A diencephalic circuit in rats for opioid analgesia but not positive reinforcement

Author:

Waung Maggie W.,Maanum Kayla A.,Cirino Thomas J.,Driscoll Joseph R.,O’Brien ChrisORCID,Bryant Svetlana,Mansourian Kasra A.,Morales MariselaORCID,Barker David J.,Margolis Elyssa B.ORCID

Abstract

AbstractMu opioid receptor (MOR) agonists are potent analgesics, but also cause sedation, respiratory depression, and addiction risk. The epithalamic lateral habenula (LHb) signals aversive states including pain, and here we found that it is a potent site for MOR-agonist analgesia-like responses in rats. Importantly, LHb MOR activation is not reinforcing in the absence of noxious input. The LHb receives excitatory inputs from multiple sites including the ventral tegmental area, lateral hypothalamus, entopeduncular nucleus, and the lateral preoptic area of the hypothalamus (LPO). Here we report that LHb-projecting glutamatergic LPO neurons are excited by noxious stimulation and are preferentially inhibited by MOR selective agonists. Critically, optogenetic stimulation of LHb-projecting LPO neurons produces an aversive state that is relieved by LHb MOR activation, and optogenetic inhibition of LHb-projecting LPO neurons relieves the aversiveness of ongoing pain.

Funder

U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke

U.S. Department of Health & Human Services | NIH | National Institute on Drug Abuse

Publisher

Springer Science and Business Media LLC

Subject

General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary

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