Original Article

Neuropsychopharmacology (2016) 41, 2122–2132; doi:10.1038/npp.2016.12; published online 27 April 2016

Mu Opioid Receptor Modulation of Dopamine Neurons in the Periaqueductal Gray/Dorsal Raphe: A Role in Regulation of Pain

Chia Li1,2,5, Jonathan A Sugam2,3,5, Emily G Lowery-Gionta2,3, Zoe A McElligott2,4, Nora M McCall2,3, Alberto J Lopez2,3, Jessica M McKlveen2,3, Kristen E Pleil2,3 and Thomas L Kash2,3

  1. 1Neurobiology Curriculum, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
  2. 2Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
  3. 3Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
  4. 4Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

Correspondence: Dr TL Kash, Department of Pharmacology, Bowles Center for Alcohol Studies, CB 7178, University of North Carolina at Chapel Hill, 104 Manning Drive, Chapel Hill, NC 27599, USA, Tel: +1 9198437867, Fax: +1 9199665640, E-mail: tkash@email.unc.edu

5These two authors contributed equally to this work.

Received 22 April 2015; Revised 8 January 2016; Accepted 8 January 2016
Accepted article preview online 21 January 2016; Advance online publication 27 April 2016



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.

Extra navigation