Development of a common peroneal nerve injury model in domestic swine for the study of translational neuropathic pain treatments

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  • 1 Departments of Neurosurgery and
  • 2 Neuroscience and Experimental Therapeutics, and
  • 3 Animals Resources Facility, Albany Medical College, Albany, New York
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OBJECTIVE

To date, muscular and bone pain have been studied in domestic swine models, but the only neuropathic pain model described in swine is a mixed neuritis model. Common peroneal nerve injury (CPNI) neuropathic pain models have been utilized in both mice and rats.

METHODS

The authors developed a swine surgical CPNI model of neuropathic pain. Behavioral outcomes were validated with von Frey filament testing, thermal sensitivity assessments, and social and motor scoring. Demyelination of the nerve was confirmed through standard histological assessment. The contralateral nerve served as the control.

RESULTS

CPNI induced mechanical and thermal allodynia (p < 0.001 [n = 10] and p < 0.05 [n = 4], respectively) and increased pain behavior, i.e., guarding of the painful leg (n = 12). Myelin protein zero (P0) staining revealed demyelination of the ligated nerve upstream of the ligation site.

CONCLUSIONS

In a neuropathic pain model in domestic swine, the authors demonstrated that CPNI induces demyelination of the common peroneal nerve, which the authors hypothesize is responsible for the resulting allodynic pain behavior. As the anatomical features of domestic swine resemble those of humans more closely than previously used rat and mouse models, utilizing this swine model, which is to the authors’ knowledge the first of its kind, will aid in the translation of experimental treatments to clinical trials.

ABBREVIATIONS CPN = common peroneal nerve; CPNI = CPN injury; DRG = dorsal root ganglion; liFUS = low intensity focused ultrasound; P0 = myelin protein zero; s.c. = subcutaneously; VFF = von Frey filament.

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Contributor Notes

Correspondence Julie G. Pilitsis: Albany Medical College, Albany, NY. jpilitsis@yahoo.com.

INCLUDE WHEN CITING Published online April 16, 2021; DOI: 10.3171/2020.9.JNS202961.

Disclosures Dr. Pilitsis is a consultant for Boston Scientific, Nevro, TerSera, Medtronic, Saluda, and Abbott and receives grant support from Medtronic, Boston Scientific, Abbott, Nevro, and TerSera. She is a medical advisor for Aim Medical Robotics and Karuna and has stock equity.

  • 1

    Gaskin D, Richard P. Appendix C: The economic costs of pain in the United States. In: Institute of Medicine (US) Committee on Advancing Pain Research, Care, and Education. Relieving Pain in America: A Blueprint for Transforming Prevention, Care, Education and Research. National Academies Press; 2011: 301308.

    • Search Google Scholar
    • Export Citation
  • 2

    Campbell JN, Meyer RA. Mechanisms of neuropathic pain. Neuron. 2006;52(1):7792.

  • 3

    Yawn BP, Wollan PC, Weingarten TN, et al. The prevalence of neuropathic pain: clinical evaluation compared with screening tools in a community population. Pain Med. 2009;10(3):586593.

    • Search Google Scholar
    • Export Citation
  • 4

    Taylor KM, Laverty R. The effect of chlordiazepoxide, diazepam and nitrazepam on catecholamine metabolism in regions of the rat brain. Eur J Pharmacol. 1969;8(3):296301.

    • Search Google Scholar
    • Export Citation
  • 5

    Taylor KM, Laverty R. The metabolism of tritiated dopamine in regions of the rat brain in vivo. II. The significance of the neutral metabolites of catecholamines. J Neurochem. 1969;16(9):13671376.

    • Search Google Scholar
    • Export Citation
  • 6

    Gewandter JS, Dworkin RH, Turk DC, et al. Research design considerations for chronic pain prevention clinical trials: IMMPACT recommendations. Pain. 2015;156(7):11841197.

    • Search Google Scholar
    • Export Citation
  • 7

    Laedermann CJ, Pertin M, Suter MR, Decosterd I. Voltage-gated sodium channel expression in mouse DRG after SNI leads to re-evaluation of projections of injured fibers. Mol Pain. 2014;10:19.

    • Search Google Scholar
    • Export Citation
  • 8

    McLachlan EM, Hu P. Inflammation in dorsal root ganglia after peripheral nerve injury: effects of the sympathetic innervation. Auton Neurosci. 2014;182:108117.

