Neuregulin‐1‐ErbB signaling promotes microglia activation contributing to mechanical allodynia of cyclophosphamide‐induced cystitis

Abstract Aims Central sensitization playsimportant roles in cyclophosphamide (CYP)‐induced cystitis. In addition, as a visceral pain, CYP‐induced chronic pain shares common pathophysiological mechanisms with neuropathic pain. Previous studies demonstrated that neuregulin‐1 (Nrg1)‐ErbB signaling contributes to neuropathic pain, but whether and how this signaling influences mechanical allodynia in CYP‐induced cystitis is unclear. This study aimed to determine whether and how Nrg1‐ErbB signaling modulates mechanical allodynia in a CYP‐induced cystitis rat model. Methods Systemic injection with CYP was used to establish a rat model of bladder pain syndrome/interstitial cystitis (BPS/IC). An irreversible ErbB family receptor inhibitor, PD168393, and exogenous Nrg1 were intrathecally injected to modulate Nrg1‐ErbB signaling. Mechanical allodynia in the lower abdomen was assessed with von‐Frey filaments using the up‐down method. Western blot analysis and immunofluorescence staining were used to measure the expression of Nrg1‐ErbB signaling, Iba‐1, p ‐p38, and IL‐1β in the L6‐S1 spinal dorsal horn (SDH). Results We observed upregulation of Nrg1‐ErbB signaling as well as overexpression of the microglia activation markers Iba‐1 and p ‐p38 and the proinflammatory factor, interleukin‐1β (IL‐1β), in the SDH of the cystitis group. Further, treatment with PD168393 attenuated mechanical allodynia in CYP‐induced cystitis and inhibited microglia activation, leading to decreased production of IL‐1β. The inhibitor PD168393 reversed the algesic effect of exogenous Nrg1 on the cystitis model. Conclusions Nrg1‐ErbB signaling may promote microglia activation, contributing to mechanical allodynia of CYP‐induced cystitis. Our study showed that modulation of Nrg1‐ErbB signaling may have therapeutic value for treating pain symptoms in BPS/IC.