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The rostromedial tegmental nucleus: a key modulator of pain and opioid analgesia

Taylor, Norman E.a,*; Long, Hub,d; Pei, JunZhuc; Kukutla, Phanidhard; Phero, Anthonya; Hadaegh, Farnazd; Abdelnabi, Ahmedd; Solt, Kend; Brenner, Gary J.d

doi: 10.1097/j.pain.0000000000001647
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A recently defined structure, the rostromedial tegmental nucleus (RMTg; aka tail of the ventral tegmental area [VTA]), has been proposed as an inhibitory control center for dopaminergic activity of the VTA. This region is composed of GABAergic cells that send afferent projections to the ventral midbrain and synapse onto dopaminergic cells in the VTA and substantia nigra. These cells exhibit µ-opioid receptor immunoreactivity, and in vivo, ex vivo, and optogenetic/electrophysiological approaches demonstrate that morphine excites dopamine neurons by targeting receptors on GABAergic neurons localized in the RMTg. This suggests that the RMTg may be a key modulator of opioid effects and a major brake regulating VTA dopamine systems. However, no study has directly manipulated RMTg GABAergic neurons in vivo and assessed the effect on nociception or opioid analgesia. In this study, multiplexing of GABAergic neurons in the RMTg was achieved using stimulatory Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) and inhibitory kappa-opioid receptor DREADDs (KORD). Our data show that locally infused RMTg morphine or selective RMTg GABAergic neuron inhibition produces 87% of the maximal antinociceptive effect of systemic morphine, and RMTg GABAergic neurons modulate dopamine release in the nucleus accumbens. In addition, chemoactivation of VTA dopamine neurons significantly reduced pain behaviors both in resting and facilitated pain states and reduced by 75% the dose of systemic morphine required to produce maximal antinociception. These results provide compelling evidence that RMTg GABAergic neurons are involved in processing of nociceptive information and are important mediators of opioid analgesia.

RMTg GABAergic neurons are important mediators of opioid analgesia and nociception, in part through actions on ventral tegmental area dopamine neurons.

aDepartment of Anesthesiology, University of Utah, Salt Lake City, UT, United States

bDepartment of Dentistry, West China Hospital of Stomatology, Sichuan University Chengdu, China

cDepartment of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA, United States

dDepartment of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Boston, MA, United States

*Corresponding author. Address: Department of Anesthesiology, University of Utah School of Medicine, 30 North 1900 East, SOM 3C444, Salt Lake City, UT 84132-2304, United States. Tel.: (801) 581-6393. E-mail address: norman.taylor@hsc.utah.edu (N.E. Taylor).

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.painjournalonline.com).

N.E. Taylor and H. Long contributed equally to this work.

© 2019 International Association for the Study of Pain
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