Human-like cutaneous neuropathologies associated with a porcine model of peripheral neuritis: A translational platform for neuropathic pain

Rice, Frank L.; Castel, David; Ruggiero, Elizabeth; Dockum, Marilyn; Houk, George; Sabbag, Itai; Albrecht, Phillip J.; Meilin, Sigal

doi:10.1016/j.ynpai.2018.07.002

Cited by 14 publications

(26 citation statements)

References 80 publications

(122 reference statements)

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“…Slides were incubated under primary antibodies for one night with refrigeration. Immunolabeling for PGP and CGRP innervation, and Nav1.6, Nav1.7, and CGRP expression and immunolabeling among keratinocytes has been well-validated and previously published by our group ( 7 , 36 , 44 , 56 , 57 , 59 , 60 ).…”

Section: Methodssupporting

confidence: 67%

“…Immunolabeling for PGP and CGRP innervation, and Nav1.6, Nav1.7, and CGRP expression and immunolabeling among keratinocytes has been well-validated and previously published by our group (7,36,44,56,57,59,60). Following primary antibody incubations, slides were rinsed in excess PBS and then incubated with appropriate species secondary antibodies conjugated with either Cy3 (red fluorescence) or Alexa488 (green fluorescence) diluted 1:500 in PBS-T at room temperature for 2 hrs.…”

Section: Biopsy Processingmentioning

confidence: 96%

“…Consistent with the IMMPACT recommendations for expanded research on skin biopsies to identify reliable objective chronic pain biomarkers, we developed a comprehensive evaluation platform, referred to as chemomorphometric analysis (CMA), that extensively uses PGP immunolabeling among combinations of immunolabels for numerous functionally implicated neuronal signaling molecules. By varying the combinations among alternating serial sections, CMA has enabled comprehensive biomarker profiling of normal, experimental, and pathological specimens from human, monkey, and a variety of rodent and non-primate mammalian species (7,36,(56)(57)(58)(59)(60).…”

Section: Introductionmentioning

confidence: 99%

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Keratinocyte Biomarkers Distinguish Painful Diabetic Peripheral Neuropathy Patients and Correlate With Topical Lidocaine Responsiveness

Albrecht

Houk²,

Ruggiero³

et al. 2021

Front. Pain Res.

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This study investigated quantifiable measures of cutaneous innervation and algesic keratinocyte biomarkers to determine correlations with clinical measures of patient pain perception, with the intent to better discriminate between diabetic patients with painful diabetic peripheral neuropathy (PDPN) compared to patients with low-pain diabetic peripheral neuropathy (lpDPN) or healthy control subjects. A secondary objective was to determine if topical treatment with a 5% lidocaine patch resulted in correlative changes among the quantifiable biomarkers and clinical measures of pain perception, indicative of potential PDPN pain relief. This open-label proof-of-principle clinical research study consisted of a pre-treatment skin biopsy, a 4-week topical 5% lidocaine patch treatment regimen for all patients and controls, and a post-treatment skin biopsy. Clinical measures of pain and functional interference were used to monitor patient symptoms and response for correlation with quantitative skin biopsy biomarkers of innervation (PGP9.5 and CGRP), and epidermal keratinocyte biomarkers (Nav1.6, Nav1.7, CGRP). Importantly, comparable significant losses of epidermal neural innervation (intraepidermal nerve fibers; IENF) and dermal innervation were observed among PDPN and lpDPN patients compared with control subjects, indicating that innervation loss alone may not be the driver of pain in diabetic neuropathy. In pre-treatment biopsies, keratinocyte Nav1.6, Nav1.7, and CGRP immunolabeling were all significantly increased among PDPN patients compared with control subjects. Importantly, no keratinocyte biomarkers were significantly increased among the lpDPN group compared with control. In post-treatment biopsies, the keratinocyte Nav1.6, Nav1.7, and CGRP immunolabeling intensities were no longer different between control, lpDPN, or PDPN cohorts, indicating that lidocaine treatment modified the PDPN-related keratinocyte increases. Analysis of the PDPN responder population demonstrated that increased pretreatment keratinocyte biomarker immunolabeling for Nav1.6, Nav1.7, and CGRP correlated with positive outcomes to topical lidocaine treatment. Epidermal keratinocytes modulate the signaling of IENF, and several analgesic and algesic signaling systems have been identified. These results further implicate epidermal signaling mechanisms as modulators of neuropathic pain conditions, highlight a novel potential mode of action for topical treatments, and demonstrate the utility of comprehensive skin biopsy evaluation to identify novel biomarkers in clinical pain studies.

