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PO3-1-44

Roles of NOX1/NADPH oxidase in neuropathic pain and its related emotional behaviors

[Speaker] Masakazu Ibi:1
[Co-author] Chihiro Yabe-Nishimura:1
1:Pharmacology, Kyoto Prefectural University of Medicine, Japan

Background
While the involvement of reactive oxygen species (ROS) in neural functions has been reported, the source of ROS in the nervous system has not been clearly identified. We previously reported the involvement of ROS derived from NOX1, a catalytic subunit of NADPH oxidase, in carrageenan-induced hyperalgesia as well as in stress-induced emotional behaviors. However, the functional significance of NOX1 in neuropathic pain has not been elucidated. In this study, we investigated the role of NOX1/NADPH oxidase in the development of neuropathic pain and its related emotional behaviors using mice deficient in Nox1 gene (Nox1-KO).

Methods
Two to three-month-old Nox1-KO and littermates (WT) were used for the study. A spared nerve injury (SNI) model was made in accordance with a conventional method. Tactile allodynia was assessed by the up-down method using calibrated von Frey filaments. At 4 weeks after SNI, the anxiety- and depressive-like behaviors were evaluated. In another line of experiments, mice were injected with chemotherapeutic agents, paclitaxel (4mg/kg, i.p. on day 1, 3, 5, 7), oxaliplatin (5mg/kg, i.p. on day 1) or bortezomib (0.8mg/kg, i.p., three times/weekly for 4 weeks). Silencing of NOX1 was performed by adeno-associated virus harboring artificial miRNA against NOX1.

Results
Development of the tactile allodynia was demonstrated until 4 weeks after SNI. Administration of paclitaxel and oxaliplatin induced allodynia, which sustained for 7 days, while bortezomib-induced allodynia sustained for 4 weeks. There was, however, no difference in the levels of neuropathic pain between WT and Nox1-KO. On the other hand, the SNI-induced anxiety- and depressive-like behaviors were significantly suppressed in Nox1-KO. In the hippocampus and hypothalamus of WT, the expression of NOX1 mRNA was significantly elevated following SNI. Delivery of miRNA against NOX1 to the hippocampus, but not to the hypothalamus of WT, restored SNI-induced emotional behaviors without affecting mechanical allodynia.

Conclusions
Taken together, the anxiety- and depressive-like behaviors induced by neuropathic pain may be mediated by up-regulation of NOX1 in the hippocampus.

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