An Ascending Excitatory Circuit from the Dorsal Raphe for Sensory Modulation of Pain

The dorsal raphe nucleus (DRN) is an important nucleus in pain regulation. However, the underlying neural pathway and the function of specific cell types remain unclear. Here, we report a previously unrecognized ascending facilitation pathway, the DRN to mesoaccumbal dopamine (DA) circuit, for regulating pain. Chronic pain increased the activity of DRN glutamatergic, but not serotonergic, neurons projecting to the ventral tegmental area (VTA) (DRNGlu-VTA) in male mice. Optogenetic activation of DRNGlu-VTA circuit induced a pain-like response in naïve male mice and its inhibition produced analgesic effect in male mice with neuropathic pain. Furthermore, we discovered that DRN ascending pathway regulated pain through strengthened excitatory transmission onto the VTA DA neurons projecting to the ventral part of nucleus accumbens medial shell (vNAcMed), thereby activated the mesoaccumbal DA neurons. Correspondingly, optogenetic manipulation of this three-node pathway bilaterally regulated pain behaviors. These findings identified a DRN ascending excitatory pathway that is crucial for pain sensory processing, which can potentially be exploited toward targeting pain disorders.Significance StatementThe dorsal raphe nucleus (DRN) in the midbrain contributes to pain processing, yet the detailed cellular and circuitry mechanisms remain largely unknown. Here, we report that chronic pain increases the activity of a specific subpopulation of DRN glutamatergic neurons, which project to the ventral tegmental area (VTA). The elevated excitability of DRN glutamatergic neurons causes the increased excitatory inputs to VTA dopamine neurons that selectively innervate the ventral part of the nucleus accumbens medial shell (vNAcMed). Optogenetic activation of the DRN-VTA-vNAcMed pathway induced neuronal plasticity in the VTA and resulted in pain hypersensitivity. These findings shed light on how ascending DRN excitatory circuit is involved in the sensory modulation of pain.