https://orcid.org/0000-0002-9066-2969
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ABSTRACT
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.
Author contributions
R.K. developed the concept of indirectly targeting NaV1.7.; J.L., S.A.L., and P.M.G. designed the experiments; J.L., and S.A.L., collected and analyzed the data; R.K. provided funding; J.L., H.J.S., S.A.L., P.M.G., and R.K. wrote the manuscript; and P.M.G. supervised all experiments. All authors had the opportunity to discuss results and comment on the manuscript.
Availability of data and materials
The authors confirm that the data supporting the findings of this study are available within the article.
Disclosure statement
No potential conflict of interest was reported by the author(s).
Ethics approval for use of animals
The MD Anderson Cancer Center Institutional Animal Care and Use Committee sanctioned all experiments.
Statements and declarations
R. Khanna is the co-founder of Regulonix LLC, a company developing non-opioid drugs for chronic pain. In addition, R. Khanna 481 has patents US10287334 (Non-narcotic CRMP2 peptides targeting sodium channels for chronic 482 pain) and US10441586 (SUMOylation inhibitors and uses thereof) issued to Regulonix LLC. R. Khanna is also a co-founder of ElutheriaTx Inc., a company developing gene therapy approaches for chronic pain.