    • Search Google Scholar
    • Export Citation
  • 9

    Berta T, Qadri Y, Tan PH, Ji RR. Targeting dorsal root ganglia and primary sensory neurons for the treatment of chronic pain. Expert Opin Ther Targets. 2017;21(7):695703.

    • Search Google Scholar
    • Export Citation
  • 10

    Deer TR, Levy RM, Kramer J, et al. Dorsal root ganglion stimulation yielded higher treatment success rate for complex regional pain syndrome and causalgia at 3 and 12 months: a randomized comparative trial. Pain. 2017;158(4):669681.

    • Search Google Scholar
    • Export Citation
  • 11

    Parker T, Huang Y, Raghu ALB, et al. Dorsal root ganglion stimulation modulates cortical gamma activity in the cognitive dimension of chronic pain. Brain Sci. 2020;10(2):E95.

    • Search Google Scholar
    • Export Citation
  • 12

    Koetsier E, Franken G, Debets J, et al. Dorsal root ganglion stimulation in experimental painful diabetic polyneuropathy: delayed wash-out of pain relief after low-frequency (1Hz) stimulation. Neuromodulation. 2020;23(2):177184.

    • Search Google Scholar
    • Export Citation
  • 13

    Hellman A, Maietta T, Byraju K, et al. Effects of external low intensity focused ultrasound on electrophysiological changes in vivo in a rodent model of common peroneal nerve injury. Neuroscience. 2020;429:264272.

    • Search Google Scholar
    • Export Citation
  • 14

    Prabhala T, Hellman A, Walling I, et al. External focused ultrasound treatment for neuropathic pain induced by common peroneal nerve injury. Neurosci Lett. 2018;684:145151.

    • Search Google Scholar
    • Export Citation
  • 15

    Ruan Y, Robinson NB, Khan FM, et al. The translation of surgical animal models to human clinical research: a cross-sectional study. Int J Surg. 2020;77:2529.

    • Search Google Scholar
    • Export Citation
  • 16

    Di Giminiani P, Petersen LJ, Herskin MS. Characterization of nociceptive behavioural responses in the awake pig following UV-B-induced inflammation. Eur J Pain. 2014;18(1):2028.

    • Search Google Scholar
    • Export Citation
  • 17

    Bishop JH, Fox JR, Maple R, et al. Ultrasound evaluation of the combined effects of thoracolumbar fascia injury and movement restriction in a porcine model. PLoS One. 2016;11(1):e0147393.

    • Search Google Scholar
    • Export Citation
  • 18

    Macfadyen MA, Daniel Z, Kelly S, et al. The commercial pig as a model of spontaneously-occurring osteoarthritis. BMC Musculoskelet Disord. 2019;20(1):70.

    • Search Google Scholar
    • Export Citation
  • 19

    Castel D, Sabbag I, Brenner O, Meilin S. Peripheral neuritis trauma in pigs: a neuropathic pain model. J Pain. 2016;17(1):3649.

  • 20

    Seltzer Z, Dubner R, Shir Y. A novel behavioral model of neuropathic pain disorders produced in rats by partial sciatic nerve injury. Pain. 1990;43(2):205218.

    • Search Google Scholar
    • Export Citation
  • 21

    Vadakkan KI, Jia YH, Zhuo M. A behavioral model of neuropathic pain induced by ligation of the common peroneal nerve in mice. J Pain. 2005;6(11):747756.

    • Search Google Scholar
    • Export Citation
  • 22

    Swindle MM, Makin A, Herron AJ, et al. Swine as models in biomedical research and toxicology testing. Vet Pathol. 2012;49(2):344356.

  • 23

    National Pork Board. Swine Health Recommendations: Exhibitors of All Pigs Going to Exhibits or Sales. Published 2013. Accessed November 18, 2020. https://datcp.wi.gov/Documents/SwineExhibitsSales.pdf

    • Search Google Scholar
    • Export Citation
  • 24

    Hellman A, Maietta T, Byraju K, et al. Low intensity focused ultrasound modulation of vincristine induced neuropathy. Neuroscience. 2020;430(1):8293.

    • Search Google Scholar
    • Export Citation
  • 25

    Youn Y, Hellman A, Walling I, et al. High-intensity ultrasound treatment for vincristine-induced neuropathic pain. Neurosurgery. 2018;83(5):10681075.

    • Search Google Scholar
    • Export Citation
  • 26

    Chaplan SR, Bach FW, Pogrel JW, et al. Quantitative assessment of tactile allodynia in the rat paw. J Neurosci Methods. 1994;53(1):5563.

