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Neurofibromatosis Type 1 (NF1) is an autosomal dominant genetic disorder resulting from germline mutations in the NF1 gene, which encodes neurofibromin. Patients experience a variety of symptoms, but pain in the context of NF1 remains largely underrecognized. Here, we characterize nociceptive signaling and pain behaviors in a miniswine harboring a disruptive NF1 mutation (exon 42 deletion). We explore these phenotypes in relationship to collapsin response mediator protein 2 (CRMP2), a known interactor of neurofibromin. Mechanistically, we found two previously unknown phosphorylated residues of CRMP2 in NF1+/ex42del pig dorsal root ganglia (DRGs) and replicated increased voltage-gated calcium channel currents in NF1+/ex42del pig DRGs previously described in rodent models of NF1. We present the first characterization of pain-related behaviors in a pig model of NF1, identifying unchanged agitation scores, lower tactile thresholds (allodynia), and decreased response latencies to thermal laser stimulation (hyperalgesia) in the NF1 mutant animals; NF1+/ex42del pigs demonstrated sexually dimorphic behaviors. NF1+/ex42del pigs showed reduced sleep quality and increased resting, two health-related quality of life symptoms found to be comorbid in people with NF1 pain. Finally, we show decreased depolarization-evoked calcium influx in both wildtype and NF1+/ex42del pig DRGs treated with CRMP2 phosphorylation inhibitor (S)-lacosamide. Our data supports use of NF1+/ex42del pigs as an ideal model for studying NF1-associated pain and are a better model for understanding the pathophysiology of NF1 compared to rodents. Moreover, our findings demonstrate that interfering with CRMP2 phosphorylation might be a promising therapeutic strategy for NF1-related pain management.

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