Calcineurin inhibitors, including tacrolimus (FK506), are used as immunosuppressive agents and can cause unexplained calcineurin inhibitor-induced pain syndrome (CIPS). We investigated how FK506 affects the expression of NaV1.7, a voltage-gated Na+ channel implicated in pain perception that is upregulated in dorsal root ganglion (DRG) neurons in several pain disorders. We generated a model of FK506-induced pain by administering FK506 to NaV1.7-ChR2 mice, which exhibit light-responsive pain. To evaluate nociceptive responses, paw withdrawal threshold (PWT) was measured using the von Frey test. The optogenetic place aversion (OPA) and light irradiation paw withdrawal tests were also performed. On the 11th day of initial injection, DRGs were dissected from mice under anesthesia and analyzed for NaV1.7 expression using quantitative reverse transcription PCR (RT-qPCR). PWT was also measured for mice that received the selective NaV1.7 inhibitor or vehicle. PWT was lower in FK506-treated mice than in those administered the vehicle on the 8th and 12th days after initial FK506 injection (p < 0.05). Mechanical hypersensitivity was reversible and peaked at around 10 days after FK506 administration. OPA and light irradiation paw withdrawal test results corroborated the hypersensitivity to light-responsivity. NaV1.7 mRNA levels in DRG were higher in FK506-treated mice than in those administered the vehicle on the 11th day (p < 0.05). A selective NaV1.7 inhibitor reversed FK506-induced pain. Increased NaV1.7 expression in DRG neurons may be responsible for FK506-induced peripheral neuropathy. Our findings suggest that endogenous calcineurin regulates NaV1.7 expression. Thus, selective NaV1.7 inhibition could be a potential therapeutic strategy for CIPS.
Keywords: FK506; NaV1.7; calcineurin inhibitor-induced pain syndrome; dorsal root ganglion; optogenetics; tacrolimus.