title: Kappa Opioid Receptor-Induced Aversion Requires p38 MAPK Activation in VTA Dopamine Neurons.
abstract: The endogenous dynorphin-κ opioid receptor (KOR) system encodes the dysphoric component of the stress response and controls the risk of depression-like and addiction behaviors; however, the molecular and neural circuit mechanisms are not understood. In this study, we report that KOR activation of p38α MAPK in ventral tegmental (VTA) dopaminergic neurons was required for conditioned place aversion (CPA) in mice. Conditional genetic deletion of floxed KOR or floxed p38α MAPK by Cre recombinase expression in dopaminergic neurons blocked place aversion to the KOR agonist U50,488. Selective viral rescue by wild-type KOR expression in dopaminergic neurons of KOR(-/-) mice restored U50,488-CPA, whereas expression of a mutated form of KOR that could not initiate p38α MAPK activation did not. Surprisingly, while p38α MAPK inactivation blocked U50,488-CPA, p38α MAPK was not required for KOR inhibition of evoked dopamine release measured by fast scan cyclic voltammetry in the nucleus accumbens. In contrast, KOR activation acutely inhibited VTA dopaminergic neuron firing, and repeated exposure attenuated the opioid response. This adaptation to repeated exposure was blocked by conditional deletion of p38α MAPK, which also blocked KOR-induced tyrosine phosphorylation of the inwardly rectifying potassium channel (GIRK) subunit Kir3.1 in VTA dopaminergic neurons. Consistent with the reduced response, GIRK phosphorylation at this amino terminal tyrosine residue (Y12) enhances channel deactivation. Thus, contrary to prevailing expectations, these results suggest that κ opioid-induced aversion requires regulation of VTA dopaminergic neuron somatic excitability through a p38α MAPK effect on GIRK deactivation kinetics rather than by presynaptically inhibiting dopamine release.
  
  
  CONCLUSIONS
  Kappa opioid receptor (KOR) agonists have the potential to be effective, nonaddictive analgesics, but their therapeutic utility is greatly limited by adverse effects on mood. Understanding how KOR activation produces dysphoria is key to the development of better analgesics and to defining how the endogenous dynorphin opioids produce their depression-like effects. Results in this study show that the aversive effects of κ receptor activation required arrestin-dependent p38α MAPK activation in dopamine neurons but did not require inhibition of dopamine release in the nucleus accumbens. Thus, contrary to the prevailing view, inhibition of mesolimbic dopamine release does not mediate the aversive effects of KOR activation and functionally selective κ opioids that do not activate arrestin signaling may be effective analgesics lacking dysphoric effects.
authors.affiliation: Graduate Program in Neurobiology and Behavior, Department of Pharmacology, and.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Ehrich
authors.affiliation: Department of Pharmacology, and.
authors.forename: Daniel I
authors.initials: DI
authors.lastname: Messinger
authors.affiliation: Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington 98195, and.
authors.forename: Cerise R
authors.initials: CR
authors.lastname: Knakal
authors.affiliation: Department of Pharmacology, and.
authors.forename: Jamie R
authors.initials: JR
authors.lastname: Kuhar
authors.affiliation: Department of Pharmacology, and.
authors.forename: Selena S
authors.initials: SS
authors.lastname: Schattauer
authors.affiliation: Department of Pharmacology, and.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Bruchas
authors.affiliation: Graduate Program in Neurobiology and Behavior, Department of Pharmacology, and Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington 98195, and.
authors.forename: Larry S
authors.initials: LS
authors.lastname: Zweifel
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique/Institut National de la Santé et de la Recherche Médicale/Université de Strasbourg, Illkirch, France.
authors.forename: Brigitte L
authors.initials: BL
authors.lastname: Kieffer
authors.affiliation: Graduate Program in Neurobiology and Behavior, Department of Pharmacology, and Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington 98195, and.
authors.forename: Paul E M
authors.initials: PE
authors.lastname: Phillips
authors.affiliation: Graduate Program in Neurobiology and Behavior, Department of Pharmacology, and cchavkin@uw.edu.
authors.forename: Charles
authors.initials: C
authors.lastname: Chavkin
mesh_terms: D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer / Q000494:pharmacology; D000200:Action Potentials / Q000187:drug effects; D018712:Analgesics, Non-Narcotic / Q000494:pharmacology; D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects / Q000502:physiology*; D003214:Conditioning, Classical / Q000187:drug effects / Q000502:physiology; D004298:Dopamine / Q000378:metabolism / Q000502:physiology*; D059290:Dopaminergic Neurons / Q000502:physiology*; D004789:Enzyme Activation; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000378:metabolism; D055785:Gene Knockdown Techniques; D015640:Ion Channel Gating / Q000187:drug effects; D020935:MAP Kinase Signaling System / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009714:Nucleus Accumbens / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011188:Potassium / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D017473:Receptors, Opioid, kappa / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D045442:Rotarod Performance Test; D059326:Serotonergic Neurons / Q000502:physiology; D017557:Ventral Tegmental Area / Q000166:cytology / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
chemical_list: D018712:Analgesics, Non-Narcotic; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D017473:Receptors, Opioid, kappa; D011993:Recombinant Fusion Proteins; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D048051:p38 Mitogen-Activated Protein Kinases; D011188:Potassium; D004298:Dopamine
keywords: GIRK; depression; dopamine; dynorphin; kappa opioid receptor; stress