrindole, a delta-opioid receptor antagonist, was potent versus the ED80 of (-)-NIH 11082 in the PPQ test [AD50=0.75 (0.26-2.20) mg/kg, s.c]. beta-Funaltrexamine and nor-binaltorphimine, selective mu- and kappa-receptor antagonists, respectively, were inactive versus the ED80 of (-)-NIH 11082. In rats with inflammation-induced pain, (-)-NIH 11082 produced antihyperalgesic effects that were attenuated by naltrindole. In morphine-dependent rhesus monkeys of both sexes, (-)-NIH 11082 neither substituted for morphine nor exacerbated withdrawal signs in the dose range of 4.0 to 32.0 mg/kg, s.c. Neither convulsions nor other overt behavioral signs were observed in any of the species tested. The results indicate that (-)-NIH 11082 has delta-opioid receptor properties.

Topics: Analgesics, Opioid; Animals; Arthritis, Experimental; Benzomorphans; Female; Hot Temperature; Macaca mulatta; Male; Mice; Mice, Inbred ICR; Morphine Dependence; Naltrexone; Narcotic Antagonists; Pain; Rats; Rats, Inbred Lew; Receptors, Opioid, delta; Stereoisomerism; Substance Withdrawal Syndrome

Behavioural measures are considered to be highly sensitive indices of opioid withdrawal. Opioids, depending on dose and time protocols may induce both reduction and enhancement of locomotor activity and chronic opioid treatment results in tolerance and sensitisation to these effects. In the present study the locomotor activity as experimental model was used to assess the development of tolerance to subcutaneous morphine challenge at different time points following morphine withdrawal in rats exposed to gradually increasing subcutaneous doses of morphine for 11 days. Tolerance developed to the inhibitory action of morphine (10 mg/kg) was observed even 8 weeks after morphine withdrawal, while tolerance to its locomotor activity enhancing effect (3 mg/kg) was detected 18 h after withdrawal, but not 3 weeks later. In the other series of experiments the locomotor activity of animals exposed to chronic morphine treatment was tested 18 h after spontaneous or subcutaneously administrated opioid antagonists precipitated withdrawal. Spontaneous withdrawal resulted in a moderate decrease of locomotion. Both the non-selective antagonist naloxone in low, mu opioid-receptor selective doses and the delta opioid-receptor selective naltrindole induced marked reduction of locomotor activity. The results provide further evidence that both mu and delta opioid-receptors might be affected during chronic morphine treatment.

Topics: Animals; Behavior, Animal; Drug Interactions; Male; Morphine; Morphine Dependence; Motor Activity; Naloxone; Naltrexone; Narcotic Antagonists; Narcotics; Rats; Rats, Wistar; Time Factors

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

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 mu- and delta-opioid receptors in the mediation of butorphanol-, as compared to morphine-, dependence was examined with the use of highly selective antagonists at mu- and delta-opioid receptors. Extracellular fluid levels of glutamate (Glu) and aspartate (Asp) were measured within the pontine locus coeruleus following precipitation of withdrawal from dependence on either butorphanol or morphine in conscious Sprague-Dawley rats. Dependence was induced by intracerebroventricular (i.c.v.) infusion of butorphanol (26 nmol/mu l/h), morphine (26 nmol/mu l/h) or saline vehicle (1 mu l/h) for 3 days by means of an osmotic minipump. Microdialysis probes (2 mm tip) were inserted into the locus coeruleus 24 h before precipitation of withdrawal by i.c.v. injection of either the mu-opioid receptor antagonist, D-Pen-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP; 48 nmol/5 mu l or 48 nmol/5 mu l), or the delta-opioid receptor antagonist, naltrindole (17-cyclopropy;methyl-6,7-dehydro-4,5-epoxy-3, 14-dihydroxy-6,7,2'3'-indolmorphinan hydrochloride; 48 nmol/5 mu l or 100 nmol/5 mu l). Baseline levels of Glu ranged from 9.59 + or - 1.27 to 12.84 + or - 3.01 mu M in the various treatment groups. Levels of Asp were similar. Precipitation of withdrawal by CTOP elicited significant increases of Glu and Asp in both morphine- and butorphanol-dependent rats. Maximal increases in Glu of 425% and 258% above baseline levels were elicited in the first 15 min microdialysis sample following i.c.v. injection of CTOP in morphine- and butorphanol-dependent rats, respectively. Behavioral signs of withdrawal were greater in morphine than butorphanol-dependent groups. The i.c.v. treatment with naltrindole elicited increases in Glu and Asp that were similar, although less marked, than those precipitated by CTOP treatment. Administration of naltrindole produced equivalent signs of withdrawal in both morphine- and butorphanol-dependent rats. Withdrawal from dependence on both morphine and butorphanol is characterized by elevations in coerulear levels of excitatory amino acids. Responses elicited following the use of selective mu- and delta-opioid receptor antagonists to precipitate withdrawal suggest that the role played by these receptors in mediation of the signs and symptoms of withdrawal do not differ greatly between butorphanol- and morphine-dependent rats.

