Astrocyte Activation in Locus Coeruleus Is Involved in Neuropathic Pain Exacerbation Mediated by Maternal Separation and Social Isolation Stress

Kazuo Nakamoto, Fuka Aizawa, Megumi Kinoshita, Yutaka Koyama, Shogo Tokuyama

Our previous studies demonstrated that emotional dysfunction associated with early life stress exacerbated nerve injury-induced mechanical allodynia. Sex differences were observed in several anxiety tests, but not in mechanical allodynia. To elucidate the mechanism underlying these findings, we have now investigated the involvement of astrocytes in emotional dysfunction and enhancement of nerve injury-induced mechanical allodynia in mice subjected to maternal separation combined with social isolation (MSSI) as an early life stress. We measured expression of glial fibrillary acidic protein (GFAP), an astrocyte maker, in each brain area by immunohistochemistry. GFAP expression in the locus coeruleus (LC) of female, but not of male mice, significantly increased after MSSI, corresponding to the behavioral changes at 7 and 12 weeks of age. Lipopolysaccharide (LPS)-treated astrocyte-derived supernatant was administered to local brain regions, including LC. Intra-LC injection of conditioned medium from cultured astrocytes treated with LPS increased GFAP expression, anxiety-like behavior and mechanical allodynia in both male and female mice. Furthermore, increases in anxiety-like behavior correlated with increased mechanical allodynia. These findings demonstrate that emotional dysfunction and enhanced nerve injury-induced mechanical allodynia after exposure to MSSI are mediated, at least in part, by astrocyte activation in the LC. Male but not female mice may show resistance to MSSI stress during growth.