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.