heroin and methylnaltrexone

Methylnaltrexone, a peripheral opioid μ-receptor antagonist is licensed for subcutaneous administration for the treatment of severe opioid-induced constipation in adults. We describe the use of intravenous methylnaltrexone in a 3-year-old boy receiving a subcutaneous diamorphine infusion for palliation from widely metastatic alveolar rhabdomyosarcoma. The patient, who had not opened his bowels for 3 weeks despite use of regular conventional laxatives, was given a 150 mcg/kg dose via indwelling central venous catheter. Constipation was relieved within minutes of the injection. There were no side effects noted during or following injection, and no clinically apparent reduction in analgesia. Intravenous methylnaltrexone may provide a valuable additional treatment option in paediatric palliative care, especially for those with an oncological diagnosis, the majority of whom will have indwelling central venous access devices.

Topics: Administration, Intravenous; Analgesics, Opioid; Child, Preschool; Constipation; Heroin; Humans; Male; Naltrexone; Narcotic Antagonists; Palliative Care; Quaternary Ammonium Compounds

3-O-Methylnaltrexone (3-MNTX), a putative antagonist of morphine-6-beta-d-glucuronide (M6G) receptors, has been reported to block the behavioral effects of heroin at doses that do not block those of morphine, suggesting that M6G receptors may play a unique role in the addictive properties of heroin. This study investigated the effects of 3-MNTX in monkeys trained to discriminate i.v. heroin from vehicle or to self-administer i.v. heroin under a progressive-ratio schedule. Additional in vitro studies determined the effects of 3-MNTX and reference drugs on adenylyl cyclase activity in caudate-putamen membranes of monkeys and rats. In drug discrimination experiments, heroin, morphine, and M6G substituted for heroin in all subjects, whereas 3-MNTX substituted for heroin in one-half the monkeys tested. In these latter monkeys, the effects of 3-MNTX were antagonized by naltrexone, and pretreatment with 3-MNTX enhanced the effects of heroin, M6G, and morphine, indicative of micro-agonist activity. In monkeys showing no substitution of 3-MNTX for heroin, 3-MNTX antagonized the effects of heroin, M6G, and morphine. In self-administration experiments, heroin and 3-MNTX maintained injections per session significantly above those maintained by vehicle when the initial response requirement (IRR) was low; only heroin maintained significant self-administration when the IRR was high. In vitro, 3-MNTX inhibited adenylyl cyclase activity in both monkey and rat brain membranes. The degree of inhibition produced by 3-MNTX was less than that produced by the full agonist [d-Ala(2),N-Me-Phe(4),Gly(5)-ol]-enkephalin (DAMGO). The results suggest that 3-MNTX functions primarily as a partial agonist at micro-receptors in monkeys and do not support a singular role for M6G receptors in the abuse-related effects of heroin.

Topics: Adenylyl Cyclases; Animals; Cocaine; Discrimination Learning; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Heroin; Heroin Dependence; Macaca mulatta; Male; Morphine; Morphine Derivatives; Naltrexone; Narcotics; Quaternary Ammonium Compounds; Receptors, Opioid, mu; Self Administration

Heroin produced antinociception in the tail flick test through mu receptors in the brain of ICR and CD-1 mice, a response inhibited by 3-O-methylnaltrexone. Tolerance to morphine was produced by subcutaneous morphine pellet implantation. By the third day, the heroin response was produced through delta opioid receptors. The response was inhibited by simultaneous intracerebroventricular (i.c. v.) administration of naltrindole, a delta opioid receptor antagonist. More specifically, delta1 rather than delta2 receptors were involved because 7-benzylidenenaltrexone, a delta1 receptor antagonist, inhibited but naltriben, a delta2 antagonist, did not. Also, antinociception produced by i.c.v. heroin was inhibited by intrathecal administration of bicuculline and picrotoxin consistent with the concept that delta1 receptors in the brain mediated the antinociceptive response through descending neuronal pathways to the spinal cord to activate GABAA and GABAB receptors rather than spinal alpha2-adrenergic and serotonergic receptors activated originally by the mu agonist action in naive mice. The mu response of 6-monoacetylmorphine, a metabolite of heroin, was changed by morphine pellet implantation to a delta2 response (inhibited by naltriben but not 7-benzylidenenaltrexone). The agonist action of morphine in these morphine-tolerant mice remained mu. Thus, the opioid receptor selectivity of heroin and 6-monoacetylmorphine in the brain is changed by production of tolerance to morphine. Such a change explains how morphine tolerant mice are not cross-tolerant to heroin.

Topics: Analgesics, Opioid; Animals; Drug Tolerance; Heroin; Injections, Intraventricular; Male; Mice; Mice, Inbred ICR; Morphine; Morphine Derivatives; Naltrexone; Narcotic Antagonists; Narcotics; Quaternary Ammonium Compounds; Receptors, Opioid, delta; Receptors, Opioid, mu

In mice, 3-O-methylnaltrexone blocks the analgesic actions of morphine-6beta-glucuronide and heroin at doses which are inactive against morphine. We found a similar selectivity in rats. 3-O-Methylnaltrexone antagonized the analgesic actions of 6-acetylmorphine in Sprague-Dawley rats and heroin in Wistar rats at doses that were inactive against morphine. Inclusion of a fixed dose of 3-O-methylnaltrexone significantly shifted the analgesic dose-response curves for 6-acetylmorphine and heroin without altering the morphine dose-response curves. In a self-administration model, 3-O-methylnaltrexone treatment significantly increased both heroin and morphine intake during the first hour, suggestive of an antagonist effect. This effect at doses of 3-O-methylnaltrexone which were inactive against morphine analgesia implied a role for the morphine-6beta-glucuronide opioid receptor in the reinforcing properties of heroin and morphine.

