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

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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.