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BACKGROUND: Mu opioid receptors (MORs) are key for reward processing, mostly studied in dopaminergic pathways. MORs are also expressed in the dorsal raphe nucleus (DRN), which is central for the modulation of reward and mood, but MOR function in the DRN remains underexplored. Here, we investigated whether MOR-expressing neurons of the DRN (DRN-MOR neurons) participate in reward and emotional responses. METHODS: We characterized DRN-MOR neurons anatomically using immunohistochemistry and functionally using fiber photometry in responses to morphine and rewarding/aversive stimuli. We tested the effect of opioid uncaging on the DRN on place conditioning. We examined the effect of DRN-MOR neuron optostimulation on positive reinforcement and mood-related behaviors. We mapped their projections and selected DRN-MOR neurons projecting to the lateral hypothalamus for a similar optogenetic experimentation. RESULTS: DRN-MOR neurons form a heterogeneous neuronal population essentially composed of GABAergic (gamma-aminobutyric acidergic) and glutamatergic neurons. Calcium activity of DRN-MOR neurons was inhibited by rewarding stimuli and morphine. Local photo-uncaging of oxymorphone in the DRN produced conditioned place preference. DRN-MOR neuron optostimulation triggered real-time place preference and was self-administered, promoted social preference, and reduced anxiety and passive coping. Finally, specific optostimulation of DRN-MOR neurons projecting to the lateral hypothalamus recapitulated the reinforcing effects of total DRN-MOR neuron stimulation. CONCLUSIONS: Our data show that DRN-MOR neurons respond to rewarding stimuli and that their optoactivation has reinforcing effects and promotes positive emotional responses, an activity which is partially mediated by their projections to the lateral hypothalamus. Our study also suggests a complex regulation of DRN activity by MOR opioids, involving mixed inhibition/activation mechanisms that fine-tune DRN function.

Pain associates both sensory and emotional aversive components, and often leads to anxiety and depression when it becomes chronic. Here, we characterized, in a mouse model, the long-term development of these sensory and aversive components as well as anxiodepressive-like consequences of neuropathic pain and determined their electrophysiological impact on the anterior cingulate cortex (ACC, cortical areas 24a/24b). We show that these symptoms of neuropathic pain evolve and recover in different time courses following nerve injury in male mice. In vivo electrophysiological recordings evidence an increased firing rate and bursting activity within the ACC when anxiodepressive-like consequences developed, and this hyperactivity persists beyond the period of mechanical hypersensitivity. Whole-cell patch-damp recordings also support ACC hyperactivity, as shown by increased excitatory postsynaptic transmission and contribution of NMDA receptors. Optogenetic inhibition of the ACC hyperactivity was sufficient to alleviate the aversive and anxiodepressive-like consequences of neuropathic pain, indicating that these consequences are underpinned by ACC hyperactivity. [ABSTRACT FROM AUTHOR]