Bradykinin B2 Receptor Triggers ITPR1-Mediated ER Calcium Release in Trigeminal Ganglion Neurons to Drive Trigeminal Neuropathic Pain.

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Abstract
To elucidate the role and underlying mechanism of bradykinin (BK) B2 receptor and its downstream inositol 1,4,5-trisphosphate receptor type 1 (ITPR1)-mediated endoplasmic reticulum (ER) calcium release signaling in the development and maintenance of trigeminal neuropathic pain. A partial infraorbital nerve transection (pIONT) mouse model of trigeminal neuralgia was employed. Mechanical allodynia was assessed using von Frey filaments. The expression and localization of BK, B2 receptor, and related molecules in the trigeminal ganglion (TG) were analyzed by quantitative real-time PCR (qPCR), Western blot, and immunofluorescence staining. Whole-cell patch-clamp recordings were performed to evaluate TG neuronal excitability. Intracellular calcium signals induced by BK were monitored through Fluo-4 AM calcium imaging. Pharmacological and genetic interventions were conducted via local TG injection of B2 receptor antagonist Icatibant, ITPR1 inhibitor 2-APB, and Itpr1-siRNA. pIONT induced persistent facial mechanical allodynia in mice, accompanied by a significant upregulation of BK mRNA and B2 receptor expression in the TG, which was primarily localized to myelinated neurons (NF200+), peptidergic neurons (CGRP+), and non-peptidergic neurons (IB4+). Local injection of Icatibant into the TG significantly alleviated mechanical nociceptive responses and reduced the hyperexcitability of nociceptive neurons. Calcium imaging showed that BK evoked ITPR1-dependent ER calcium release in TG neurons, which was abolished by both 2-APB and Itpr1-siRNA. Co-application of 2-APB also reversed BK-induced neuronal hyperexcitability and attenuated facial withdrawal responses. Following peripheral nerve injury, the B2 receptor-ITPR1 signaling mediated ER calcium release represents an essential mechanism underlying the development and maintenance of trigeminal neuropathic pain. Targeting this signaling pathway effectively attenuates peripheral neuronal hyperexcitability, providing novel experimental evidence and potential therapeutic targets for the management of trigeminal neuralgia.
Funding Information
  • National Natural Science Foundation of China (NSFC 82471249)
  • National Natural Science Foundation of China (82271256)
  • QING-LAN Project of Jiangsu Province

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