TY - JOUR
T1 - A diencephalic circuit in rats for opioid analgesia but not positive reinforcement
AU - Waung, Maggie W.
AU - Maanum, Kayla A.
AU - Cirino, Thomas J.
AU - Driscoll, Joseph R.
AU - O’Brien, Chris
AU - Bryant, Svetlana
AU - Mansourian, Kasra A.
AU - Morales, Marisela
AU - Barker, David J.
AU - Margolis, Elyssa B.
N1 - Funding Information:
The authors would like to thank Ryan Carothers, Gabrielle Mintz, Lucy He, Venkateswaran Ganesh, and Benjamin Snyder for their technical assistance with histology, stereotaxic surgeries, and behavioral studies. We also thank Allan Basbaum for feedback on the manuscript. This work was supported by National Institutes of Health grants R01DA042025 (to E.B.M.), K08 NS097632 (to M.W.W.), the Intramural Research Program (IRP) of the National Institute on Drug Abuse (IRP/NIDA/NIH), and a NIDA K99/R00 pathway to independence award (DA043572) to D.J.B.
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - Mu 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.
AB - Mu 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.
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U2 - 10.1038/s41467-022-28332-6
DO - 10.1038/s41467-022-28332-6
M3 - Article
C2 - 35140231
AN - SCOPUS:85124286093
VL - 13
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 764
ER -