A hyperexcitable state and spontaneous activity of nociceptors have been suggested to play a critical role in the development of chronic neuropathic pain following spinal cord injury (SCI). In male rats, we employed the action potential-clamp technique to determine the underlying ionic mechanisms responsible for driving SCI-nociceptors to a hyperexcitable state and for triggering their spontaneous activity. We found that the increased activity of low voltage activated T-type calcium channels induced by the injury sustains the bulk (~60–70%) of the inward current active at subthreshold voltages during the interspike interval in SCI-nociceptors, with a modest contribution (~10–15%) from tetrodotoxin (TTX)-sensitive and TTX-resistant sodium channels and hyperpolarization-activated cyclic nucleotide-gated (HCN) channels. In current-clamp recordings, inhibition of T-type calcium channels with 1 μm TTA-P2 reduced both the spontaneous and the evoked firing in response to current injections in SCI-nociceptors to a level similar to sham-nociceptors. Electrophysiology in vitro was then combined with the conditioned place preference (CPP) paradigm to determine the relationship between the increased activity of T-type channels in SCI-nociceptors and chronic neuropathic pain following SCI. The size of the interspike T-type calcium current recorded from nociceptors isolated from SCI rats showing TTA-P2-induced CPP (responders) was ~6 fold greater than the interspike T-type calcium current recorded from nociceptors isolated from SCI rats without TTA-P2-induced CPP (non-responders). Taken together, our data suggest that the increased activity of T-type calcium channels induced by the injury plays a primary role in driving SCI-nociceptors to a hyperexcitable state and contributes to chronic neuropathic pain following SCI.

SIGNIFICANCE STATEMENT Chronic neuropathic pain is a major comorbidity of spinal cord injury (SCI), affecting up to 70–80% of patients. Anticonvulsant and tricyclic antidepressant drugs are first line analgesics used to treat SCI-induced neuropathic pain, but their efficacy is very limited. A hyperexcitable state and spontaneous activity of SCI-nociceptors have been proposed as a possible underlying cause for the development of chronic neuropathic pain following SCI. Here, we show that the increased activity of T-type calcium channels induced by the injury plays a major role in driving SCI-nociceptors to a hyperexcitable state and for promoting their spontaneous activity, suggesting that T-type calcium channels may represent a pharmacological target to treat SCI-induced neuropathic pain.

有人认为，伤害性感受器的过度兴奋状态和自发活动在脊髓损伤（SCI）后慢性神经性疼痛的发生中起关键作用。在雄性大鼠中，我们采用了动作电位钳技术来确定导致SCI伤害感受器进入高兴奋状态并触发其自发活动的潜在离子机制。我们发现，由损伤引起的低压激活的T型钙通道的活性增强，在SCI伤害感受器的尖峰间间隔期间，维持了在亚阈值电压下有效的内向电流的大部分（〜60–70％）。 （〜10–15％）来自河豚毒素（TTX）敏感和抗TTX的钠通道和超极化激活的环状核苷酸门控（HCN）通道。在电流钳记录中米TTA-P2响应于当前对SCI伤害感受器的注射，将自发性和诱发性射击均降低至类似于假伤害感受器的水平。体外电生理然后将其与条件性位置偏爱（CPP）范式结合，以确定SCI伤害感受器中T型通道活性增加与SCI引起的慢性神经性疼痛之间的关系。从显示出TTA-P2诱导的CPP的SCI大鼠的伤害感受器记录的突触T型钙电流的大小比从没有TTA-SCI的SCI大鼠的伤害感受器记录的突触T型钙电流的大小大约6倍。 P2诱导的CPP（无反应者）。综上所述，我们的数据表明，由损伤引起的T型钙通道活性增加在驱动SCI伤害感受器进入高兴奋性状态中起主要作用，并导致SCI后的慢性神经性疼痛。

重要声明慢性神经性疼痛是脊髓损伤（SCI）的主要合并症，影响70％至80％的患者。抗惊厥药和三环类抗抑郁药是用于治疗SCI引起的神经性疼痛的一线止痛药，但其疗效非常有限。SCI伤害感受器的过度兴奋状态和自发活动已被提出，可能是SCI引起慢性神经性疼痛发展的潜在根本原因。在这里，我们表明由损伤引起的T型钙通道活性的增加在驱动SCI伤害感受器进入高兴奋状态并促进其自发活动中起主要作用，这表明T型钙通道可能代表了药理学目标来治疗SCI引起的神经性疼痛。