title: Mu Opioid Receptor Modulation of Dopamine Neurons in the Periaqueductal Gray/Dorsal Raphe: A Role in Regulation of Pain.
abstract: The periaqueductal gray (PAG) is a brain region involved in nociception modulation, and an important relay center for the descending nociceptive pathway through the rostral ventral lateral medulla. Given the dense expression of mu opioid receptors and the role of dopamine in pain, the recently characterized dopamine neurons in the ventral PAG (vPAG)/dorsal raphe (DR) region are a potentially critical site for the antinociceptive actions of opioids. The objectives of this study were to (1) evaluate synaptic modulation of the vPAG/DR dopamine neurons by mu opioid receptors and to (2) dissect the anatomy and neurochemistry of these neurons, in order to assess the downstream loci and functions of their activation. Using a mouse line that expresses eGFP under control of the tyrosine hydroxylase (TH) promoter, we found that mu opioid receptor activation led to a decrease in inhibitory inputs onto the vPAG/DR dopamine neurons. Furthermore, combining immunohistochemistry, optogenetics, electrophysiology, and fast-scan cyclic voltammetry in a TH-cre mouse line, we demonstrated that these neurons also express the vesicular glutamate type 2 transporter and co-release dopamine and glutamate in a major downstream projection structure-the bed nucleus of the stria terminalis. Finally, activation of TH-positive neurons in the vPAG/DR using Gq designer receptors exclusively activated by designer drugs displayed a supraspinal, but not spinal, antinociceptive effect. These results indicate that vPAG/DR dopamine neurons likely play a key role in opiate antinociception, potentially via the activation of downstream structures through dopamine and glutamate release.
authors.affiliation: Neurobiology Curriculum, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.|Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Chia
authors.initials: C
authors.lastname: Li
authors.affiliation: Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.|Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Sugam
authors.affiliation: Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.|Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Emily G
authors.initials: EG
authors.lastname: Lowery-Gionta
authors.affiliation: Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.|Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Zoe A
authors.initials: ZA
authors.lastname: McElligott
authors.affiliation: Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.|Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Nora M
authors.initials: NM
authors.lastname: McCall
authors.affiliation: Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.|Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Alberto J
authors.initials: AJ
authors.lastname: Lopez
authors.affiliation: Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.|Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Jessica M
authors.initials: JM
authors.lastname: McKlveen
authors.affiliation: Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.|Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Kristen E
authors.initials: KE
authors.lastname: Pleil
authors.affiliation: Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.|Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Thomas L
authors.identifier: 0000-0002-4747-4495
authors.initials: TL
authors.lastname: Kash
mesh_terms: D000818:Animals; D004298:Dopamine / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000737:chemistry / Q000502:physiology*; D065847:Dorsal Raphe Nucleus / Q000737:chemistry / Q000502:physiology*; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000008:administration & dosage; D018698:Glutamic Acid / Q000378:metabolism; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D058748:Pain Perception / Q000502:physiology*; D010487:Periaqueductal Gray / Q000737:chemistry / Q000502:physiology*; D017450:Receptors, Opioid, mu / Q000819:agonists / Q000502:physiology*; D012686:Septal Nuclei / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D017450:Receptors, Opioid, mu; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D018698:Glutamic Acid; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine