- 學位論文
電針風池穴對癲癇及癲癇誘發之睡眠障礙的作用
Electroacupuncture of Feng-Chi acupoints on epilepsy and epilepsy-induced sleep disruptions
摘要
臨床和實驗上證實，睡眠和癲癇二者會相互影響，癲癇病人通常會有夜間失眠和白天嗜睡等睡眠障礙。睡眠已知是經由兩個因子來調控: 一、恆定因子 (homeostatic factors)，它和睡眠調控物質有關；二、週期節律因子 (circadian rhythm)。目前為止，我們尚不清楚，當癲癇發作在不同時間點 (zeitgeber times; ZTs) 時，是因受到何種因素影響而導致產生不同的睡眠問題。在第一章的實驗裡，我們在不同時間點，即 ZT0 和 ZT13，利用 kindling 誘發大鼠產生癲癇，藉此來探討大鼠的睡眠會產生何種變化，而這些變化又是經由甚麼機制來調控。我們發現在 ZT0 kindling 的大鼠，會降低其 rapid eye movement (REM; 快速動眼期) 和 non-REM (NREM; 非快速動眼期) 睡眠，而這些反映主要是經由增加 corticotropine-releasing hormone (CRH) 作用而來。在 ZT13 kindling 的大鼠，則會增加 interleukin-1 (IL-1) 的表現量進而增加非快速動眼期睡眠。從這些結果我們推論，在不同時間點誘發老鼠產生癲癇會改變不同的睡眠恆定因子，進而產生不同的睡眠障礙。 假若有一種治療模式既可以抑制癲癇又可以改善睡眠障礙，那麼它將是治療癲癇的優先選擇。在中國古籍靈樞經上有記載，針灸風池穴可以抑制癲癇產生和改善失眠症狀，然而這些記載卻缺乏科學證實，因此在第二章裡我們使用腦內注射的方式將 pilocarpine 注射進入大鼠的左側杏仁核，誘發老鼠產生癲癇，並在兩側風池穴給予不同頻率的電針刺激，藉此來觀察其抗癲癇作用。實驗發現給予 100 Hz 電針刺激不但不能抑制 pilocarpine 引起的癲癇，反而更進一步惡化癲癇，並且這些現象皆可被鴉片受體拮抗劑，例如: naloxone、naloxonazine、nor-binaltorphimine 和naltrindole 等阻斷，因此我們推論 100 Hz 電針刺激風池穴會惡化癲癇的作用是經由杏仁核上的鴉片受體所產生的。 第三章裡我們一樣將 pilocarpine 打入大鼠左側杏仁核內誘發局部癲癇的產生，同時在兩側風池穴給予 100 Hz 電針刺激，藉此來觀察對睡眠的作用。結果發現大鼠的非快速動眼期睡眠和快速動眼期睡眠兩者皆減少，並且這些睡眠減少的現象可以被鴉片受體拮抗劑，例如: naloxone、naloxonazine、nor-binaltorphimine和naltrindole 等阻斷。因此我們推論 100 Hz 電針刺激風池穴會經由杏仁核上的鴉片受體去進一步惡化癲癇老鼠的睡眠。 第四章裡我們在癲癇老鼠之兩側風池穴給予 10 Hz 刺激，觀察 10 Hz 電針刺激是否具有抗癲癇及改善睡眠的作用。實驗結果發現：由 pilocarpine 誘發癲癇發作的大鼠，若給予 10 Hz 電針刺激，則會抑制癲癇發作，而且此抗癲癇的作用會被 naloxone 阻斷。10 Hz 電針刺激也會改善並增加癲癇老鼠之非快速動眼期睡眠，且此增加睡眠的現象會被 naloxonazine 所阻斷。由此可知，10 Hz 電針刺激之抗癲癇及改善睡眠的作用是和杏仁核中的鴉片受體有關。 經由上述四個章節的實驗，我們認為在不同的時間點誘發大鼠產生癲癇，會經由不同的神經機轉而產生不同的睡眠障礙。另外在癲癇大鼠的兩側風池穴給予不同頻率的電針刺激，也會產生不同的抗癲癇作用和睡眠反應。
並列摘要
Clinical and experimental evidence demonstrates that sleep and epilepsy reciprocally affect each other. Controversial sleep disruptions (e.g. poor nighttime sleep and daytime somnolence) are common in epilepsy patients. Sleep is known to be regulated by homeostatic factors, which mediate sleep propensity, and circadian oscillator, a clocklike mechanism. However, how epilepsy occurred at different zeitgeber times (ZTs) alters sleep regulation remains unknown. Chapter 1 was designed to elucidate the sleep disruptions and their underlying mechanisms by delivering kindled epilepsy at different ZTs－ZT0 and ZT13. We found that kindled epilepsy occurring at ZT0 and ZT13 predominantly affected the homeostatic factors. ZT0-kindling decreased rapid eye movement (REM) and non-REM (NREM) sleep, which was mediated by corticotrophin-releasing hormone. On the other hand, ZT13-kindling enhanced interleukin-1 and consequently increased NREM sleep. These observations suggest that the occurrence of epilepsy at different ZTs alters sleep processes differently. If a therapy possesses both epilepsy suppression and sleep improvement, it would be the priority choice for seizure control. Effects of acupuncture of Feng-Chi (GB20) acupoints on epilepsy suppression and insomnia treatment have been documented in the ancient Chinese literature, Lingshu Jing; however, there is a lack of scientific evidence. Chapter 2 was designed to elucidate the effect of electroacupuncture (EA) of bilateral Feng-Chi acupoints on the epileptic activity by employing pilocarpine into left central nucleus of amygdala (CeA) to induce focal epilepsy. 100 Hz EA stimulation did not suppress the pilocarpine-induced epileptiform electroencephalograms (EEGs), whereas it further increased the duration of epileptiform EEGs. EA-induced augmentation of epileptic activity was blocked by naloxone, naloxonazine, nor-binaltorphimine or naltrindole, suggesting that activation of opioid receptors in the CeA mediates EA-exacerbated epilepsy. Chapter 3 was designed to investigate the effect of 100 Hz EA stimulation of bilateral Feng-Chi acupoints on sleep disruptions in rats with focal epilepsy. Administration of pilocarpine into the left CeA decreased both REM sleep and NREM sleep. 100 Hz EA further deteriorated pilocarpine-induced sleep disruptions. The EA-induced exacerbation of sleep disruption was blocked by naloxone,naloxonazine, nor-binaltorphimine or naltrindole, suggesting the involvement of amygdaloid opioid receptors. Chapter 4 was further designed to investigate the effects of 10 Hz EA of Feng-Chi acupoints on both epilepsy and epilepsy-induced sleep disturbances. 10 Hz EA suppressed pilocarpine-induced epileptiform EEGs, and this effect was blocked by naloxone. EA also reversed the pilocarpine-induced NREM suppression. EA effect on the sleep disruption was blocked by naloxonazine, suggesting the role of opioid receptors. In summary, this dissertation elucidated the underlying mechanisms for sleep disruptions when epilepsy occurrence at different zeitgeber time, and the effects of EA of bilateral Feng-Chi acupoints on epileptogenesis and epilepsy-induced sleep disruptions.