Obacunone Alleviates Thalamic Pain via Promoting LCN2-Mediated Phagocytosis of Astrocytes in Mice

Thalamic pain is a common pain syndrome following thalamic stroke with limited therapeutic options. Though the pathogenesis of thalamic pain is far from clear, accumulating studies have demonstrated that the ectopic activity of thalamic glial cells contributes to allodynia development after thalamic hemorrhage (TH). Obacunone (Oba) is a highly oxygenated triterpenoid extracted from a Chinese edible medicinal herb, Phellodendron, with a broad spectrum of biological activities in mediating glial depolarization. We herein investigated the analgesic effect of Oba and its underlying reasons on the collagenase-induced TH model of mice. We found that Oba suppressed TH-induced allodynia dose-dependently. Mechanistically, gavage Oba promoted the expression of lipocalin (LCN) 2, accompanied by the reduction of C-X-C Chemokine Receptor type (CXCR) 4 and the increase of nuclear factor erythroid 2-related factor (NRF) 2 and activated extracellular signal-regulated kinase (ERK) 1/2 within thalamic astrocytes following chronic TH. In addition, the suppression of Oba to allodynia and ectopic activity of cortical neurons, as well as the promotion of Oba to phagocytosis of thalamic astrocytes to synapses, could be reversed by inhibiting LCN2, which was in line with the analgesic effect of adenovirus-mediated overexpression of astrocytic LCN2. Furthermore, neutralizing the macrophage migration inhibitory factor (MIF), the potential target of Oba, suppressed TH-induced allodynia, which was not further regulated by Oba treatment. These results collectively conclude that Oba promotes the phagocytotic function of thalamic astrocytes to synapses via elevating astrocyte LCN2. This process may be mediated by MIF-related signaling, including CXCR4, NRF2, and ERK1/2. The elimination of thalamic synapses obtunds nociceptive input and eventually alleviates TH-induced allodynia. Oba may represent a therapeutic candidate for thalamic pain and pain disorders caused by cerebral stroke.

LCN2; astrocyte; obacunone; phagocytosis; thalamic pain.