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

Pan, Ying Xian; Xu, Jin; Xu, Mingming; Rossi, Grace C.; Matulonis, Joshua E.; Pasternak, Gavril W.

doi:10.1073/pnas.0811586106

Cited by 100 publications

(146 citation statements)

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“…Loss of the exon 11-associated variants has no significant effect on morphine or methadone analgesia (16). In contrast, IBNtxA analgesia was lost in the exon 11 MOR-1 KO mouse (Fig.…”

Section: Resultsmentioning

confidence: 92%

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Truncated G protein-coupled mu opioid receptor MOR-1 splice variants are targets for highly potent opioid analgesics lacking side effects

Majumdar

Grinnell

Rouzic

et al. 2011

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

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Pain remains a pervasive problem throughout medicine, transcending all specialty boundaries. Despite the extraordinary insights into pain and its mechanisms over the past few decades, few advances have been made with analgesics. Most pain remains treated by opiates, which have significant side effects that limit their utility. We now describe a potent opiate analgesic lacking the traditional side effects associated with classical opiates, including respiratory depression, significant constipation, physical dependence, and, perhaps most important, reinforcing behavior, demonstrating that it is possible to dissociate side effects from analgesia. Evidence indicates that this agent acts through a truncated, six-transmembrane variant of the G protein-coupled mu opioid receptor MOR-1. Although truncated splice variants have been reported for a number of G protein-coupled receptors, their functional relevance has been unclear. Our evidence now suggests that truncated variants can be physiologically important through heterodimerization, even when inactive alone, and can comprise new therapeutic targets, as illustrated by our unique opioid analgesics with a vastly improved pharmacological profile.opiate receptor | rewarding behavior | kappa 3 receptor T he utility of opioids in the management of pain is not disputed, but they come at a price. Along with their ability to relieve pain comes a variety of opioid receptor-mediated side effects, including respiratory depression, constipation, physical dependence, and reward behavior felt by many to contribute to their addictive potential. Most of the clinical opioids act through mu receptors, which mediate both analgesia and these side effects. Pharmacological studies have long suggested subtypes of mu receptors (1) and the possibility of dissociating analgesia from respiratory depression (2, 3), physical dependence (4), and the inhibition of gastrointestinal transit (5, 6). However, attempts to develop opiate analgesics that avoid these side effects have not been very fruitful. The isolation of a series of splice variants of the cloned mu opioid receptor from mice ( Fig. 1), rats, and humans with similar splicing patterns (7, 8) reveals a complexity far exceeding the pharmacological classification of mu receptor subtypes (1). However, this complexity has yet to be exploited in generating new classes of opioid analgesics. We now report an unexpected and unusual target for potent opioid analgesic drugs that lack respiratory depression, physical dependence, reward behavior, and significant constipation. ResultsRecently, we synthesized iodobenzoylnaltrexamide (IBNtxA), a naltrexone derivative (Fig. 2) (9). In vivo, it is a very potent analgesic (ED 50 = 0.48 ± 0.05 mg/kg s.c.) (Fig. 3A and Fig. S1), ∼10-fold more potent than morphine (4.6 ± 0.97 mg/kg s.c.) (10), with a mechanism of action quite distinct from traditional opiates. It was active s.c. as well as orally (Fig. S1), with a peak effect after oral administration that was delayed relative to parenteral administration. In ...

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“…Loss of the exon 11-associated variants has no significant effect on morphine or methadone analgesia (16). In contrast, IBNtxA analgesia was lost in the exon 11 MOR-1 KO mouse (Fig.…”

Section: Resultsmentioning

confidence: 92%

“…The exon 1 KO and triple-KO mice came from J.P.'s laboratory (14,40), and the exon 11 mice were from our laboratory (16). All mice were maintained on a 12-h light/dark cycle with Purina rodent chow and water available ad libitum, housed in groups of five until testing.…”

Section: Methodsmentioning

confidence: 99%

Truncated G protein-coupled mu opioid receptor MOR-1 splice variants are targets for highly potent opioid analgesics lacking side effects

