title: Biased agonists of the kappa opioid receptor suppress pain and itch without causing sedation or dysphoria.
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.
authors.affiliation: Departments of Molecular Therapeutics and Neuroscience, The Scripps Research Institute, Jupiter, FL 33458, USA.
authors.forename: Tarsis F
authors.initials: TF
authors.lastname: Brust
authors.affiliation: Departments of Molecular Therapeutics and Neuroscience, The Scripps Research Institute, Jupiter, FL 33458, USA.
authors.forename: Jenny
authors.initials: J
authors.lastname: Morgenweck
authors.affiliation: Department of Anesthesiology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.
authors.forename: Susy A
authors.initials: SA
authors.lastname: Kim
authors.affiliation: Department of Physiology and Pharmacology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.
authors.forename: Jamie H
authors.initials: JH
authors.lastname: Rose
authors.affiliation: Department of Physiology and Pharmacology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.
authors.forename: Jason L
authors.initials: JL
authors.lastname: Locke
authors.affiliation: Departments of Molecular Therapeutics and Neuroscience, The Scripps Research Institute, Jupiter, FL 33458, USA.
authors.forename: Cullen L
authors.initials: CL
authors.lastname: Schmid
authors.affiliation: Departments of Molecular Therapeutics and Neuroscience, The Scripps Research Institute, Jupiter, FL 33458, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Departments of Molecular Therapeutics and Neuroscience, The Scripps Research Institute, Jupiter, FL 33458, USA.
authors.forename: Edward L
authors.initials: EL
authors.lastname: Stahl
authors.affiliation: Departments of Molecular Therapeutics and Neuroscience, The Scripps Research Institute, Jupiter, FL 33458, USA.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Cameron
authors.affiliation: Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Scarry
authors.affiliation: Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Aubé
authors.affiliation: Department of Physiology and Pharmacology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.
authors.forename: Sara R
authors.initials: SR
authors.lastname: Jones
authors.affiliation: Department of Anesthesiology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Martin
authors.affiliation: Departments of Molecular Therapeutics and Neuroscience, The Scripps Research Institute, Jupiter, FL 33458, USA. lbohn@scripps.edu.
authors.forename: Laura M
authors.initials: LM
authors.lastname: Bohn
mesh_terms: D000818:Animals; D008297:Male; D051379:Mice; D010146:Pain / Q000188:drug therapy* / Q000378:metabolism; D011537:Pruritus / Q000188:drug therapy* / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D017473:Receptors, Opioid, kappa / Q000819:agonists* / Q000378:metabolism; D014230:Triazoles / Q000737:chemistry / Q000494:pharmacology*; D000071560:beta-Arrestin 2 / Q000378:metabolism
chemical_list: C000605258:Arrb2 protein, mouse; D017473:Receptors, Opioid, kappa; D014230:Triazoles; D000071560:beta-Arrestin 2