Institutional Animal Care and Use Committee Considerations for Animal Models of Peripheral Neuropathy

Brabb, Thea; Carbone, Larry; Snyder, Jessica M.; Phillips, Nona

doi:10.1093/ilar/ilt045

Cited by 12 publications

(2 citation statements)

References 53 publications

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“…All rats had recovered from anesthesia within 5 minutes and were walking normally without altered gait. Following recovery from anesthesia the subjects did not demonstrate observable pain behaviors 51 nor clinical evidence of tissue injury. Throughout the duration of the study all the rats were observed to have normal gait and were without visible evidence of inflammation, swelling, increased warmth, weakness, deformities or positional changes noted on the operated hindpaw, at any time.…”

Section: Resultsmentioning

confidence: 93%

The refined biomimetic NeuroDigm GEL™ model of neuropathic pain in a mature rat

et al. 2017

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Background: Many humans suffering with chronic neuropathic pain have no objective evidence of an etiological lesion or disease. Frequently their persistent pain occurs after the healing of a soft tissue injury. Based on clinical observations over time, our hypothesis was that after an injury in mammals the process of tissue repair could cause chronic neural pain. Our objectives were to create the delayed onset of neuropathic pain in rats with minimal nerve trauma using a physiologic hydrogel, and characterize the rats’ responses to known analgesics and a targeted biologic. Methods: In mature male Sprague Dawley rats (age 9.5 months) a percutaneous implant of tissue-derived hydrogel was placed in the musculofascial tunnel of the distal tibial nerve. Subcutaneous morphine (3 mg/kg), celecoxib (10 mg/kg), gabapentin (25 mg/kg) and duloxetine (10 mg/kg) were each screened in the model three times each over 5 months after pain behaviors developed. Sham and control groups were used in all screenings. A pilot study followed in which recombinant human erythropoietin (200 units) was injected by the GEL™ neural procedure site. Results: The GEL group gradually developed mechanical hypersensitivity lasting months. Morphine, initially effective, had less analgesia over time. Celecoxib produced no analgesia, while gabapentin and duloxetine at low doses demonstrated profound analgesia at all times tested. The injected erythropoietin markedly decreased bilateral pain behavior that had been present for over 4 months, p ≤ 0.001. Histology of the GEL group tibial nerve revealed a site of focal neural remodeling, with neural regeneration, as found in nerve biopsies of patients with neuropathic pain. Conclusion: The refined NeuroDigm GEL™ model induces a neural response resulting in robust neuropathic pain behavior. The analgesic responses in this model reflect known responses of humans with neuropathic pain. The targeted recombinant human erythropoietin at the ectopic neural lesion appears to alleviate the persistent pain behavior in the GEL™ model rodents.

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Section: Resultsmentioning

confidence: 93%

The refined biomimetic NeuroDigm GEL™ model of neuropathic pain in a mature rat

et al. 2017

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“…All rats had recovered from anesthesia within 5 minutes and were walking normally without altered gait. Following recovery from anesthesia the subjects did not demonstrate observable pain behaviors (65) or clinical evidence of tissue injury. Throughout the duration of the study all the rats were observed to have normal gait and were without visible evidence of inflammation, swelling, weakness, deformities or positional changes noted on the operated hindfoot, at any time.…”

Section: Behavioral Observationsmentioning

confidence: 93%

Refined biomimetic model of chronic pain is healed with erythropoietin

et al. 2016

Preprint

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Humans suffering with chronic pain may have no evidence of a lesion or disease. They are managed with a morass of drugs and invasive procedures. In many, their persistent pain occurs after the healing of a soft tissue injury, with a neural source hypothesized. Opiates, commonly used to mitigate their symptoms, can cause an increase in neuropathic pain over time. Current animal models of neuropathic pain commonly create direct neural damage with open surgeries using ligatures, neurectomies, chemicals or other forms of intentional trauma. However, we have observed clinically that after an injury in humans, the naturally occurring process of tissue repair can cause chronic neural pain. We show here how the refined biomimetic NeuroDigm GEL TM Model, in the mature male rat, gradually induces neuropathic pain behavior with a nonsurgical percutaneous injection of tissue-derived hydrogel in the tunnel of the distal tibial nerve. This perineural model creates a mononeuritis with the biogenic matrix induction of tissue remodeling, the last stage of tissue repair. Repeated behavioral analgesic testing over 5 months in the model implied a unique predictive validity for all analgesics tested. Morphine, initially effective, had an increase in pain behavior over time, suggesting an opioid-induced hyperalgesia, as seen in humans. Celecoxib produced no analgesia, while gabapentin and duloxetine at low doses had profound analgesia. Histology reveals focal neural remodeling, with neural regeneration, as in human biopsies. For the first time, targeted erythropoietin appears to heal neuropathic pain, by extinguishing bilateral pain behavior present for over 4 months.translational model, neuropathic pain, erythropoietin, neural regeneration, soft tissue injuries, neuritis, tissue repair, hydrogel, animal model of disease, neural remodeling, age, opioid-induced hyperalgesia, morphine resistance, analgesics, refined pain model, matrix remodeling, neuroinflammation, predictive validity, habituation, estrogen Pages 1 -41 factors we used in developing this model were the rodent's correlated human age (51) and the clinical relevance of the biologic pathophysiology embodied by the model (1). Presently, animal models with neuropathic pain behaviors are created using forms of direct intentional nerve trauma or irritation, chemicals, drugs, usually with open surgical procedures (52,53). The most commonly used of these are the Spinal Nerve Ligation (SNL) model (54), the Chronic Constriction Injury (CCI) model (55), and the Spared Nerve Injury (SNI) model (56). These models use ligations, neurectomies or a combination to create pain with sensory and motor debility. While these open surgical models are useful in mimicking direct nerve trauma, they do not reproduce the pathophysiology of the delayed onset of neural pain without debility, as usually happens in many patients with neuropathic pain.Our report details the creation of a biomimetic pain model based on clinical observations of injured patients with soft tissue injuries. The NeuroDigm...

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Care of Surgical and Other Fragile Models

Slate

Shoulson

2020

The Laboratory Rat

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Institutional Animal Care and Use Committee Considerations for Animal Models of Peripheral Neuropathy

Cited by 12 publications

References 53 publications

The refined biomimetic NeuroDigm GEL™ model of neuropathic pain in a mature rat

The refined biomimetic NeuroDigm GEL™ model of neuropathic pain in a mature rat

Refined biomimetic model of chronic pain is healed with erythropoietin

Care of Surgical and Other Fragile Models

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