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

Abstract

Pain involves neuroimmune crosstalk, but the mechanisms of this remain unclear. Here we showed that the splenic T helper 2 (T_H2) 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_H2 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_H2 immune cells. The chronic pain condition increased inhibition from GABA^CeA neurons to spleen-projecting ACh^DMV neurons and decreased splenic T_H2 immune cells. Our study thus demonstrates how the brain encodes pain-state-specific immune responses in the spleen.