    • Search Google Scholar
    • Export Citation
  • 27

    Gaboreanu AM, Hrstka R, Xu W, et al. Myelin protein zero/P0 phosphorylation and function require an adaptor protein linking it to RACK1 and PKC alpha. J Cell Biol. 2007;177(4):707716.

    • Search Google Scholar
    • Export Citation
  • 28

    D’Urso D, Ehrhardt P, Müller HW. Peripheral myelin protein 22 and protein zero: a novel association in peripheral nervous system myelin. J Neurosci. 1999;19(9):33963403.

    • Search Google Scholar
    • Export Citation
  • 29

    Gregory NS, Harris AL, Robinson CR, et al. An overview of animal models of pain: disease models and outcome measures. J Pain. 2013;14(11):12551269.

    • Search Google Scholar
    • Export Citation
  • 30

    Jaggi AS, Jain V, Singh N. Animal models of neuropathic pain. Fundam Clin Pharmacol. 2011;25(1):128.

  • 31

    Henze DA, Urban MO. Large animal models for pain therapeutic development. In: Kruger L, Light AR, eds. Translational Pain Research: From Mouse to Man. CRC Press; 2010: chapter 17.

    • Search Google Scholar
    • Export Citation
  • 32

    Mitsuzawa S, Ikeguchi R, Aoyama T, et al. The efficacy of a scaffold-free bio 3D conduit developed from autologous dermal fibroblasts on peripheral nerve regeneration in a canine ulnar nerve injury model: a preclinical proof-of-concept study. Cell Transplant. 2019;28(9-10):12311241.

    • Search Google Scholar
    • Export Citation
  • 33

    Bundgaard L, Sørensen MA, Nilsson T, et al. Evaluation of systemic and local inflammatory parameters and manifestations of pain in an equine experimental wound model. J Equine Vet Sci. 2018;68:8187.

    • Search Google Scholar
    • Export Citation
  • 34

    Reddy CG, Miller JW, Abode-Iyamah KO, et al. Ovine model of neuropathic pain for assessing mechanisms of spinal cord stimulation therapy via dorsal horn recordings, von Frey filaments, and gait analysis. J Pain Res. 2018;11:11471162.

    • Search Google Scholar
    • Export Citation
  • 35

    Bashkuev M, Reitmaier S, Schmidt H. Is the sheep a suitable model to study the mechanical alterations of disc degeneration in humans? A probabilistic finite element model study. J Biomech. 2019;84:172182.

    • Search Google Scholar
    • Export Citation
  • 36

    Wang S, Zhou X, Huang B, et al. Spinal cord stimulation suppresses atrial fibrillation by inhibiting autonomic remodeling. Heart Rhythm. 2016;13(1):274281.

    • Search Google Scholar
    • Export Citation
  • 37

    Renner S, Blutke A, Clauss S, et al. Porcine models for studying complications and organ crosstalk in diabetes mellitus. Cell Tissue Res. 2020;380(2):341378.

    • Search Google Scholar
    • Export Citation
  • 38

    Hellman A, Maietta T, Clum A, et al. Pilot study on the effects of low intensity focused ultrasound in a swine model of neuropathic pain. J Neurosurg. Published online April 16, 2021. doi: 10.3171/2020.9.JNS202962

    • Search Google Scholar
    • Export Citation
  • 39

    Shah SB, Bremner S, Esparza M, et al. Does cryoneurolysis result in persistent motor deficits? A controlled study using a rat peroneal nerve injury model. Reg Anesth Pain Med. 2020;45(4):287292.

    • Search Google Scholar
    • Export Citation
  • 40

    Wilkes D, Li G, Angeles CF, et al. A large animal neuropathic pain model in sheep: a strategy for improving the predictability of preclinical models for therapeutic development. J Pain Res. 2012;5:415424.

    • Search Google Scholar
    • Export Citation
  • 41

    Baron R. Neuropathic pain: a clinical perspective. Handb Exp Pharmacol. 2009;(194):330.

  • 42

    Rosberg MR, Alvarez S, Krarup C, Moldovan M. Functional recovery of regenerating motor axons is delayed in mice heterozygously deficient for the myelin protein P(0) gene. Neurochem Res. 2013;38(6):12661277.

    • Search Google Scholar
    • Export Citation
  • 43

    Henderson Plastics. Pig growth rates and feed trough requirements. Accessed November 18, 2020. http://www.hendersons.co.uk/pigequip/Pig_growth_rate.html

    • Search Google Scholar
    • Export Citation

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