Untranslated Region of Mu-Opioid-Receptor Gene Contributes to Morphine Sensitivity Laboratory for Neurobiology of Emotion Laboratory for Cellular Information Processing Researchers in the laboratories for Neurobiology of Emotion (Head, Dr. Hiroaki Niki) and Cellular Information Processing (Head, Dr. Ryoji Yano,) in collaboration with the Brain Research Institute of Niigata University, clarified that an untranslated region in the mu-opioid-receptor gene affected the pain-killing efficacy of morphine. This finding suggests the possibility that differences in the untranslated region may be the genetic basis of individual differences in morphine sensitivity. We expect that further studies on this possibility will lead to the creation of custom-made medications in the future. Morphine is the main component of opium which is extracted from the buds of the poppy plant. Opium has been used for a long time by humans as a palliative drug and narcotic. The opium poppy is even mentioned in Greek mythology. Morphine, which is very effective in relieving pain and inducing pleasant feelings, is still widely used today to reduce post-operative pain and as treatment for patients with terminal cancer. Recently, the importance of controlling pain has become seriously recognized in various clinical fields and the amount of morphine used has increased annually. These trends indicate the significance of developing an appropriate pain-relieving regimen for the use of morphine. In contrast to these advantages, it is acknowledged that opium and morphine are narcotics which cause physical and mental addiction. Therefore, morphine must be used under an appropriate regimen with minimal side effects, but still a substantial pain-relieving efficacy. However, morphine sensitivity greatly differs among individuals, and the bases for such individual differences have not been clarified. For this study, we utilized the widely held rationale that studying genetic mechanisms of strain differences in mice is an effective way to investigate the genetic bases of individual differences in humans. Therefore, we studied the genetic bases of pain-relieving mechanisms in the CXBK mouse model, which is known for having a low responce to the pain-relieving efficacy of morphine. First, we clarified that in mu-opioid-receptor genes in the CXBK mouse abnormalities were observed not in the region which determines the protein structure (coding region), but in the untranslated region which remains largely unknown (Fig. 1). The mu-opioid-receptor in the brain is the target of morphine. Next, we clarified that certain characteristics of CXBK mice are caused by mu-opioid-receptor genes of CXBK mice (Fig. 2). As shown in Fig. 2, mice (CX) with only mu-opioid-receptor genes derived from CXBK mice (CX), mice (B6 ) with only mu-opioid-receptor genes derived from normal mice (B6), and mice (He ) with one mu-opioid-receptor gene derived from CX and one from B6 were generated. All of the mice were littermates. In CX mice, the untranslated region of the mu-opioid-receptor mRNA was longer and expressed at lower levels than that in its siblings. The efficacy of morphine was also lowest in CXmice, which was the same level as observed in CXBK mice. It is reported that differences in the untranslated region influence the stability of mRNA, causing differences in the level of protein produced as a result of translation. We therefore propose the following hypothesis: CXBK mice have a completely normal mu-opioid-receptor, but since abnormalities are observed in the untranslated region, the level of mu-opioid-receptor mRNA in the brain decreases, resulting in a reduction in the level of the mu-opioid-receptor protein in the brain which in turn results in the insufficient transmission of pain-relieving signals induced by morphine. Consequently, the pain-relieving efficacy of morphine in CXBK mice is insufficient. In addition, it was reported that unlike in the coding region, the DNA sequence is not conserved in the untranslated region evolutionally and therefore, individual differences are observed in the untranslated region. We consider the possibility that differences in the untranslated region of the mu-opioid-receptor mRNA may be one of the genetic bases of individual differences in morphine sensitivity. Furthermore, we assume that not only in mu-opioid-receptor, but also in proteins which govern various brain functions, individual differences in the amount of protein expressed due to variations in the untranslated regions occur, resulting in individual differences in brain functions. 　 (*): Methods used to estimate length and level of mRNAs. Fig. 1. In CXBK mice, the untranslated region of the mu-opioid-receptor mRNA is long. Fig. 2. Mu-opioid-receptor genes derived from the CXBK mouse contribute to a decrease in the level of the mu-opioid-receptor proteins and morphine sensitivity. Ikeda, K., Kobayashi, T., Ichikawa, T., Kumanishi, T., Niki, H. and Yano, R., The untranslated region of mu-opioid-receptor mRNA contributes to reduced opioid sensitivity in CXBK mice, J. Neurosci., (2001)21: 1334-1339.