Fig. 3.

Pain gateway reflex. In a transfer EAE-recovered mouse, induction of trigeminal pain by ligation of the infraorbital sensory nerve causes EAE relapse. In this condition, pathway carrying nociceptive information activates the ACC (1), a pain-processing area of the brain, which in turn stimulates sympathetic centers (2) and their neural output to the ventral spinal vessels (3). NE release around these vessels induces chemokine CX3CL1 expression from activated monocytes and endothelial cells (4). CX3CL1 recruits these activated monocytes around the ventral vessels in an autocrine/paracrine manner (5). Because the L5 spinal cord contains a high number of activated monocytes in EAE-recovered mice, the L5 region is most affected in terms of the accumulation of activated monocytes. Activated monocytes present MOG antigens to reactivate circulating pathogenic CD4+ T cells (6), thus causing their accumulation in the spinal cord and EAE relapse (7). Abbreviations: EAE, experimental autoimmune encephalomyelitis; ACC, anterior cingulate cortex; NE, norepinephrine; MOG, myelin oligodendrocyte glycoprotein; TG, trigeminal ganglion