Somatosensory cortex and central amygdala regulate neuropathic pain-mediated peripheral immune response via vagal projections to the spleen.

Pain involves neuroimmune crosstalk, but the mechanisms of this remain unclear. Here we showed that the splenic T helper 2 (T H 2) immune cell response is differentially regulated in male mice with acute versus chronic neuropathic pain and that acetylcholinergic neurons in the dorsal motor nucleus of the vagus (ACh DMV ) directly innervate the spleen. Combined in vivo recording and immune cell profiling revealed the following two distinct circuits involved in pain-mediated peripheral T H 2 immune response: glutamatergic neurons in the primary somatosensory cortex (Glu S1HL )→ACh DMV →spleen circuit and GABAergic neurons in the central nucleus of the amygdala (GABA CeA )→ACh DMV →spleen circuit. The acute pain condition elicits increased excitation from Glu S1HL neurons to spleen-projecting ACh DMV neurons and increased the proportion of splenic T H 2 immune cells. The chronic pain condition increased inhibition from GABA CeA neurons to spleen-projecting ACh DMV neurons and decreased splenic T H 2 immune cells. Our study thus demonstrates how the brain encodes pain-state-specific immune responses in the spleen.