The neuropeptide nociceptin/orphanin FQ (N/OFQ) can be released by stressors and is associated with disorders of emotion regulation and reward processing. N/OFQ and its receptor, NOP, are enriched in dopaminergic pathways, and intra-ventricular agonist delivery decreases dopamine levels in the dorsal striatum, nucleus accumbens (NAc), and ventral tegmental area (VTA). We used whole-cell electrophysiology in acute rat midbrain slices to investigate synaptic actions of N/OFQ. N/OFQ was primarily inhibitory, causing outward currents in both immunocytochemically identified dopaminergic (tyrosine hydroxylase positive (TH(+))) and non-dopaminergic (TH(–)) VTA neurons; effect at 1 μ m : 20 ± 4 pA. Surprisingly, this effect was mediated by augmentation of postsynaptic GABA A R currents, unlike the substantia nigra pars compacta (SNc), where the N/OFQ-induced outward currents were K + channel dependent. A smaller population, 17% of all VTA neurons, responded to low concentrations of N/OFQ with inward currents (10 n m : −11 ± 2 pA). Following 100 n m N/OFQ, the response to a second N/OFQ application was markedly diminished in VTA neurons (14 ± 10% of first response) but not in SNc neurons (90 ± 20% of first response). N/OFQ generated outward currents in medial prefrontal cortex (mPFC)-projecting VTA neurons, but inward currents in a subset of posterior anterior cingulate cortex (pACC)-projecting VTA neurons. While N/OFQ inhibited NAc-projecting VTA cell bodies, it had little effect on electrically or optogenetically evoked terminal dopamine release in the NAc measured ex vivo with fast scan cyclic voltammetry (FSCV). These results extend our understanding of the N/OFQ system in brainstem circuits implicated in many neurobehavioral disorders.

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.

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.

1The neuropeptide nociceptin/orphanin FQ (N/OFQ) system can be activated under 2 conditions of stress and is associated with disorders of emotional regulation and reward 3 processing. N/OFQ and its cognate receptor, NOP, are highly enriched in dopaminergic 4 pathways, and intra-ventricular agonist delivery decreases dopamine levels in the dorsal 5 striatum, nucleus accumbens (NAc), and the ventral tegmental area (VTA). We used whole cell 6 electrophysiology in acute rat brain slices to investigate synaptic actions of N/OFQ in VTA 7 neurons. Consistent with previous reports, we found that N/OFQ is primarily inhibitory, causing 8 outward currents in both immunocytochemically identified dopaminergic (tyrosine hydroxylase 9 positive (TH(+)) and non-dopaminergic (TH(-)) VTA neurons (effect at 1 µM: 20 ± 4 pA). A

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