A diencephalic circuit for opioid analgesia but not positive reinforcement

Abstract

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.

Glutamate inputs send prediction error of reward but not negative value of aversive stimuli to dopamine neurons

“…While opioids affect multiple sites in pain pathways, as well as reward pathways, in the brain [63][64][65] , we found that buprenorphine, a partial µ-opioid agonist/k-opioid antagonist, dramatically decreased inhibitory responses to an aversive stimulus in dopamine neurons but it did not affect their glutamate inputs. µ-opioid receptor expression is enriched in the RMTg and its direct and indirect upstream inputs such as the parabrachial nucleus (PBN), lHb, and the lateral preoptic area of the hypothalamus (LPO) 21,[32][33][34]66 , and µ-opioid receptor activation inhibits signaling of these neurons [51][52][53][54] . Thus, it is highly probable that opioids preferentially decrease inhibitory input to dopamine neurons and tip the excitatory-inhibitory balance of inputs to dopamine neurons towards excitation (Figure 8F).…”

“…If both glutamate inputs and GABA inputs are excited by aversive stimuli, and thus compete each other to shape dopamine responses, the dopamine responses to aversive stimuli may be flexibly altered by slight modulations in the relative strength of excitatory and inhibitory inputs, depending on an animal's state or context (Figure 7G). We focus here on one state alteration: the exogenous administration of opioids, common and effective analgesics which lead to an increase in dopamine excitability and inhibit some direct and indirect inputs to dopamine neurons [47][48][49][50][51][52][53][54] .…”