Biased agonists of the kappa opioid receptor suppress pain and itch without causing sedation or dysphoria

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  • Brust, Tarsis F.
    • Other Affiliation: Departments of Molecular Therapeutics and Neuroscience; Scripps Research Institute
  • Morgenweck, Jenny
    • Other Affiliation: Departments of Molecular Therapeutics and Neuroscience; Scripps Research Institute
  • Kim, Susy A.
    • Other Affiliation: Department of Anesthesiology; Wake Forest School of Medicine
  • Rose, Jamie H.
    • Other Affiliation: Department of Physiology and Pharmacology; Wake Forest School of Medicine
  • Locke, Jason L.
    • Other Affiliation: Department of Physiology and Pharmacology; Wake Forest School of Medicine
  • Schmid, Cullen L.
    • Other Affiliation: Departments of Molecular Therapeutics and Neuroscience; Scripps Research Institute
  • Zhou, Lei
    • Other Affiliation: Departments of Molecular Therapeutics and Neuroscience; Scripps Research Institute
  • Stahl, Edward L.
    • Other Affiliation: Departments of Molecular Therapeutics and Neuroscience; Scripps Research Institute
  • Cameron, Michael D.
    • Other Affiliation: Departments of Molecular Therapeutics and Neuroscience; Scripps Research Institute
  • Scarry, Sarah M.
    • Eshelman School of Pharmacy, Division of Chemical Biology and Medicinal Chemistry
  • Aubé, Jeffrey
    • Eshelman School of Pharmacy, Division of Chemical Biology and Medicinal Chemistry
  • Jones, Sara R.
    • Other Affiliation: Department of Physiology and Pharmacology; Wake Forest School of Medicine
  • Martin, Thomas J.
    • Other Affiliation: Department of Anesthesiology; Wake Forest School of Medicine
  • Bohn, Laura M.
    • Other Affiliation: Departments of Molecular Therapeutics and Neuroscience; Scripps Research Institute
Abstract
  • Agonists targeting the kappa opioid receptor (KOR) have been promising therapeutic candidates because of their efficacy for treating intractable itch and relieving pain. Unlike typical opioid narcotics, KOR agonists do not produce euphoria or lead to respiratory suppression or overdose. However, they do produce dysphoria and sedation, side effects that have precluded their clinical development as therapeutics. KOR signaling can be fine-tuned to preferentially activate certain pathways over others, such that agonists can bias signaling so that the receptor signals through G proteins rather than other effectors such as βarrestin2. We evaluated a newly developed G protein signaling–biased KOR agonist in preclinical models of pain, pruritis, sedation, dopamine regulation, and dysphoria. We found that triazole 1.1 retained the antinociceptive and antipruritic efficacies of a conventional KOR agonist, yet it did not induce sedation or reductions in dopamine release in mice, nor did it produce dysphoria as determined by intracranial self-stimulation in rats. These data demonstrated that biased agonists may be used to segregate physiological responses downstream of the receptor. Moreover, the findings suggest that biased KOR agonists may present a means to treat pain and intractable itch without the side effects of dysphoria and sedation and with reduced abuse potential.
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  • Article
Rights statement
  • In Copyright
Journal title
  • Science Signaling
Journal volume
  • 9
Journal issue
  • 456
Page start
  • ra117
Page end
  • ra117
Language
  • English
ISSN
  • 1937-9145
  • 1945-0877

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