Topics: Animals; Butorphanol; Drug Evaluation, Preclinical; Injections, Intraventricular; Locus Coeruleus; Male; Morphine; Morphine Dependence; Naltrexone; Narcotic Antagonists; Rats; Rats, Sprague-Dawley; Receptors, Opioid, delta; Receptors, Opioid, mu; Somatostatin; Substance Withdrawal Syndrome

Recent reports from several laboratories have suggested a role for delta opioid receptors in expressing some of the biochemical and behavioral effects of cocaine. Here, this possibility has been further explored by evaluating the propensity of rats to self-administer i.v. cocaine in the absence or presence of naltrindole, a selective delta opioid antagonist. Following a number of days of stable cocaine intake, and before a day's session, naltrindole (3 or 10 mg kg-1) reduced pressing for cocaine, regardless of the schedule of reinforcement. These data further support the role of processes associated with delta opioid receptors in the ability of cocaine to reinforce its own use.

Topics: Animals; Cocaine; Conditioning, Operant; Drug Implants; Female; Male; Morphine; Morphine Dependence; Naltrexone; Narcotic Antagonists; Narcotics; Rats; Rats, Inbred Lew; Rats, Sprague-Dawley; Receptors, Opioid, delta; Self Administration

The effect of pretreatment with a delta opioid receptor antagonist, naltrindole (NTI), on the development of physical dependence on morphine was investigated in mice. Several withdrawal signs, an increase in cortical noradrenaline (NA) turnover and a decrease in dopamine (DA) turnover in the limbic forebrain were observed following naloxone challenge in morphine-dependent mice. Pretreatment with NTI (0.3-5 mg/kg, s.c.) during chronic morphine treatment dose-dependently suppressed the behavioral and biochemical changes after withdrawal. The blocking effects of NTI suggest that delta opioid receptors may play a significant role in modulating the development of physical dependence on morphine.

Topics: Animals; Behavior, Animal; Body Weight; Male; Mice; Mice, Inbred Strains; Morphine Dependence; Naloxone; Naltrexone; Narcotic Antagonists; Receptors, Opioid; Sodium Chloride; Time Factors

We examined the effects of i.c.v. treatment with naltrindole, and the two highly selective peptide delta-opioid receptor antagonists H-Tyr-Tic-Phe-Phe-OH (TIPP) and H-Tyr-Tic psi [CH2-NH]-Phe-Phe- OH (TIPP[psi]), on the development of morphine tolerance and dependence. Each treatment significantly decreased naloxone-precipitated withdrawal, with TIPP[psi] reducing the most symptoms. TIPP[psi], but neither naltrindole nor TIPP, attenuated the development of analgesic tolerance in the tail-flick test. These results suggest that delta-opioid receptors are critically involved in the development of morphine tolerance and dependence.

Topics: Animals; Behavior, Animal; Morphine Dependence; Naloxone; Naltrexone; Narcotic Antagonists; Oligopeptides; Rats; Receptors, Opioid, delta; Substance Withdrawal Syndrome; Tetrahydroisoquinolines

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