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Neuregulin-1-ErbB Signaling Promotes Microglia Activation Contributing to Mechanical Allodynia of Cyclophosphamide-Induced Cystitis

Neuregulin-1-ErbB Signaling Promotes Microglia Activation Contributing to Mechanical Allodynia of Cyclophosphamide-Induced Cystitis

Jia-Liang Chen, Xin Zhou, Hong-Lu Ding, Hai-Lun Zhan, Fei Yang, Wen-Biao Li, Jun-Cong Xie, Xian-Guo Liu, Yuan-Cheng Xu, Min-Zhi Su, Bo-Long Liu, Xiang-Fu Zhou

Neurourol Urodyn. 2019 Jun;38(5):1250-1260.

PMID: 30989724

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP194423159-B	PD168393		194423-15-9	Price

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