Molecular mechanisms of the development of opioid tolerance in neuropathic pain model in mice.

众所周知，神经性疼痛对阿片类药物治疗相对难治。这种对阿片类药物无效的机制尚未完全了解。受体蛋白通常在内质网（ER）的膜上合成，分泌到细胞质中，通过高尔基体转运到细胞膜上，然后作为细胞膜上的受体发挥作用。在内质网中，受体蛋白折叠形成立体结构。经过这一成熟过程，受体蛋白最终获得其作为受体的功能。在本研究中，我们研究了这种成熟过程对神经病理性疼痛阿片类药物难治性发展的作用。特别地，我们选择了受体蛋白成熟的关键蛋白之一Bip蛋白，利用Bip转基因小鼠研究了Bip在阿片类药物不应性形成中的作用。首先，我们给Bip转基因小鼠腹腔注射吗啡5天（每天2次），发现Bip转基因小鼠在吗啡治疗后没有产生吗啡耐受。虽然我们需要更多的数据，但我们的数据表明Bip可能参与吗啡耐受的形成，并且Bip可能是神经病理性疼痛患者对阿片类药物不应性形成的关键蛋白之一。

It is well known that neuropathic pain is relatively refractory to opioid therapy. The mechanisms of this refractoriness to opioids are not fully understood. Receptor protein is usually synthesized on the membrane of endoplasmic reticulum (ER), is secreted to cytoplasm, is transported to the cell membrane via Golgi body, and then act as a receptor on the cell membrane. In ER, receptor protein is folded and formed tridimensional structure. After this maturation process, receptor protein finally obtains its function as a receptor. In the present study, we investigated the role of this maturation process on the development of refractoriness to opioids of neuropathic pain. Especially, we chose Bip protein, one of the key proteins for the maturation of receptor protein, and studied the role of Bip on the development of refractoriness to opioid with Bip transgenic mice. At first, we administered morphine intraperitoneally to the Bip transgenic mice 5 days (2 times per day) and found that morphine tolerance did not develop after this morphine treatment in the Bip transgenic mice. Although we need more data, our data suggested that Bip may be involved in the development of morphine tolerance and that it is possible that Bip is one of the key protein on the development of refractoriness to opioids in the neuropathic pain patients.