Absence of Cross-Tolerance to Heroin in Morphine-Tolerant Mice

Lange, David G.; Roerig, Sandra C.; Fujimoto, James M.; Wang, R. I. H.

doi:10.1126/science.7361110

Cited by 47 publications

(15 citation statements)

References 18 publications

(10 reference statements)

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“…Swiss Cox mice made highly tolerant to morphine are not cross-tolerant to heroin (45). In MP implanted CD-1 mice, tolerance develops to the m action of heroin, but the appearance of d-agonist action induced by MP implantation counter balances the tolerance so that the net result is no manifestation of overall tolerance to heroin (5).…”

Section: Discussionmentioning

confidence: 99%

Methadone and Heroin Antinociception: Predominant £-Opioid-Receptor Responses in Methadone-Tolerant Mice

Rady

Portoghese

Fujimoto

2002

Japanese Journal of Pharmacology

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ABSTRACT-Antinociceptive tail flick responses to heroin and 6-monoacetylmorphine mediated in the brain by m-opioid receptor are switched by morphine pellet implantation to d 1 -and d 2 -opioid-receptors mediation, respectively. Present results showed that the m-receptor response (inhibited by b-funaltrexamine) to methadone was changed by morphine pellet implantation to d1 (inhibited by 7-benzylidenenaltrexone)-and d2 (inhibited by naltriben)-opioid-receptor responses. Methadone pellet implantation likewise changed mediation from m-to d-opioid receptors for heroin and methadone but not for morphine (b-funaltrexamine continued to inhibit). Methadone m action in the brain was linked through a descending system to activate spinal serotonin receptors (inhibited by methysergide), but this link was gone in the methadone-pelletimplanted group. In the latter group, the new d1-and d2-receptor responses were mediated by spinal GABAA (inhibited by bicuculline) and GABAB (inhibited by 2-hydroxysaclofen) receptors. These shifts in neuronal systems meant that m receptors on a given neuron were not changed into d receptors. Preliminary results showed that d-agonist action for methadone was prevented from appearing by MK801, a NMDA-receptor antagonist, and did not occur in 129S6 /SvEv mice which lack NMDA responsiveness. Could methadone maintenance treatment in humans uncover d-agonist actions?Keywords: Methadone, Heroin, Antinociception, d-Opioid receptor, Chronic methadone Heroin and its metabolites, 6-monacetylmorphine (6MAM) and morphine act on m -opioid receptors in the brain to produce antinociception in CD-1 and ICR mice (1, 2). These m-receptor actions are inhibited by b-funaltrexamine (b -FNA). Further differentiation between m-agonist actions is possible because the m actions of heroin and 6MAM but not morphine are inhibited by 3O-methylnaltrexone, OMeNTX (3 -5), while morphine but not heroin and 6MAM action is inhibited by naloxonazine (3, 6). The explanation for these differences is given as alternative splicing of the m receptor (7 -9). Morphine pellet (MP) implantation, which produces tolerance to morphine, changes the receptor selectivity in the brain for heroin and 6MAM to d-opioid-receptor-mediated responses, but the response to morphine remains m-receptor-mediated (5). In this situation, heroin activates d1 (inhibited by 7-benzylidenenaltrexone, BNTX) and 6MAM activates d2 (inhibited by naltriben) receptors in the brain. In the tail flick test in mice, the m responses from the brain for heroin, 6MAM and morphine are mediated by spinal serotonergic and adrenergic receptors and d responses by spinal GABAA and GABAB receptors (1,2, 5,10,11). Thus, when the changes in opioid receptor selectivity from m to d for heroin and 6MAM are produced by MP implantation, the descending pathway shifts from spinal serotonergic to GABAergic receptors (5). These effects of MP implantation further differentiate heroin and 6MAM analgesic actions from that of morphine.Methadone maintenance is used to treat heroin abuse in human subje...

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Section: Discussionmentioning

confidence: 99%

Methadone and Heroin Antinociception: Predominant £-Opioid-Receptor Responses in Methadone-Tolerant Mice

Rady

Portoghese

Fujimoto

2002

Japanese Journal of Pharmacology

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“…Incomplete tolerance can be demonstrated in animal models. Whereas complete tolerance is seen between morphine and codeine, incomplete cross-tolerance is observed between morphine and several other mu drugs, including morphine-6b-glucuronide, heroin, and methadone (Lange et al, 1980;Rossi et al, 1996). Unidirectional cross-tolerance, an extreme example of incomplete cross-tolerance, exists between morphine and levorphanol (Moulin et al, 1988).…”

Section: G Incomplete Cross-tolerancementioning

confidence: 99%

Mu Opioids and Their Receptors: Evolution of a Concept

2013

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“…Why addicts and patients should be able to distinguish between 2 -agonists that presumably act through only -opioid-receptors is not clear. Although some investigators have favored pharmacokinetic factors, several studies raised the possibility of pharmacodynamic causes (2,6). This inability to reconcile the diverse pharmacology of -opioids with their binding selectivity led to the proposal of multiple -opioid-receptors (7), a concept initially proposed based on binding and pharmacological studies in animal models and subsequently confirmed with the identification of a large number of splice variants of the cloned -opioid-receptor MOR-1 in mice, rats, and humans ( Fig.…”

mentioning

confidence: 99%

Involvement of exon 11-associated variants of the mu opioid receptor MOR-1 in heroin, but not morphine, actions

Pan

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

100

140

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Heroin remains a major drug of abuse and is preferred by addicts over morphine. Like morphine, heroin has high affinity and selectivity for -receptors, but its residual analgesia in exon 1 MOR-1 knockout mice that do not respond to morphine suggests a different mechanism of action. MOR-1 splice variants lacking exon 1 have been observed in mice, humans, and rats, raising the possibility that they might be responsible for the residual heroin and morphine-6␤-glucuronide (M6G) analgesia in the exon 1 knockout mice. To test this possibility, we disrupted exon 11 of MOR-1, which eliminates all of the variants that do not contain exon 1. Morphine and methadone analgesia in the exon 11 knockout mouse was normal, but the analgesic actions of heroin, M6G, and fentanyl were markedly diminished in the radiant heat tailflick and hot-plate assays. Similarly, the ability of M6G to inhibit gastrointestinal transit was greatly diminished in these exon 11 knockout mice, whereas the ability of morphine was unchanged. These findings identify receptors selectively involved with heroin and M6G actions and confirm the relevance of the exon 11-associated variants and raise important issues regarding the importance of atypical truncated G-protein-coupled receptors.knockout ͉ analgesia ͉ opiate receptor

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Absence of Cross-Tolerance to Heroin in Morphine-Tolerant Mice

Cited by 47 publications

References 18 publications

Methadone and Heroin Antinociception: Predominant £-Opioid-Receptor Responses in Methadone-Tolerant Mice

Methadone and Heroin Antinociception: Predominant £-Opioid-Receptor Responses in Methadone-Tolerant Mice

Mu Opioids and Their Receptors: Evolution of a Concept

Involvement of exon 11-associated variants of the mu opioid receptor MOR-1 in heroin, but not morphine, actions

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