猴子脊髓內注射Somatostatin產生止痛作用之研究

The Antinociceptive Effect of Intrathecal Somatostatin in Monkeys

洪鴻龍(Hung-Long Hung) ； 葉春興(Tsun-Shin Yeh) ； 楊永定(Yong-Ding Yang) ； 蔡勝國(Shen-Kuo Tsai) ； 李德譽(Tak-Yu Lee)

《Acta Anaesthesiologica Sinica》 29卷4期 (1991/12) Pp. 677-682

摘要

本實驗乃利用與人類生理接近且具適當行爲能力的猴子爲對象，探討somatostatin（SST）脊髓內注射所產生的止痛效果，先於猴子腰椎處作成一椎盤窗，以利藥物注入脊髓內腔，再以55°C熱板測試其所產生的止痛作用，並以最大百分比作用（maximal percentage effect，MPE）表示之，另以脊髓內注射morphine sulfate（MS）1 mg作對照組。結果顯示注射morphine時具完全止痛作用（MPE 100%），且可維持2小時以上。但注射SST時，不論是50或250 μg，僅能產生輕微而短暫的止痛作用（MPE最高僅47%，維持時間不足30分鐘），此兩種劑量的止痛效果並無顯著差別。同時肌肉注射naloxone 400μg並未顯著改變SST的止痛作用，表示SST的作用機轉與opiate有所不同。以radioimmunoassay（RIA）測得SST血漿濃度與當時的MPE止痛相對照，發現兩者有某種程度的正向相關；但SST之止痛機轉可能包括對脊髓後角處的特定接受體作用，或是透過減少sub-stance P釋放及抑制leu-enkephalin分解等。本實驗中MS的良好止痛效果，證明脊髓內注射是止痛藥劑發揮作用的良好途徑之一；但脊髓內注射SST，雖未發現有明顯神經毒性反應，卻祇能產生輕微而短暫的止痛效果，是否能應用到臨床止痛上仍有待商榷。

關鍵字

Analgesia: spinal ； Somatostatin ； Antinociception ； Monkey

並列摘要

The distribution of somatostatin (SST) throughout the nervous system suggests that this tetradecapeptide may play a physiological role in CNS in the mediation of analgesia. The present study was undertaken to evaluate the antinociceptive properties of intrathecal (IT) injection of SST in the comparison of morphine sulfate (MS) in a primate model. The study was conducted after institutional approval and adhered to the regulations of the animal research committee. Seven adult monkeys (Maccaca cyclopis Swinhoe) weighing 4-6 kg were used. In each animal a L_5 laminectomy window was created to facilitate IT injection. No neurological damage from surgery was noted. With the monkey standing in a specially constructed cage, all animals randomly received the following agents at one-week interval: (1) MS 1 mg, IT; (2) SST 50 μg, IT; (3) SST 250 μg, IT; and (4) SST 250 μg, IT+ intramuscular (IM) naloxone 400 μg. The measured withdrawal latency (HPWL) was converted to the maximal percentage effect (MPE %) for comparison. The HPWL was measured at predrug and 5, 15, 30, 45, 60, 90 and 120 min after injection. Venous blood sample was obtained every 15 min to determine the plasma SST level by radioimmunoassay (RIA) technique in group 3 only. The results showed that MS (1mg, IT) produced potent antinociception (MPE 100 %) for more than 2 h. Intrathecal SST 50 μg, however, induced mild antinociception (MPE 43 %) for only a short period and a 5-fold larger dose (250 μg) did not significantly change the nociceptive threshold with MPE only up to 47 %. IM naloxone did not antagonize the antinociceptive effect, indicating that the mechanism of SST is different from opiates in the mediation of nociception. Plasma SST concentration showed some positive correlation with the nociceptive threshold but IT SST might also exert its action via local receptors in the spinal cord level. No significant changes in conscious level and motor function were observed. Pathologic examination of the spinal cord in one monkey (due to pneumonia) showed no neurotoxicity. Intrathecal injection is a good route for analgesic agents to produce analgesia as shown in this study. However, intrathecal SST only produced mild antinociceptive effect which, however, was not potent enough to obtain adequate pain relief. Thus its clinical application is limited and awaits further investigation.