期刊
CHANNELS
卷 16, 期 1, 页码 1-8出版社
TAYLOR & FRANCIS INC
DOI: 10.1080/19336950.2021.2023383
关键词
Chronic pain; NaV1; 7; CRMP2; SUMOylation; nociceptor; Ubc9
资金
- National Institutes of Health [NS098772, NS120663]
- NIDA (National Institute on Drug Abuse) [DA042852]
- National Institute of Neurological Disorders and Stroke [NS098772, NS120663]
Recent studies have shown that compound 194, a small-molecule inhibitor of CRMP2 SUMOylation, selectively reduces NaV1.7 currents and reverses mechanical allodynia in various models of neuropathic pain. The efficacy of 194 in both traditional measures of pain behavior and operator-independent mechanical conflict-avoidance assay suggests its robust anti-nociception effect in alleviating mechanical allodynia associated with nerve injury.
The voltage-gated sodium channel isoform NaV1.7 is a critical player in the transmission of nociceptive information. This channel has been heavily implicated in human genetic pain disorders and is a validated pain target. However, targeting this channel directly has failed, and an indirect approach - disruption of interactions with accessory protein partners - has emerged as a viable alternative strategy. We recently reported that a small-molecule inhibitor of CRMP2 SUMOylation, compound 194, selectively reduces NaV1.7 currents in DRG neurons across species from mouse to human. This compound also reversed mechanical allodynia in a spared nerve injury and chemotherapy-induced model of neuropathic pain. Here, we show that oral administration of 194 reverses mechanical allodynia in a chronic constriction injury (CCI) model of neuropathic pain. Furthermore, we show that orally administered 194 reverses the increased latency to cross an aversive barrier in a mechanical conflict-avoidance task following CCI. These two findings, in the context of our previous report, support the conclusion that 194 is a robust inhibitor of NaV1.7 function with the ultimate effect of profoundly ameliorating mechanical allodynia associated with nerve injury. The fact that this was observed using both traditional, evoked measures of pain behavior as well as the more recently developed operator-independent mechanical conflict-avoidance assay increases confidence in the efficacy of 194-induced anti-nociception.
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