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

Rajesh Khanna, Aubin Moutal, Katherine A. White, Aude Chefdeville, Pedro Negrao de Assis, Song Cai, Vicki J. Swier, Shreya S. Bellampalli, Marissa D. Giunta, Benjamin W. Darbro, Dawn E. Quelle, Jessica C. Sieren, Margaret R. Wallace, Christopher S. Rogers, David K. Meyerholz, Jill M. Weimer

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)2473-2486
Number of pages14
JournalPain
Volume160
Issue number11
DOIs
StatePublished - Nov 1 2019

Fingerprint

Neurofibromatosis 1
Nociception
Swine
Quality of Life
Neurofibromin 1
Pain
Hyperalgesia
Pain Management
Neurofibromatosis 1 Genes
Nociceptive Pain
Inborn Genetic Diseases
Germ-Line Mutation
Calcium Channels
Ion Channels
Reaction Time
Exons
Sleep
Lasers

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology
  • Anesthesiology and Pain Medicine

Cite this

Khanna, R., Moutal, A., White, K. A., Chefdeville, A., Negrao de Assis, P., Cai, S., ... Weimer, J. M. (2019). Assessment of nociception and related quality-of-life measures in a porcine model of neurofibromatosis type 1. Pain, 160(11), 2473-2486. https://doi.org/10.1097/j.pain.0000000000001648

Assessment of nociception and related quality-of-life measures in a porcine model of neurofibromatosis type 1. / Khanna, Rajesh; Moutal, Aubin; White, Katherine A.; Chefdeville, Aude; Negrao de Assis, Pedro; Cai, Song; Swier, Vicki J.; Bellampalli, Shreya S.; Giunta, Marissa D.; Darbro, Benjamin W.; Quelle, Dawn E.; Sieren, Jessica C.; Wallace, Margaret R.; Rogers, Christopher S.; Meyerholz, David K.; Weimer, Jill M.

In: Pain, Vol. 160, No. 11, 01.11.2019, p. 2473-2486.

Research output: Contribution to journalArticle

Khanna, R, Moutal, A, White, KA, Chefdeville, A, Negrao de Assis, P, Cai, S, Swier, VJ, Bellampalli, SS, Giunta, MD, Darbro, BW, Quelle, DE, Sieren, JC, Wallace, MR, Rogers, CS, Meyerholz, DK & Weimer, JM 2019, 'Assessment of nociception and related quality-of-life measures in a porcine model of neurofibromatosis type 1', Pain, vol. 160, no. 11, pp. 2473-2486. https://doi.org/10.1097/j.pain.0000000000001648
Khanna, Rajesh ; Moutal, Aubin ; White, Katherine A. ; Chefdeville, Aude ; Negrao de Assis, Pedro ; Cai, Song ; Swier, Vicki J. ; Bellampalli, Shreya S. ; Giunta, Marissa D. ; Darbro, Benjamin W. ; Quelle, Dawn E. ; Sieren, Jessica C. ; Wallace, Margaret R. ; Rogers, Christopher S. ; Meyerholz, David K. ; Weimer, Jill M. / Assessment of nociception and related quality-of-life measures in a porcine model of neurofibromatosis type 1. In: Pain. 2019 ; Vol. 160, No. 11. pp. 2473-2486.
@article{2f0035212d0f45289f31ed3fe75216cd,
title = "Assessment of nociception and related quality-of-life measures in a porcine model of neurofibromatosis type 1",
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.",
author = "Rajesh Khanna and Aubin Moutal and White, {Katherine A.} and Aude Chefdeville and {Negrao de Assis}, Pedro and Song Cai and Swier, {Vicki J.} and Bellampalli, {Shreya S.} and Giunta, {Marissa D.} and Darbro, {Benjamin W.} and Quelle, {Dawn E.} and Sieren, {Jessica C.} and Wallace, {Margaret R.} and Rogers, {Christopher S.} and Meyerholz, {David K.} and Weimer, {Jill M.}",
year = "2019",
month = "11",
day = "1",
doi = "10.1097/j.pain.0000000000001648",
language = "English (US)",
volume = "160",
pages = "2473--2486",
journal = "Pain",
issn = "0304-3959",
publisher = "Elsevier",
number = "11",

}

TY - JOUR

T1 - Assessment of nociception and related quality-of-life measures in a porcine model of neurofibromatosis type 1

AU - Khanna, Rajesh

AU - Moutal, Aubin

AU - White, Katherine A.

AU - Chefdeville, Aude

AU - Negrao de Assis, Pedro

AU - Cai, Song

AU - Swier, Vicki J.

AU - Bellampalli, Shreya S.

AU - Giunta, Marissa D.

AU - Darbro, Benjamin W.

AU - Quelle, Dawn E.

AU - Sieren, Jessica C.

AU - Wallace, Margaret R.

AU - Rogers, Christopher S.

AU - Meyerholz, David K.

AU - Weimer, Jill M.

PY - 2019/11/1

Y1 - 2019/11/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85073584148&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85073584148&partnerID=8YFLogxK

U2 - 10.1097/j.pain.0000000000001648

DO - 10.1097/j.pain.0000000000001648

M3 - Article

C2 - 31246731

AN - SCOPUS:85073584148

VL - 160

SP - 2473

EP - 2486

JO - Pain

JF - Pain

SN - 0304-3959

IS - 11

ER -