KMUP-1改善神經性疼痛經由抑制脊髓背角ERK及NF-κB之路徑

KMUP-1 Ameliorates Neuropathic Pain via Inhibition of ERK and NF-κB Pathways in the Dorsal Horn of Spinal Cord

許雯晴(Wun-Ching Hsu)

指導教授 ： 吳炳男

高雄醫學大學/醫學院/藥理學科研究所/碩士(2013年)

摘要

神經性疼痛是一個會影響周邊或中樞自體感覺系統的疾病，發生於神經系統有原發性損害或功能不良時，對感覺傳遞的傷害；當周邊神經損害時，會誘導痛覺過敏、觸覺疼痛與自發性疼痛。而神經性疼痛的病人，比起其他慢性疼痛的病人而言，有著更高的疼痛指數。
慢性疼痛被歸為發炎性疼痛，主要藉由周邊組織發炎所誘導，而造成神經系統的損害與功能不良。很多研究已經顯示，神經性疼痛會產生發炎反應，而造成神經性疼痛的出現與維持。儘管在市面上有大量的止痛劑可供選擇，但因為這些藥物有嚴重的副作用，因此對於慢性疼痛的有效治療依然無法被滿足。
在近年，我們嘗試研究KMUP-1是否可以減輕，藉由慢性神經壓迫損傷所造成的疼痛過敏與發炎物質，並且探討可能作用於脊髓背角的治療機轉。
SD公鼠被隨機分為4組:分別為sham、sham+KMUP-1、CCI (慢性神經壓迫損傷)與CCI+KMUP-1。在CCI手術之後，經由每日一次腹腔給予KMUP-1 (5 mg/kg)，直至第3天、第7天和第14天。在手術與犧牲前，給予KMUP-1劑量1小時後，分別藉由von Frey test測量機械性觸覺疼痛，與利用Plantar test偵測老鼠腳掌的縮足反應，以測量對熱反應的痛覺過敏。
坐骨神經的壓迫性損傷，會誘導機械性觸覺疼痛與熱過敏反應的發生，並伴隨著發炎物質的增加。取下脊髓背角的組織並區分同側或對側，以利用西方點墨法與酵素連結免疫吸附法，分別
我們證明當在神經性疼痛的老鼠，腹腔給予KMUP-1後，可以減輕發炎過程所產生的觸覺疼痛與痛覺過敏，更進一步KMUP-1在脊髓背角可以減輕術後第3天、第7天與第14天，由於壓迫性神經損傷所誘導的發炎蛋白質與發炎物質的表現。
最後，KMUP-1透過抑制ERK/NF-κB的活化，具有抗發炎與減輕疼痛過敏的作用，以改善神經損傷後所誘導的疼痛發展，因此KMUP-1可以提供神經性疼痛作為新的治療選擇。

關鍵字

神經性疼痛 ； 脊髓背角 ； ERK及NF-κB之路徑

並列摘要

Neuropathic pain occurs as a result of injury to the sensory transmission after a primary lesion or dysfunction in the nervous system. Peripheral nerve injury may produce chronic pain states characterized by hyperalgesia, allodynia and spontaneous pain. Patients with neuropathic pain have higher pain scores and lower quality of life than other chronic pain patients.
Chronic pain is categorized into inflammatory pain, induced by peripheral tissue inflammation, and causes damage and malfunction of the nerve system. Many reports have been shown that peripheral nerve injury could induce inflammatory states, resulting in the genesis and maintenance of neuropathic pain. Despite the large number of approved analgesic drugs, effective treatment of chronic pain is still unsatisfactory because of the severe side effects from these drugs.
In the present study, we tried to investigate whether KMUP-1 could attenuate pain hypersensitivity and inflammatory mediators, and to explore its possible mechanisms in the dorsal horn of spinal cord of rats after chronic constriction injury-induced neuropathic pain.
Male SD rats were randomly assigned to four groups: sham, sham plus KMUP-1, chronic constriction injury (CCI) of bilateral sciatic nerve and CCI plus KMUP-1 groups. After the CCI model was established, KMUP-1 (5 mg/kg) was administrated intraperitoneally once daily for 3, 7 and 14 days. Measurements of mechanical withdrawal threshoulds using von Frey filaments and thermal withdrawal latency using radiant heat applied to the plantar surface, were made daily before and after the injection of each dose.
CCI of the sciatic nerve induced mechanical allodynia and thermal hyperalgesia and this effect was accompanied by increased levels of inflammatory mediators. The dorsal horn of spinal cord was divided into ipsilateral and contralateral parts for western blots and enzyme-linked immunosorbent assay to analyze the levels of inflammatory proteins and cytokines, respectively.
We demonstrated that chronic intraperitoneally KMUP-1 has beneficial effects on the behaviors of both thermal and mechanical stimulations in the neuropathic pain animals. Furthermore, KMUP-1 reduced the expression of inflammatory protein and cytokines in the spinal dorsal horn on Day 3, 7, 14 for the model rats of CCI.
In conclusion, KMUP-1 has anti-inflammatory and anti-pain hypersensitivity properties through inhibition of ERK and NF-κB activation in the development of pain hypersensitivity after nerve injury. Therefore, KMUP-1 could be a potential pharmacotherapeutic agent for the treatment of neuropathic pain.

並列關鍵字

KMUP-1 ； Neuropathic Pain ； Inhibition of ERK and NF-κB Pathways ； Dorsal Horn of Spinal Cord

參考文獻

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