神經病變痛起因於體感覺系統損傷或病變後所誘發的痛覺過度敏感和觸摸痛的症狀。在神經病變痛患者中利用高頻率神經電刺激來舒緩疼痛已被廣泛運用，然而高頻率神經電刺激的治療仍存有缺失，包含感覺異常及止痛效果無法持久。此外近期有些研究顯示，低頻率神經電刺激在發炎疾病的動物模型中能有效降低發炎反應，同時也可以藉由活化血清素路徑(serotonergic pathway) 來調控下行疼痛抑制系統(descending pain inhibitory system) 進而抑制疼痛。據此，本論文旨在探討低頻率坐骨神經電刺激對於神經病變痛大鼠的神經調節作用。本實驗使用第五腰椎神經結紮術(L5 spinal nerve ligation) 建立神經病變痛之大鼠模型，術後隨即分別施予 2 赫茲、20 赫茲及 60 赫茲坐骨神經電刺激。術後 7 天結果顯示，2 赫茲與 20 赫茲的坐骨神經電刺激能有效緩解神經結紮造成的痛覺過敏現象，此外，在探討神經發炎的結果顯示，2 赫茲與 20 赫茲坐骨神經電刺激能降低傷側脊髓背角中的發炎激素，也能抑制神經損傷造成的星狀膠細胞及微膠細胞活化現象。並進一步確認坐骨神經電刺激對於下行疼痛抑制系統的反應，我們在腦幹區域的頭腹內側延腦 (rostral ventromedial medulla) 進行血清素神經元(serotonergic neuron)的螢光免疫染色，實驗結果顯示，經 20 赫茲坐骨神經電刺激後，頭腹內側延腦的血清素神經元有活化之情形。總而言之，本研究發現 2 赫茲與 20 赫茲坐骨神經電刺激透過降低發炎反應及活化下行疼痛抑制路徑來緩解神經結紮術造成的神經病變痛。

Neuropathic pain is derived from a lesion or disease of the somatosensory nervous system, resulting in hyperalgesia and allodynia. Among the current treatment modalities, high-frequency (HF) electrical nerve stimulation is widely used in clinical settings. However, HF stimulation exhibits drawbacks, including the inducement of paresthesia and short-term analgesic effect. Recent studies showed that low-frequency (LF) nerve stimulation not only exerts anti-inflammatory effect on various inflammatory disease models but also modulates the descending pain inhibitory system by upregulating the serotonergic pathway to attenuate the conduction of pain signals. Consequently, we hypothesize that the LF sciatic nerve stimulation can attenuate neuroinflammation and activate the descending pain inhibitory system to prevent pain hypersensitivity. In this study, neuropathic rats were induced by L5 spinal nerve ligation (SNL) and randomly divided into sham, SNL with sham stimulation, and 2 Hz, 20 Hz and 60 Hz with the intensity in the range of 0.1-1.0 mA electrical stimulation groups. The results indicated that 2 Hz and 20 Hz but not 60 Hz electrical stimulation can attenuate pain hypersensitivity for at least 7 days. At the spinal level, the inflammatory cytokines of NF-κB, IL-6, IL-1β and TNF-α and the activation of gliosis were suppressed by the 2 Hz and 20 Hz treatment on 7 days post-SNL, which is in contrast the observation with the 60 Hz group. At the supraspinal level, the expressions of serotonergic neuron in rostral ventromedial medulla were upregulated after 20 Hz electrical stimulation. Based on the current results, a 2 Hz and 20 Hz electrical stimulation can promote the analgesic effect with neuropathic pain via anti-inflammation and activating the descending pain inhibitory system. Therefore, LF electrical stimulation could be translated into a new therapeutic modality for neuropathic pain clinically.

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