Topics: Animals; Conditioning, Operant; Dose-Response Relationship, Drug; Heroin; Injections, Subcutaneous; Male; Morphine; Morphine Derivatives; Naltrexone; Narcotic Antagonists; Narcotics; Pain Measurement; Quaternary Ammonium Compounds; Rats; Rats, Sprague-Dawley; Rats, Wistar; Self Administration

The role of opiate receptors in the periaqueductal grey and nucleus accumbens in maintenance of intravenous heroin self-administration was examined by means of intracranial microinjections of the quaternary opiate antagonist methyl naltrexone. Over a dose range of 0-3.0 micrograms, pre-session infusions of methyl naltrexone in either brain site produced dose-related increases in responding for heroin (0.06 mg/kg/infusion) on a CRF schedule, without causing significant changes in responding on a second activity control lever. Involvement of the periaqueductal grey was also examined in animals administering a lower heroin dose (0.03 mg/kg/infusion) in shorter sessions in order to minimize drug exposure prior to treatment. In this experiment, infusion of methyl naltrexone produced selective increases in responding for heroin, whereas treatment with the identical dose of methyl naltrexone had no effect on cocaine self-administration (1.0 mg/kg/infusion) in the same animals. With respect to the nucleus accumbens, these data confirm its involvement in opiate self-administration. Data for the periaqueductal grey provide the first evidence that opiate receptors in the vicinity of this brain region may play a role in intravenous opiate self-administration.

Topics: Animals; Cocaine; Heroin; Male; Microinjections; Naltrexone; Narcotic Antagonists; Nucleus Accumbens; Periaqueductal Gray; Quaternary Ammonium Compounds; Rats; Rats, Inbred Strains; Self Administration

The involvement of the lateral hypothalamus and medial prefrontal cortex in mediating heroin self-administration was examined by means of intracranial microinjections of the quaternary opiate antagonist methyl naltrexone over a dose range of 0-3.0 micrograms. In animals trained to respond on a continuous reinforcement schedule for intravenous heroin (0.03 mg/kg/infusion), microinfusions of antagonist into the lateral hypothalamus prior to a self-administration session produced significant dose-related increases in responding on the drug manipulandum, similar to increases in responding observed after treatment with naltrexone systemically. Microinfusions of quaternary antagonist into the medial prefrontal cortex over the same dose range effective in the lateral hypothalamus did not produce response increases. These data suggest that opiate action in the lateral hypothalamus, but not in the medial prefrontal cortex, is salient in maintenance of intravenous self-administration.

Topics: Animals; Catheterization; Conditioning, Operant; Dose-Response Relationship, Drug; Drug Interactions; Heroin; Hypothalamus; Male; Microinjections; Naltrexone; Quaternary Ammonium Compounds; Rats; Self Administration

The role of opiate receptors in the periaqueductal grey (PAG) and nucleus accumbens (NA) in the expression of heroin-induced locomotor activation was investigated. Rats received subcutaneous injections of heroin (0.5 mg/kg) in combination with intra-PAG or intra-NA microinjections of the quaternary opiate antagonist methyl naltrexone (MN) in doses of 0.0 (saline vehicle), 0.3, 1.0 and 3.0 micrograms. When injected into the NA, all three doses of MN were found to attenuate heroin-induced locomotor activity compared to saline vehicle. In contrast, intra-PAG MN treatment did not have any significant effect on heroin-induced locomotor activity. With regard to the NA, these results confirm previous findings showing that blockade of NA opiate receptors attenuates heroin-induced locomotor activity. The lack of effect in the PAG indicates that PAG opiate receptors do not participate in the expression of heroin-induced locomotor activation. The implications of these results for the anatomical overlap found between sites mediating opiate reward and locomotor activation are discussed.

Topics: Animals; Heroin; Injections; Male; Motor Activity; Naltrexone; Narcotic Antagonists; Nucleus Accumbens; Periaqueductal Gray; Quaternary Ammonium Compounds; Rats; Rats, Inbred Strains; Septal Nuclei

Quaternary derivatives of naloxone and naltrexone, methyl naloxonium chloride(ORG 10908) and naltrexone methobromide ( MRZ 2663BR ), respectively, were compared with the parent compounds for their ability to antagonize the reinforcing properties of heroin as measured in an operant, i.v., self-administration paradigm. As expected, lower doses (up to 0.2 mg/kg) of naloxone and naltrexone produced dose-dependent increases in heroin self-administration, but at higher doses (10-30 mg/kg) these drugs produced transient decreases (20-100 min) in self-administration followed by recovery. Naltrexone was approximately 1.5 times more potent than naloxone in increasing heroin self-administration at the lower doses (up to 0.2 mg/kg) and had a slightly longer duration of action. The quaternary derivatives were ineffective as antagonists of heroin self-administration in doses 200 times greater than the effective antagonist dose of naloxone or naltrexone. These results support the hypothesis that the acute reinforcing properties of i.v. opiates associated with the sensation of the "rush" involve opiate receptors located within the central nervous system and do not involve peripheral opiate receptors.

Topics: Animals; Dose-Response Relationship, Drug; Heroin; Male; Naloxone; Naltrexone; Narcotic Antagonists; Quaternary Ammonium Compounds; Rats; Rats, Inbred Strains; Reinforcement, Psychology; Self Administration; Time Factors