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Section: Methodssupporting

confidence: 67%

Section: Biopsy Processingmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

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Keratinocyte Biomarkers Distinguish Painful Diabetic Peripheral Neuropathy Patients and Correlate With Topical Lidocaine Responsiveness

Albrecht

Houk²,

Ruggiero³

et al. 2021

Front. Pain Res.

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“…A recent article investigating proximal sciatic nerve irritation in as a porcine model of chronic neuropathic pain found significant reduction in fluorescently labeled IENF between 7 and 14 days postprocedure, whereas loss of dermal innervation was more gradual. 118 Marked reduction in distal IENF density has also been reported in an feline immunodeficiency virus infection model of HIV-associated neuropathy. 5…”

Section: Intraepidermal Nerve Fiber Analysis In Other Laboratory Speciesmentioning

confidence: 83%

Intraepidermal Nerve Fiber Analysis in Human Patients and Animal Models of Peripheral Neuropathy: A Comparative Review

2019

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Analysis of intraepidermal nerve fibers (IENFs) in skin biopsy samples has become a standard clinical tool for diagnosing peripheral neuropathies in human patients. Compared to sural nerve biopsy, skin biopsy is safer, less invasive, and can be performed repeatedly to facilitate longitudinal assessment. Intraepidermal nerve fiber analysis is also more sensitive than conventional nerve histology or electrophysiological tests for detecting damage to small-diameter sensory nerve fibers. The techniques used for IENF analysis in humans have been adapted for large and small animal models and successfully used in studies of diabetic neuropathy, chemotherapy-induced peripheral neuropathy, HIV-associated sensory neuropathy, among others. Although IENF analysis has yet to become a routine end point in nonclinical safety testing, it has the potential to serve as a highly relevant indicator of sensory nerve fiber status in neurotoxicity studies, as well as development of neuroprotective and neuroregenerative therapies. Recently, there is also interest in the evaluation of IENF via skin biopsy as a biomarker of small fiber neuropathy in the regulatory setting. This article provides an overview of the anatomic and pathophysiologic principles behind IENF analysis, its use as a diagnostic tool in humans, and applications in animal models with focus on comparative methodology and considerations for study design.

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“…These findings suggest pigs as a new and promising model organisms to study neuropathic pain‐associated changes in the peripheral nervous system and their treatment, for example, the application of local analgesics (Castel et al., 2017). On the basis of this knowledge, a porcine trauma model was established (Rice et al., 2018). The animals developed a peripheral neuritis after loose ligatures were tied around the sciatic nerve.…”

Section: Animal Modelsmentioning

confidence: 99%

Neuropathic pain: Spotlighting anatomy, experimental models, mechanisms, and therapeutic aspects

Kankowski

Grothe

Haastert‐Talini

2021

Eur J of Neuroscience

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Pain serves to protect us from physical damage. But unlike physiologic pain, neuropathic pain does not originate from adequate stimulation of distal nerve endings. In neuropathic pain, the protective nature of pain gets lost. An initial event triggers activity driven changes in the periphery that lead to painful sensations. While the acute stimulus decays, persisting alterations in the peripheral nervous system continuously alert the whole body. As a consequence, the patient experiences

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Human-like cutaneous neuropathologies associated with a porcine model of peripheral neuritis: A translational platform for neuropathic pain

Abstract: Highlights Pig peripheral neuritis trauma model mimics cutaneous human pathologies. Pig skin anatomically similar to humans, unlike rodent. Pig PNT model provides better data than rodent for translational pain research.

Cited by 14 publications

References 80 publications

Keratinocyte Biomarkers Distinguish Painful Diabetic Peripheral Neuropathy Patients and Correlate With Topical Lidocaine Responsiveness

Keratinocyte Biomarkers Distinguish Painful Diabetic Peripheral Neuropathy Patients and Correlate With Topical Lidocaine Responsiveness

Intraepidermal Nerve Fiber Analysis in Human Patients and Animal Models of Peripheral Neuropathy: A Comparative Review

Neuropathic pain: Spotlighting anatomy, experimental models, mechanisms, and therapeutic aspects

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