Analysis of neural-network in sleep disorders under neuropathic pain Akira YAMASHITA Department of Pharmacognosy, Hoshi University Pai

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2 Analysis of neural-network in sleep disorders under neuropathic pain Akira YAMASHITA Department of Pharmacognosy, Hoshi University Pain commentary QOL 5, 6, Rapid eye movement REM non rapid eye movement non-rem REM non-rem electromyogram EMG electroencephalogram EEG

8, 9 2 10 11 2 0 5 BOLD ON/OFF B fmri BOLD 2 3.

3 1 24 WAKE NREM REM Error bars represent S.E.M., n=6, * p 0.05 REM non-rem - 7 non-rem REM 1 non- REM 2. 8, BOLD ON/OFF B fmri BOLD B, Error barsrepresent S.E.M., n=3, ** p 0.01, *** p 0.001

GABA 13, 14 in vivo microdialysis 7 3 4. 15 4A 4B 5.

GABA transporter-3 GAT-3 16, 17 GAT-3 GABA GABA 18 GAT-3

24 GFAP PBS GFAP B-iii Error bars represent S.E.M., *** p 0.

4 GABA 13, 14 in vivo microdialysis A 4B 5. GABA GABA -aminobutyric acid GABA GABA GABA transporter 1 GABA transporter-3 GAT-3 16, 17 GAT-3 GABA GABA 18 GAT-3 GABA GAT-3 GAT-3 4 A-ii A-i GFAP A-iii, v A-v, B-i PBS B-ii 24 GFAP PBS GFAP B-iii Error bars represent S.E.M., *** p GAT-3 GAT-3 GAT-3 GFAP GFAP, GAT-3 GFAP GAT-3 6 GAT-3 24 GAT-3 GAT-3

7 GABA A 0 5 GABA B Error bars represent S E.M. n=4 * p 0.

inhibitor SNAP-5114 - SNA-5114 8 GAT-3 GABA 9 8 GAT-3 GABA A SNAP-5114 GAT-3 SNAP-5114

5 7 GABA A 0 5 GABA B Error bars represent S E.M. n=4 * p GAT-3 GAT-3 GAT-3 6 GAT-3 GABA GABA in vivo microdialysis GAT-3 7 GAT-3 GABA GAT-3 inhibitor SNAP SNA GAT-3 GABA 9 8 GAT-3 GABA A SNAP-5114 GAT-3 SNAP-5114 lnmol/mouse 8:00, Error bars represent S.E.M., n=6, * p 0.05, *** p v,s. -Vehicle, #<0.05 v.s. -Vehicle 9 GABA GAT-3 GAT-3 GABA GABA 6.

6 ChR2 non-rem 10 NREM 10 A ChR2 loxp cre ChR2 FLEX AAV AAV GFAP cre GFAP-cre A-i A-ii B AAV GFAP-cre AAV AAV Error bars represent S E M. n=4 ** p , 20, 21 2 ChR2 22 ChR2 loxp Cre ChR2 FLEX AAV-FLEX-ChR2 GFAP Cre GFAP-Cre AAV-FLEX-ChR2 GAT-3 GABA GABA QOL QOL

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8 Analysis of neural-network in sleep disorders under neuropathic pain Akira YAMASHITA Department of Pharmacology, Hoshi University Abstract Insomnia is common problem for people with neuropathic pain. In the present study, I confirmed that sciatic nerve ligation caused thermal hyperalgesia and tactile allodynia in mice. In this experimental model for neuropathic pain, I found an increase in wakefulness and a decrease in non-rapid eye movement sleep under a neuropathic pain-like state. In addition, I used functional magnetic resonance imaging to visualize the increased blood oxygenation level-dependent signal intensity in the anterior cingulate cortex (ACC) of mice with sciatic nerve ligation under mild noxious stimuli. Such stimuli significantly increased the release of glutamate in the ACC of nerve-ligated mice. Moreover, sciatic nerve ligation and mild noxious stimuli changed the morphology of astrocytes in the ACC. Treatment of cortical astrocytes with glutamate caused astrocytic activation, as detected by a stellate morphology. Additionally, glutamate induced the translocation of GAT-3 to cell membranes of astrocytes using primary cultured glial cells from the mouse cortex. As a result, the GABA level at the synaptic cleft in the ACC of nerve-ligated mice was significantly decreased exposure to mild noxious stimuli. These results indicate that neuropathic pain-like stimuli could activate astrocytes in the ACC and decreased the extracellular concentration of GABA via an increase in the release of glutamate. Furthermore, I investigated whether astrocytic activation in the ACC could directly mediate sleep disorder. With the optogenetic tool ChR2, I demonstrated that selective photostimulation of these astrocytes in vivo triggered sleep disturbance. Taken together, the present findings provide novel evidence that astrocytic activation in the ACC can mimic sleep disturbance in mice. In conclusion, sleep impairment by neuropathic pain-like stimuli may be associated with the dysregulation of the GABA transmitter and astrocytes activation in cortical regions.

得られず不安やうつ症状が増悪し,QOL の低下を引き起こすと考えられている 5 7).この現状は, 痛みの治療において, 痛み以外の合併症状も考慮に入れて治療していく必要性を示している( 図 1).

得られず不安やうつ症状が増悪し,QOL の低下を引き起こすと考えられている 5 7).この現状は, 痛みの治療において, 痛み以外の合併症状も考慮に入れて治療していく必要性を示している( 図 1). 慢性痛と睡眠障害 Chronic Pain and Sleep Dysregulation 星薬科大学薬理学教室山下哲成田年痛みは本来, 組織損傷を避けるための警告反応としてなくてはならない感覚であるが, 慢性化すると痛みを提供するだけの病態像そのものになってしまう.こうした痛みの難治