Spinal translocator protein alleviates chronic neuropathic pain behavior and modulates spinal astrocyte-neuronal function in rats with L5 spinal nerve ligation model

摘要

Recent studies reported the translocator protein (TSPO) to play critical roles in several kinds of neurological diseases including the inflammatory and neuropathic pain. However, the precise mechanism remains unclear. This study was undertaken to explore the distribution and possible mechanism of spinal TSPO against chronic neuropathic pain (CNP) in a rat model of L5 spinal nerve ligation (SNL). Our results showed that TSPO was upregulated in a time-related manner in the spinal dorsal horn after SNL. Spinal TSPO was predominately expressed in astrocytes. A single intrathecal injection of TSPO agonist Ro5-4864, but not TSPO antagonist PK11195, alleviated the mechanical allodynia in a dose-dependent manner. A single intraspinal injection of TSPO overexpression lentivirus (LV-TSPO), but not TSPO inhibited lentivirus (LV-shTSPO), also relieved the development of CNP. Intrathecal administration of 2 mu g Ro5-4864 on day 3 induced a significant increase of TSPO protein content at the early stage (days 5-7) while inhibited the TSPO activation during the chronic period (days 14-21) compared with the control group. Ro5-4864 suppressed the astrocytes and p-JNK1 activation and decreased the CXCL1 expression in both in vivo and in vitro studies. Ro5-4864 also attenuated the spinal CXCR2 and p-ERK expressions. These results suggested that early upregulation of TSPO could elicit potent analgesic effects against CNP, which might be partly attributed to the inhibition of CXCL1-CXCR2-dependent astrocyte-to-neuron signaling and central sensitization. TSPO signaling pathway may present a novel strategy for the treatment of CNP.