對於類嗎啡(opioid)成癮之療法，除了以單一類嗎啡(opioid)藥物如 buprenorphine來治療外，因精神因素也常影響治療之成敗，所以目前也常以治寮精神疾病之三環抗憂鬱藥(tricyclic antidepressants, TCAs)來做為輔助治療之藥物，加強原本藥物之療效並減輕其戒斷症狀。 我們先期研究已証實三環抗憂鬱藥可減輕小鼠之戒斷反應，desipramine 和 buprenorphine合併給藥時更可產生協同作用(synergistic effect)，然而其它三環抗憂鬱藥 和 buprenorphine 合併給藥之效果尚未被研究，而產生協同作用之機轉仍未清楚亦沒有具體可行之給藥模式。 因此在本研究中我們擬深入研究，探討 buprenorphine 和各三環抗憂鬱藥合併使用 於減輕嗎啡戒斷反應之機轉，並應用於開發減癮藥物。首先我們將以小鼠為研究對象， 探討 buprenorphine 和不同特性如接受器親合力大小及代謝酵素種類之三環抗憂鬱藥合併給藥時，彼此間在藥效學上之交互作用，接者以大鼠探討此合併給藥時，兩者藥物動力學上之交互作用，進而推估適合做為 buprenorphine輔助治療藥物之性質及其最適之合併給藥模式，作為日後開發減癮藥物之平台。 本研究共分三年：第一年評估 buprenorphine 和各三環抗憂鬱藥合併給藥時之藥效反應。第二年建立以微透析高效能液相層析法，同時分析血中 buprenorphine和各三環 抗憂鬱藥之方法。第三年進行 buprenorphine和各三環抗憂鬱藥單獨及合併給藥時之藥物動力學研究。 Psychological factor plays a significant role in the treatments of opioid addiction. Presently these treatments not only use opioids (e.g., buprenorphine) but also combine with tricyclic antidepressants (TCAs, a psychosis drug) as adjuvants to enhance the effect of the main medicine and reduce the withdrawal symptoms. In our preceding study, we pointed out that TCAs can reduce the withdrawal symptoms in morphine dependence mice and the combination of buprenorphine and desipramine produce the synergistic effects. However, the real mechanisms are still unclear and many other TCAs are not involved in the combination study. This study is design to explore the efficacy and mechanism of buprenorphine and TCAs combination with the application of reducing morphine withdrawal symptoms in drug discovery. First we will study the pharmacodynamic interactions of the combination of buprenorphine and TCAs including different binding receptors and metabolic enzymes in morphine dependence mice. And then we will evaluate the pharmacokinetic interaction in the combination of buprenorphine and TCAs in rat. We will identify the appropriate distinguishing characteristics as buprenorphine adjuvants and the model of combination treatment. The study takes 3 years. In the first year, the pharmacodynamic effects of buprenorphine and TCAs combination in reducing morphine-withdrawal symptoms in mice will be evaluated. In the second year, a micro-dialysis sampling with high performance liquid chromatography method will be set up to determine buprenorphine and TCAs in rat blood. In the third year, the pharmacokinetic interactions of buprenorphine and TCAs combination in rat will be studied.
