| Budget Amount *help |
¥4,090,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥390,000)
Fiscal Year 2007: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2006: ¥2,400,000 (Direct Cost: ¥2,400,000)
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| Research Abstract |
We have investigated the roles of spinal astrocytes in chronic pain. Intrathecal administration of ATP to rats produced short-lasting hyperalgesia (<20 min) and subsequently long-lasting allodynia, which appeared within 5 min, reached a plateau between 15 and 30min and lasted fm 3-4 weeks. In the spinal cord, intrathecal ATP administration caused microglia activation within 1 day (induction phase) and subsequently astrocytic activation, which peaked at 1-3 days (transition and early maintenance phase). Taken together with further behavioral studies using inhibitors for microglial and astrocytic activation, and MAPK inhibitors, it is suggested that early microglia activation contributes to the initial induction of chronic pain and precipitates, in turn, the subsequent and sustained astrocytic activation, which is implicated in the transition and maintenance of the persistent pain state.
In the inflammatory (carrageenan/kaolin) and neuropathic pain (partial sciatic nerve ligation (pSNL))
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rat models, the total expression or membrane localization of a glial glutamate transporter GLT-1, which is mainly expressed in astrocytes, in the spinal cord was decreased. Gene transfer of GLT-1 into the spinal cord by the recombinant adenoviruses reduced the induction of inflammatory mechanical hyperalgesia and pSNL-induced allodynia (neuropathic pain), although it had no effect in acute mechanical and thermal pain. These results suggest that dysfunction of GLT-1 by decreased expression of intracellular trafficking in astrocytes contributes to the induction of chronic pain.
Finally, to elucidate the molecular mechanisms underlying GLT-1 trafficking in astrocyte, we constructed a recombinant adenovirus expressing EGFP-tagged GLT-1 and analyzed time-lapse imaging of GLT-1 dynamics in live astrocytes. In rat astroglia-neuronal mixed cultures, treatment with glutamate rapidly induced formation of clusters and intracellular trafficking of GLT-1 via endocytotic pathways. Furthermore, our results suggest that Na^+ influx associated with substrate-transport via GLT-1, but not stimulation of glutamate receptors and intracellular Ca^<2+> signaling, triggers the GLT-1 clustering. Less
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