- 期刊
類鴉片物質耐受性之細胞機轉
Cellular Mechanism of Opioid Tolerance
摘要
類鴉片物質主要作用於大腦與脊髓神經之μ，δ，和к鴉片接受器而產生止痛作用。當耐受性產生時，其藥效會減弱或喪失，此時可觀察到其劑量－反應曲線向右位移。至於此類藥物耐受性的形成機轉則仍不甚清楚。長期給予類鴉片物質之後，鴉片接受器可能增加或減少，端視檢測何種型態之鴉片接受器及其中樞區域而定。類鴉片物質被認為如同激素及其它神經傳導物一般是經由G蛋白（guanosine triphosphate binding protein）而產生作用。對長時間使用類鴉片物質的研究顯示，鴉片接受器與G蛋白之間失去連結作用可能於類鴉片物質耐受性的形成機轉上扮演重要的角色。NMDA（N-methyl-D-aspartate）接受器被認為不只與痛覺感受及疼痛傳導有關，同時也涉及類鴉片物質耐受性的形成。透過活化蛋白質激酶C（protein kinase C, PKC）可促使NMDA接受器之持續反應，而NMDA接受器又能再促使細胞內PKC的移位與活化，且此可能是類鴉片物質產生耐受性之關鍵步驟。NMDA接受器也能活化NOS（nitric oxide synthase, NOS）使其合成NO（nitric oxide），而文獻也已報告NOS抑制劑能夠預防類鴉片物質耐受性的產生。然而，儘管已有很多發現可供解釋類鴉片物質耐受性，但是，鴉片接受器的多重性及細胞內生化訊息的複雜性仍待繼續研究。
並列摘要
Opioids relieve painful stimuli by interacting with the opioid receptor subtypes, μ, δ, and к, in brain regions and spinal cord. Tolerance reduces medication effectiveness and causes a right-hand shift in the dose-respones curve. The mechanisms involved in the development of opioid tolerance remain not clear. Following long-term opioid treatment, either a decrease or increase in opioid receptors was demonstrated, depending on the types or subtypes of recepters and the central areas to which they are distributed. Opioid receptors, like most other hormone and neurotransmitter receptors, have been shown to mediate their effects through guanine nucleotide binding protein (G protein). Studies regarding chronic treatment with opioid agonists suggest that the uncoupling of the opioid receptors from their corresponding G protein may play an important role in opoid tolerance. The NMDA (N-methyl-D-aspartate) receptors have also been demonstrated involving not only in nociception and pain processing but also in the development of opioid tolerance. The sustained potentiation of NMDA receptor-mediated responses may be provided through activation of PKC (protein kinase C). Furthermore, NMDA receptor-mediated intracellular trans-location and activation of PKC may be a critical step in the development of opioid tolerance. The NMDA receptors can also induce the synthesis of NO (nitric oxide) through the activation of NOS (NO synthase). NOS inhibitors were also shown to prevent the development of opioid tolerance, therefore, NO was suggested to play a role in opioid tolerance development. Although much evidence indicates the reason s of opioid tolerance, it is still worth further invetigation to explore the mechanisms of multiplicity of opioid receptors and complexity of intracellular biochemical events.