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Emerging Insights into Mu Opioid Pharmacology

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Substance Use Disorders

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 258))

Abstract

Opioid analgesics, most of which act through mu opioid receptors, have long represented valuable therapeutic agents to treat severe pain. Concerted drug development efforts for over a 100 years have resulted in a large variety of opioid analgesics used in the clinic, but all of them continue to exhibit the side effects, especially respiratory depression, that have long plagued the use of morphine. The recent explosion in fatalities resulting from overdose of prescription and synthetic opioids has dramatically increased the need for safer analgesics, but recent developments in mu receptor research have provided new strategies to develop such drugs. This chapter reviews recent advances in developing novel opioid analgesics from an understanding of mu receptor structure and function. This includes a summary of the mechanism of agonist binding deduced from the crystal structure of mu receptors. It will also highlight the development of novel agonist mechanisms, including biased agonists, bivalent ligands, and allosteric modulators of mu receptor function, and describe how receptor phosphorylation modulates these pathways. Finally, it will summarize research on the alternative pre-mRNA splicing mechanisms that produces a multiplicity of mu receptor isoforms. Many of these isoforms exhibit different pharmacological specificities and brain circuitry localization, thus providing an opportunity to develop novel drugs with increased therapeutic windows.

This chapter is dedicated to the memory of our dear colleague and friend Dr. Gavril Pasternak (deceased February 22, 2019), whose pioneering work over four decades contributed immensely to our understanding of opioid pharmacology.

Ying-Xian Pan is a co-scientific founder of Sparian Biosciences that is an early stage pharmaceutical company whose first program is to develop a new class of analgesics, the arylepoxamides, for pain management.

Gavril W. Pasternak was a founder of Sparian Biosciences. He was also a consultant and/or speaker of Endo Pharmaceuticals, Confo Therapeutics, Nektar Therapeutics, Collegium Pharmaceuticals and Novartis.

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Authors and Affiliations

  1. Department of Neurology and Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Gavril W. Pasternak & Ying-Xian Pan

  2. Department of Physiology/Pharmacology, Wake Forest School of Medicine, Winston-Salem, NC, USA

    Steven R. Childers

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  1. Gavril W. Pasternak
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Correspondence to Steven R. Childers or Ying-Xian Pan .

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  1. Wake Forest School of Medicine, Winston-Salem, NC, USA

    Michael A. Nader

  2. Addiction Institute of Mount Sinai, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Yasmin L. Hurd

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Pasternak, G.W., Childers, S.R., Pan, YX. (2019). Emerging Insights into Mu Opioid Pharmacology. In: Nader, M., Hurd, Y. (eds) Substance Use Disorders. Handbook of Experimental Pharmacology, vol 258. Springer, Cham. https://doi.org/10.1007/164_2019_270

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