Spinal dopamine D1/D2 receptor complex stimulates NGF release to activate astrocytes and promote neuropathic pain

Blocking peripheral nerve growth factor (NGF) obviously alleviated neuropathic pain, however, the effect and mechanism of spinal NGF in neuropathic pain are remain controversial. This study further investigated the mechanism by which peripheral NGF is involved in neuropathic pain and found safe, natural compounds that target NGF to attenuate neuropathic pain.

Chronic constriction injury (CCI) of the sciatic nerve was used to instill neuropathic pain. Pain behaviors were assessed using Von Frey filaments and Hargreaves test. For in vitro studies, primary neurons and astrocytes were cultured. RT-PCR, immunofluorescence and Western blot were used to assess the cell signaling pathway.

Blocking spinal NGF effectively reduced CCI-induced neuropathic pain and suppressed astrocyte activation both in vivo and in vitro. The trends of changes in spinal NGF and the astrocyte marker matched the trends of changes in pain thresholds in CCI. Moreover, NGF-induced hypersensitivity could be abolished by astrocyte inhibitor. NGF was found mainly expressed in spinal neurons, and that the NGF receptor tropomyosin receptor kinase A (TrkA) but not p75, was widely expressed in spinal astrocytes. Dopamine D1/D2 receptor complex could promote NGF expression in spinal neurons, which bind to TrkA to promote astrocytes activation via ASK1-JNK/NF-κB signaling.

These findings imply that D1/D2 receptor complex promotes NGF secretion in spinal neurons, which bind to TrkA to promote astrocyte activation and neuropathic pain via ASK1/JNK/NF-κB pathway.