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.
bioRxiv Subject Collection: Neuroscience