title: Spinal dopaminergic projections control the transition to pathological pain plasticity via a D1/D5-mediated mechanism.
abstract: The mechanisms that lead to the maintenance of chronic pain states are poorly understood, but their elucidation could lead to new insights into how pain becomes chronic and how it can potentially be reversed. We investigated the role of spinal dorsal horn neurons and descending circuitry in plasticity mediating a transition to pathological pain plasticity suggesting the presence of a chronic pain state using hyperalgesic priming. We found that when dorsal horn neurokinin 1 receptor-positive neurons or descending serotonergic neurons were ablated before hyperalgesic priming, IL-6- and carrageenan-induced mechanical hypersensitivity was impaired, and subsequent prostaglandin E2 (PGE2) response was blunted. However, when these neurons were lesioned after the induction of priming, they had no effect on the PGE2 response, reflecting differential mechanisms driving plasticity in a primed state. In stark contrast, animals with a spinally applied dopaminergic lesion showed intact IL-6- and carrageenan-induced mechanical hypersensitivity, but the subsequent PGE2 injection failed to cause mechanical hypersensitivity. Moreover, ablating spinally projecting dopaminergic neurons after the resolution of the IL-6- or carrageenan-induced response also reversed the maintenance of priming as assessed through mechanical hypersensitivity and the mouse grimace scale. Pharmacological antagonism of spinal dopamine D1/D5 receptors reversed priming, whereas D1/D5 agonists induced mechanical hypersensitivity exclusively in primed mice. Strikingly, engagement of D1/D5 coupled with anisomycin in primed animals reversed a chronic pain state, consistent with reconsolidation-like effects in the spinal dorsal horn. These findings demonstrate a novel role for descending dopaminergic neurons in the maintenance of pathological pain plasticity.
authors.affiliation: Department of Pharmacology, University of Arizona, Tucson, Arizona 85721.
authors.forename: Ji-Young V
authors.initials: JY
authors.lastname: Kim
authors.affiliation: School of Behavioral and Brain Sciences, University of Texas at Dallas, Richardson, Texas 75080, and.
authors.forename: Dipti V
authors.initials: DV
authors.lastname: Tillu
authors.affiliation: Department of Psychology, University of Alabama at Birmingham, Birmingham, Alabama 35294.
authors.forename: Tammie L
authors.identifier: http://orcid.org/0000-0001-6002-597X
authors.initials: TL
authors.lastname: Quinn
authors.affiliation: Department of Pharmacology, University of Arizona, Tucson, Arizona 85721, School of Behavioral and Brain Sciences, University of Texas at Dallas, Richardson, Texas 75080, and.
authors.forename: Galo L
authors.initials: GL
authors.lastname: Mejia
authors.affiliation: Department of Pharmacology, University of Arizona, Tucson, Arizona 85721.
authors.forename: Adia
authors.initials: A
authors.lastname: Shy
authors.affiliation: Department of Pharmacology, University of Arizona, Tucson, Arizona 85721, School of Behavioral and Brain Sciences, University of Texas at Dallas, Richardson, Texas 75080, and.
authors.forename: Marina N K
authors.initials: MN
authors.lastname: Asiedu
authors.affiliation: Department of Pharmacology, University of Arizona, Tucson, Arizona 85721.
authors.forename: Elaine
authors.initials: E
authors.lastname: Murad
authors.affiliation: Department of Psychology, University of Alabama at Birmingham, Birmingham, Alabama 35294.
authors.forename: Alan P
authors.identifier: http://orcid.org/0000-0002-6533-8120
authors.initials: AP
authors.lastname: Schumann
authors.affiliation: Department of Psychology, University of Alabama at Birmingham, Birmingham, Alabama 35294.
authors.forename: Stacie K
authors.initials: SK
authors.lastname: Totsch
authors.affiliation: Department of Psychology, University of Alabama at Birmingham, Birmingham, Alabama 35294.
authors.forename: Robert E
authors.identifier: http://orcid.org/0000-0003-4989-9697
authors.initials: RE
authors.lastname: Sorge
authors.affiliation: Department of Pharmacology, University of Arizona, Tucson, Arizona 85721.
authors.forename: Patrick W
authors.initials: PW
authors.lastname: Mantyh
authors.affiliation: Department of Pharmacology, University of Arizona, Tucson, Arizona 85721, School of Behavioral and Brain Sciences, University of Texas at Dallas, Richardson, Texas 75080, and.
authors.forename: Gregory
authors.initials: G
authors.lastname: Dussor
authors.affiliation: Department of Pharmacology, University of Arizona, Tucson, Arizona 85721, School of Behavioral and Brain Sciences, University of Texas at Dallas, Richardson, Texas 75080, and theodore.price@utdallas.edu.
authors.forename: Theodore J
authors.initials: TJ
authors.lastname: Price
mesh_terms: D000818:Animals; D001552:Benzazepines / Q000494:pharmacology; D002351:Carrageenan / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism / Q000494:pharmacology; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000502:physiology*; D006930:Hyperalgesia / Q000139:chemically induced; D015850:Interleukin-6 / Q000494:pharmacology; D008297:Male; D051379:Mice; D020671:Posterior Horn Cells / Q000187:drug effects / Q000502:physiology*; D017447:Receptors, Dopamine D1 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000502:physiology*; D050641:Receptors, Dopamine D5 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000502:physiology*; D018040:Receptors, Neurokinin-1 / Q000502:physiology*; D059326:Serotonergic Neurons / Q000502:physiology; D013469:Sulpiride / Q000494:pharmacology
chemical_list: D001552:Benzazepines; D015850:Interleukin-6; D017447:Receptors, Dopamine D1; D018040:Receptors, Neurokinin-1; C534628:SCH 23390; D050641:Receptors, Dopamine D5; D013469:Sulpiride; D002351:Carrageenan; D015232:Dinoprostone
keywords: chronic pain; descending modulation; dopamine; nociceptive plasticity; reconsolidation; substance P