Visceral‐somatic cross‐sensitization involves increased serotonergic innervation of lumbar dorsal root ganglia (DRG)

Abstract

One of the physiological functions of 5-hydroxytryptamine (5-HT) is its modulatory role in pain perception. Release of 5-HT by serotonergic neurons causes either pro- or anti-nociceptive action by binding to different subtypes of 5-HT receptors. Here we examined the L5 DRG for serotonergic innervation in two rat models of visceral inflammation-associated somatic hypersensitivity, namely trinitrobenzenesulfonic acid (TNBS)-induced colitis and cyclophosphamide (CYP)-induced cystitis. We found that cystitis at 8h and 48h post CYP injection caused 4 to 5-fold increases, while colitis at 7 and 21 days caused 1.5 to 2-fold increases in axonal outgrowth visualized by sucrose-potassium phosphate-glyoxylic acid (SPG) staining which was associated with sympathetic sprouting and serotonergic innervation. 5-HT immunostaining revealed “beaded” fibers – presumably small and regularly spaced varicosities. The number and density of the 5-HT fibers were time-dependently increased in DRG of both models. The excitatory effects of 5-HT was examined by immunostaining of 5-HT4, a Gs-protein coupled serotonin receptor, and showed marked increases in the number of 5-HT4 cells in colitis by 1.5 to 2.3-fold, and in cystitis by 2-fold. These results suggest that serotonin/5-HT4-mediated sensory hypersensitivity may have a role in visceral inflammation-induced somatic cross-sensitization. Grant support: NIH DK077917