Translocator protein agonist Ro5-4864 alleviates neuropathic pain and promotes remyelination in the sciatic nerve.

Abstract

Our previous study reported the translocator protein to play a critical role in neuropathic pain and the possible mechanisms in the spinal cord. However, its mechanism in the peripheral nervous system is poorly understood. This study was undertaken to explore the distribution of translocator protein in the dorsal root ganglion and the possible mechanisms in peripheral nervous system in a rat model of spared nerve injury. Our results showed that translocator protein was activated in dorsal root ganglion after spared nerve injury. The translocator protein signals were primarily colocalized with neurons in dorsal root ganglion. A single intrathecal (i.t.) injection of translocator protein agonist (7-chloro-5–4-chlorophenyl)-1,3-dihydro-1-methyl-2-H-1,4-benzodiaze-pine-2) (Ro5-4864) exerted remarkable analgesic effect compared with the spared nerve injury group (P < 0.01). After i.t. administration of 2 µg Ro5-4864 on day 3, the expression of translocator protein in ipsilateral dorsal root ganglion was significantly increased on day 7(P < 0.01) but decreased on day 14 (P < 0.05) compared with the same point in time in the control group. The duration of translocator protein activation in dorsal root ganglion was remarkably shortened. Ro5-4864 also inhibited the activation of phospho-extracellular signal-regulated kinase 1(p-ERK1) (P < 0.01), p-ERK2 (D7: P < 0.01, D14: P < 0.05), and brain-derived neurotrophic factor (P < 0.05) in dorsal root ganglion. Meanwhile, i.t. administration of 2 µg Ro5-4864 on day 3 further accelerated the expression of myelin protein zero(P0) and peripheral myelin protein 22 (PMP22). Our results suggested Ro5-4864 could alleviate neuropathic pain and attenuate p-ERK and brain-derived neurotrophic factor activation in dorsal root ganglion. Furthermore, Ro5-4864 stimulated the expression of myelin regeneration proteins which may also be an important factor against neuropathic pain development. Translocator protein may present a novel target for the treatment of neuropathic pain both in the central and peripheral nervous systems.