Pharmacologic Characterization in the Rat of a Potent Analgesic Lacking Respiratory Depression, IBNtxA

Grinnell, Steven G.; Majumdar, Susruta; Narayan, Ankita; Rouzic, Valerie Le; Ansonoff, Michael; Pintar, John E.; Pasternak, Gavril W.

doi:10.1124/jpet.114.213199

Cited by 25 publications

(32 citation statements)

References 49 publications

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“…The importance of 6TM variants in IBNtxA analgesia has been established (9)(10)(11)(12). We now have extended our studies of these truncated forms of the mu opioid receptor to explore other classes of analgesics.…”

Section: Resultsmentioning

confidence: 96%

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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Section: Resultsmentioning

confidence: 96%

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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“…Transgenic mice lacking exon 11, an exon that provides an alternative promoter region for the MOR transcript, demonstrated substantial reductions in the analgesic efficacies of heroin, fentanyl, and the morphine metabolite morphine-6β-glucuronide 24 , suggesting that exon-11 containing variants play a critical role in opioid analgesia. Exon 11-containing splice variants also mediate the analgesic effects of iodobenzoylnaltrexamide (IBNtxA), a novel synthetic opioid that produces ten times the analgesic efficacy of morphine without producing respiratory distress, dependence, tolerance, or GI distress in rodents 36,40,92 . MOR-1 splice variants also promote analgesia by enhancing canonical receptor function.…”

Section: Functional Gpcr Alternative Splice Variantsmentioning

confidence: 99%

Alternative Splicing of G Protein–Coupled Receptors: Relevance to Pain Management

Oladosu

Maixner

Nackley

2015

Mayo Clinic Proceedings

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Drugs that target G-protein coupled receptors (GPCRs) represent the primary treatment strategy for patients with acute and chronic pain; however, there is substantial individual variability in both the efficacy and adverse side effects associated with these drugs. Variability in drug responses is, in part, due to individuals’ diversity in alternative splicing of pain-relevant GPCRs. GPCR alternative splice variants often exhibit distinct tissue distribution patterns, drug binding properties, and signaling characteristics that may impact disease pathology as well as the size and direction of analgesic effects. Here, we review the importance of GPCRs and their known splice variants to the management of pain.

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“…An alternative is to pursue novel targets. Recently, a new class of opioid analgesics was described with an unusual pharmacological profile (3)(4)(5)(6). IBNtxA (3-iodobenzoyl-6β-naltrexamide), a member of this group, is a potent analgesic against thermal, inflammatory and neuropathic pain, but does not depress respiration or produce physical dependence and shows no reward behavior.…”

Section: Introductionmentioning

confidence: 99%

Mediation of opioid analgesia by a truncated 6-transmembrane GPCR

Lu¹,

Xu²,

Rossi³

et al. 2015

J. Clin. Invest.

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104

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Potent opioid analgesics lacking side‐effects may be possible by targeting truncated mu receptor splice variants. Mu opioids act through G‐protein coupled receptors generated from the mu opioid receptor (Oprm1) gene which undergoes extensive alternative splicing. The most abundant set of variants encode classical full‐length 7 transmembrane domain (TM) mu opioid receptors that mediate the actions of the traditional mu drugs morphine and methadone. In contrast, IBNtxA (3‐iodobenzoyl‐6β‐naltrexamide) is a potent analgesic against thermal, inflammatory and neuropathic pain whose actions are independent of the 7TM mu opioid receptors and lost in a knockout mouse lacking a set of 6TM truncated mu receptor splice variants. Unlike traditional opioids, IBNtxA has no respiratory depression, physical dependence or reward behavior, suggesting it acts through a novel mu opioid receptor target. Here we demonstrate that a truncated 6TM splice variant, mMOR‐1G, can rescue IBNtxA analgesia in a mu opioid receptor knockout mouse lacking all Oprm1 splice variants due to disruptions of both exons 1 and 11. No mu opioids were active in these mice. A lentivirus containing the 6TM variant mMOR‐1G administered intrathecally restored IBNtxA, but not morphine, analgesia, confirming that a truncated 6TM GPCR is both necessary and sufficient for IBNtxA analgesia. This work was supported by the NIH with grants from NIDA (DA013997 and DA02944) to Y‐X.P. and (DA06241 and DA07242) to G.W.P. and a core grant from the NCI to MSKCC (CA08748).

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Pharmacologic Characterization in the Rat of a Potent Analgesic Lacking Respiratory Depression, IBNtxA

Cited by 25 publications

References 49 publications

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

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

Alternative Splicing of G Protein–Coupled Receptors: Relevance to Pain Management

Mediation of opioid analgesia by a truncated 6-transmembrane GPCR

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