Although brain-derived neurotrophic factor (BDNF) is implicated in the nociceptive signaling of peripheral sensory neurons, the underlying mechanisms remain largely unknown. Here, we elucidated the effects of BDNF on the neuronal excitability of trigeminal ganglion (TG) neurons and the pain sensitivity of rats mediated by T-type Ca²⁺ channels. BDNF reversibly and dose-dependently enhanced T-type channel currents through the activation of tropomyosin receptor kinase B (TrkB). Antagonism of phosphatidylinositol 3-kinase (PI3K) but not of its downstream target, the kinase AKT, abolished the BDNF-induced T-type channel response. BDNF application activated p38 mitogen-activated protein kinase (MAPK), and this effect was prevented by inhibition of PI3K but not of protein kinase A (PKA). Antagonism of either PI3K or p38 MAPK prevented the BDNF-induced stimulation of PKA activity, whereas PKA inhibition blocked the BDNF-mediated increase in T-type currents. BDNF increased the rate of action potential firing in TG neurons and enhanced the pain sensitivity of rats to mechanical stimuli. Moreover, inhibition of TrkB signaling abolished the increased mechanical sensitivity in a rat model of chronic inflammatory pain, and this effect was attenuated by either T-type channel blockade or knockdown of the channel Ca_v3.2. Together, our findings indicate that BDNF enhances T-type currents through the stimulation of TrkB coupled to PI3K-p38-PKA signaling, thereby inducing neuronal hyperexcitability of TG neurons and pain hypersensitivity in rats.

尽管脑源性神经营养因子（BDNF）牵涉到周围感觉神经元的伤害性信号传导中，但其潜在机制仍是未知之数。在这里，我们阐明了BDNF对三叉神经节（TG）神经元神经元兴奋性的影响以及T型Ca ²⁺介导的大鼠的疼痛敏感性渠道。BDNF通过原肌球蛋白受体激酶B（TrkB）的激活可逆地且剂量依赖性地增强T型通道电流。磷脂酰肌醇3-激酶（PI3K）的拮抗作用而不是其下游靶标激酶AKT的拮抗作用消除了BDNF诱导的T型通道反应。BDNF的应用激活了p38丝裂原活化的蛋白激酶（MAPK），通过抑制PI3K而不是蛋白激酶A（PKA）可以阻止这种作用。PI3K或p38 MAPK的拮抗作用阻止了BDNF诱导的PKA活性刺激，而PKA抑制则阻止了BDNF介导的T型电流增加。BDNF增加了TG神经元的动作电位放电速率，并增强了大鼠对机械刺激的疼痛敏感性。而且，_v 3.2。在一起，我们的研究结果表明BDNF通过刺激TrkB偶联PI3K-p38-PKA信号增强T型电流，从而诱导TG神经元的神经元过度兴奋和大鼠疼痛超敏反应。