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Pain. 2019 Jul 17. doi: 10.1097/j.pain.0000000000001648. [Epub ahead of print]

Assessment of nociception and related quality-of-life measures in a porcine model of neurofibromatosis type 1.

Author information

1
Department of Pharmacology, College of Medicine, University of Arizona, Tucson, AZ, United States.
2
Pediatrics and Rare Diseases Group, Sanford Research, Sioux Falls, SD, United States.
3
Department of Pediatrics, University of Iowa Carver College of Medicine, Iowa City, IA, United States.
4
Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA, United States.
5
Molecular Medicine Program, University of Iowa Carver College of Medicine, Iowa City, IA, United States.
6
Departments of Pathology.
7
Pharmacology, and.
8
Radiology, University of Iowa Carver College of Medicine, Iowa City, IA, United States.
9
Department of Biomedical Engineering, University of Iowa, Iowa City, IA, United States.
10
Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, FL, United States.
11
University of Florida Health Cancer Center, UF Center for Neurogenetics, University of Florida, Gainesville, FL, United States.
12
Exemplar Genetics, Coralville, IA, United States.
13
Department of Pediatrics, Sanford School of Medicine, University of South Dakota, Sioux Falls, SD, United States.

Abstract

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 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 NF1 (females only) pigs. Male NF1 pigs with tumors showed reduced sleep quality and increased resting, 2 health-related quality-of-life symptoms found to be comorbid in people with NF1 pain. We explore these phenotypes in relationship to suppression of the increased activity of the N-type voltage-gated calcium (CaV2.2) channel by pharmacological antagonism of phosphorylation of a regulatory protein-the collapsin response mediator protein 2 (CRMP2), a known interactor of neurofibromin, and by targeting the interface between the α subunit of CaV2.2 and the accessory β-subunits with small molecules. Our data support the use of NF1 pigs as a large animal model for studying NF1-associated pain and for understanding the pathophysiology of NF1. Our findings demonstrate the translational potential of 2 small molecules in reversing ion channel remodeling seen in NF1. Interfering with CaV2.2, a clinically validated target for pain management, might also be a promising therapeutic strategy for NF1-related pain management.

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