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

Susruta Majumdar, Steven Grinnell, Valerie Le Rouzic, Maxim Burgman, Lisa Polikar, Michael Ansonoff, John Pintar, Ying Xian Pan, Gavril W. Pasternak

Research output: Contribution to journalArticle

85 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)19778-19783
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume108
Issue number49
DOIs
StatePublished - Dec 6 2011

Fingerprint

Opiate Alkaloids
mu Opioid Receptor
GTP-Binding Proteins
Opioid Analgesics
Pain
Analgesics
Constipation
G-Protein-Coupled Receptors
Respiratory Insufficiency
Analgesia
Medicine
Pharmacology
Therapeutics

All Science Journal Classification (ASJC) codes

  • General

Keywords

  • Kappa receptor
  • Opiate receptor
  • Rewarding behavior

Cite this

Majumdar, Susruta ; Grinnell, Steven ; Le Rouzic, Valerie ; Burgman, Maxim ; Polikar, Lisa ; Ansonoff, Michael ; Pintar, John ; Pan, Ying Xian ; Pasternak, Gavril W. / Truncated G protein-coupled mu opioid receptor MOR-1 splice variants are targets for highly potent opioid analgesics lacking side effects. In: Proceedings of the National Academy of Sciences of the United States of America. 2011 ; Vol. 108, No. 49. pp. 19778-19783.
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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, Susruta; Grinnell, Steven; Le Rouzic, Valerie; Burgman, Maxim; Polikar, Lisa; Ansonoff, Michael; Pintar, John; Pan, Ying Xian; Pasternak, Gavril W.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 108, No. 49, 06.12.2011, p. 19778-19783.

Research output: Contribution to journalArticle

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AU - Burgman, Maxim

AU - Polikar, Lisa

AU - Ansonoff, Michael

AU - Pintar, John

AU - Pan, Ying Xian

AU - Pasternak, Gavril W.

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