The analysis of anxiety- and depression-related behaviors in neuropathic pain of mice - possible involvement of brain inflammation

[Speaker] Kazue Hisaoka-Nakashima:1
[Co-author] Yoshiaki Tomimura:1, Toshiki Yoshii:1, Fang Fang Zhang:1, Yoki Nakamura:1, Keyue Liu:2, Masahiro Nishibori:2, Yoshihiro Nakata:1, Norimitsu Morioka:1
1:Department of Pharmacology, Graduate School of Biomedical & Health Sciences, Hiroshima University, Japan, 2:Department of Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Japan

Back ground: Several reports have demonstrated a frequent association of chronic pain in humans with affective disorders, such as anxiety and depression. However, it is entirely unclear what mechanisms are involved. There is an intricate communication between the immune system and the central nervous system, and inflammation has been considered a common mediator of pain-depression comorbidity. High-mobility group box 1 protein (HMGB1) has gained much attention as an important player in innate immune responses and a modulating factor in several inflammatory diseases. Microglia activation is known to play critical roles in development of both chronic pain and depression. The current study examined characteristics of anxiety- and depression-related behaviors, and the change of HMGB1 and microglial activity in neuropathic pain of mice.
Methods: Neuropathic pain was induced by partial sciatic nerve ligation (PSNL) of the left hind limb in male ddy mice. Anxiety- and depression-related behaviors were assessed over 2 months, using a battery of tests, such as novelty suppressed feeding, social interaction, and forced swim tests. Mechanical threshold was determined using von Frey filaments. HMGB1 levels of brain and plasma were assessed by Western blotting and ELISA. Microglial activity was examined by ionized calcium binding adaptor molecule 1 (Iba1) immunoreactivity.
Results: PSNL induced the ipsilateral mechanical allodynia lasting over 8 weeks. Anxiety- and depression-related behaviors were observed after 6 to 8 weeks following PSNL surgery. Accompanying with depressive behavior induced by PSNL, the expression levels in HMGB1 in plasma and prefrontal cortex but not in hippocampus were increased. Iba1 immunoreactive intensity in frontal cortex of PSNL mice was also increased. In addition, intracerebroventricular administration of recombinant HMGB1 to naïve mice induced the development of depression-related behavior and the upregulation of microglia activation in frontal cortex.
Conclusion: The current study demonstrates that peripheral nerve injury could induce anxiety- and depression-related behaviors behind the induction of nociceptive hypersensitivity. In addition, HMGB1 and microglial activity in frontal cortex might contribute to induction of both chronic pain and depression mainly via activation of neuroinflammatory response.

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