Mechanisms and modulation of neuropathic pain by neurotrophin-3.

摘要

Neuropathic pain is a complex clinical syndrome characterized by increased sensitivity to thermal and/or mechanical stimuli that may or may not be accompanied by the phenomenon of spontaneous or aberrant pain sensations.; Over the past decade, the mechanisms underlying the behavioral manifestations of inflammatory neuropathic pain have become more clearly elucidated. These include the involvement of: (1) transient receptor potential vanilloid receptor 1 (TRPV1) in the generation of thermal hyperalgesia; (2) acid sensing ion channel 3 (ASIC3) in some aspects of the development/maintenance of mechanical hypersensitivity; (3) the tetrodotoxin resistant sodium channels Nav1.8 and Nav1.9 in both hyperalgesia and spontaneous pain; and (4) activation of the MAP Kinases p38 and ERKl/2 in the regulation of expression of the aforementioned molecules.; Interestingly, it is the pro-inflammatory neurotrophin nerve growth factor (NGF) that is the common link between all of these mediators of neuropathic pain. Increased availability of NGF under conditions of inflammation has been shown to drive increased expression/upregulation of TRPV1, ASIC3, Na v1.8 and Nav1.9, as well as phospho-p38 and phospho-ERK 1/2.; Evidence presented here continues to support a role for neurotrophin-3 (NT-3) in antagonizing the effects of increased NGF on trkA signaling, neuropathic pain behaviors and some of the molecules associated with the generation of such behaviors.; More specifically, the work culminating in this thesis demonstrates a novel role for NT-3 in negative modulation of TRPV1, ASIC3, Na v1.8 and Nav1.9, as well as phospho-p38 expression in response to the chronic constriction injury model of neuropathic pain. Finally, initial insights into how this negative regulation of these nociceptive markers might occur is elucidated in studies demonstrating that NT-3 differentially affects levels of the key signaling molecule phospho-ERK in trkA-positive versus trkC-positive neurons in naive dorsal root ganglia (DRG).