RT Journal Article
SR Electronic
T1 A diencephalic circuit for opioid analgesia but not positive reinforcement
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.12.15.422931
DO 10.1101/2020.12.15.422931
A1 Maggie W. Waung
A1 Kayla A. Maanum
A1 Joseph R. Driscoll
A1 Chris O’Brien
A1 Svetlana Bryant
A1 Kasra Mansourian
A1 Marisela Morales
A1 David J. Barker
A1 Elyssa B. Margolis
YR 2020
UL http://biorxiv.org/content/early/2020/12/15/2020.12.15.422931.abstract
AB Mu opioid receptor (MOR) agonists are the most effective analgesics, but their use risks respiratory depression and addiction. The epithalamic lateral habenula (LHb) is a critical site that signals aversive states, often via indirect inhibition of reward circuitry, and MORs are highly expressed in the LHb. We found that the LHb is a potent site for MOR-agonist analgesia. Strikingly, LHb MOR activation generates negative reinforcement but is not rewarding in the absence of noxious input. While the LHb receives inputs from multiple sites, we found that inputs from the lateral preoptic area of the hypothalamus (LPO) are excited by noxious stimulation, express MOR mRNA, and are preferentially targeted by MOR selective agonists. Critically, optogenetic stimulation of LHb-projecting LPO neurons produces an aversive state relieved by LHb MOR activation. Therefore targeting this MOR sensitive forebrain circuit can relieve pain yet lower the risk of misuse by pain free individuals.Competing Interest StatementThe authors have declared no competing interest.