Majumdar

Grinnell

Rouzic

et al. 2011

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

Self Cite

129

257

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“…C57Bl/6J mice (24-37 g) were purchased from Jackson Laboratories. Oprm1 exon 11 KO animals were derived as described (2) and backcrossed at least 10 generations on a C57BL/6J background. Exon 1/exon 11 double KO mice and their mixed background littermate controls (129/C57BL/6 mixed background) were bred by our laboratory (4).…”

Section: Discussionmentioning

confidence: 99%

“…Mice have been developed that have the selective loss of only 6TM variants (E11 KO) (2), only the exon 1-containing 7TM and 1TM variants (E1 KO) (3) or the loss of all Oprm1 variants (E1/E11 KO) (4) (SI Appendix, Fig. S1).…”

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confidence: 99%

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Truncated mu opioid GPCR variant involvement in opioid-dependent and opioid-independent pain modulatory systems within the CNS

Marrone

Grinnell

et al. 2016

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

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The clinical management of severe pain depends heavily on opioids acting through mu opioid receptors encoded by the Oprm1 gene, which undergoes extensive alternative splicing. In addition to generating a series of prototypic seven transmembrane domain (7TM) G protein-coupled receptors (GPCRs), Oprm1 also produces a set of truncated splice variants containing only six transmembrane domains (6TM) through which selected opioids such as IBNtxA (3′-iodobenzoyl-6β-naltrexamide) mediate a potent analgesia without many undesirable effects. Although morphine analgesia is independent of these 6TM mu receptor isoforms, we now show that the selective loss of the 6TM variants in a knockout model eliminates the analgesic actions of delta and kappa opioids and of α 2 -adrenergic compounds, but not cannabinoid, neurotensin, or muscarinic drugs. These observations were confirmed by using antisense paradigms. Despite their role in analgesia, loss of the 6TM variants were not involved with delta opioid-induced seizure activity, aversion to the kappa drug U50,488H, or α 2 -mediated hypolocomotion. These observations support the existence of parallel opioid and nonopioid pain modulatory systems and highlight the ability to dissociate unwanted delta, kappa 1 , and α 2 actions from analgesia.GPCR | truncation | analgesia | mu opioid receptor | morphine M odulation of pain is complex, with contributions from a variety of neurotransmitter systems. The opioid systems are particularly prominent clinically because of the availability of many potent and effective drugs, particularly those acting through mu opioid receptors. The mu opioid receptor gene, Oprm1, is complex, containing two independent promoters that generate dozens of variants through both 5′ and 3′ alternative splicing patterns that are highly conserved among multiple species (SI Appendix, Fig. S1) (1). Like the first mu opioid receptor (Oprm1) clone, MOR-1, most of the variants are traditional seven transmembrane domain (7TM) G protein-coupled receptors (GPCRs) generated from the exon 1 (E1) promoter. Each contains exons 1, 2, and 3, differing only at the intracellular C terminus due to 3′ splicing. The exon 11 (E11) promoter, located ∼30 kb upstream of exon 1, generates a set of truncated proteins lacking the first transmembrane domain because of the absence of exon 1, resulting in only six transmembrane domains (6TM).Classically, opioid mechanisms were defined pharmacologically by using selective agonists and antagonists, but genetic approaches offer a more precise approach toward assessing the pharmacological contributions of the various Oprm1 splice variants. Mice have been developed that have the selective loss of only 6TM variants (E11 KO) (2), only the exon 1-containing 7TM and 1TM variants (E1 KO) (3) or the loss of all Oprm1 variants (E1/E11 KO) (4) (SI Appendix, Fig. S1). These models provide insights into the differing pharmacology of the full-length 7TM and the truncated 6TM variants. Full-length 7TM variants are essential for morphine actions (3, 5-7). However, m...

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Alternative Pre‐mRNA Splicing of Mu Opioid Receptor Gene

Pan

2013

Pain Genetics

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

Cited by 100 publications

References 27 publications

Truncated G protein-coupled mu opioid receptor MOR-1 splice variants are targets for highly potent opioid analgesics lacking side effects

Truncated G protein-coupled mu opioid receptor MOR-1 splice variants are targets for highly potent opioid analgesics lacking side effects

Truncated mu opioid GPCR variant involvement in opioid-dependent and opioid-independent pain modulatory systems within the CNS

Alternative Pre‐mRNA Splicing of Mu Opioid Receptor Gene

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