Division of Molecular Pharmacology and Neuroscience
Nagasaki University Graduate School of Biomedical Sciences
Nagasaki University Center for Pain Research
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Theme 2
Molecular, Cellular and Behavioral Sciences of Opioids and Their Receptors
1. Topics
Prof. Ueda started opioid science from 1975, the year enkephalins were discivered by Hughes and Kosterlitz group. Since then Ueda has been working on opioid science in many ways. He has experiences in purification of biologically active peptide (Kyotorphin), purification and functional analysis of opioid receptors, studies of molecular mechanisms of tolerance and dependence, and analgesic mechanisms for acute and chronic pain.

2. Recent Discoveries
From the electrophysiological studies using Xenopus oocytes, protein kinase C (PKC) is involved in the desensitization of opioid receptor function (UEDA et al., (1995) J. Neurosci. 15(11), 7485-7499). This study was further extended in in vivo study using peripheral analgesia, and in culture studies to see dynamin-regulated receptor endocytosis (UEDA et al., (2001) J. Neurosci. 21(9), 2967-2973.). In our hypothesis morphine stimulates opioid receptor, which in turn activates PKC, followed by phosphorylation and desensitization of opioid receptor. PKC phosphorylation of opioid receptor blocks the attack by G protein coupled receptor kinases (GRKs), which accelerate GPCR endocytosis through interactions with arrestin, clathrin and dynamin. Thus it is speculated that protein kinase C inhibitors may attenuate desensitization or acute tolerance to morphine.
We have more concerns on the molecular mechanisms of chronic morphine tolerance or addiction (dependence). Particularly we proposed a hypothesis that anti-opioid systems through nociceptin and NMDA receptors are involved in the development of the plasticity of neuronal networkings following chronic morphine treatments (UEDA et al., (2000) J. Neurosci. 20(20), 7640-7647; Inoue et al., (2003) J Neurosci.; 23(16) 6529-6536). These studies have been carried out with receptor knock-out mice. Recently we firstly demonstrated the locus-specific NMDA receptor rescue in mutant mice recovers morphine tolerance and dependence by use of electroporation technique. The editor of Nature Review Neuroscience gets interested in this study, and will introduce our study in this review journal in September, 2003.
Most recently, we also found that morphine induces significant changes in both morphology and gene expression of cultured microglia (Takayama and Ueda, 25, 430-5, 2005). Phosphoinositide 3-kinase gamma (PI3K gamma) activation and Rac activation following MOR and Gi/o activation by morphine are involved in chemotaxis, while indirect pathways through ERK1/2 phosphorylation induced by unknown growth factors generated through a MOR-mediated metalloprotease activation are linked to the enhanced BDNF gene expression. These findings many provide a new aspect of the molecular basis of mechanisms for morphine-tolerance and dependence through neuron-glia (astrocyte and microglia) interactions.