scholarly journals Refined biomimetic model of chronic pain is healed with erythropoietin

2016 ◽  
Author(s):  
Mary R. Hannaman ◽  
Douglas A. Fitts ◽  
Rose M. Doss ◽  
David E. Weinstein ◽  
Joseph L. Bryant
Keyword(s):  
Chronic Pain ◽  
Neuropathic Pain ◽  
Soft Tissue ◽  
Predictive Validity ◽  
Tissue Repair ◽  
Pain Behavior ◽  
Neural Regeneration ◽  
Opioid Induced Hyperalgesia ◽  
Neural Remodeling ◽  
Over Time

AbstractHumans 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 GELTM 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 neural 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

scholarly journals The refined biomimetic NeuroDigm GEL™ Model of neuropathic pain in the mature rat

F1000Research ◽  
2016 ◽  
Vol 5 ◽  
pp. 2516 ◽  
Author(s):  
Mary R. Hannaman ◽  
Douglas A. Fitts ◽  
Rose M. Doss ◽  
David E. Weinstein ◽  
Joseph L. Bryant
Keyword(s):  
Neuropathic Pain ◽  
Recombinant Human Erythropoietin ◽  
Tissue Injury ◽  
Soft Tissue Injury ◽  
Pain Behavior ◽  
Neural Regeneration ◽  
Male Rat ◽  
Human Erythropoietin ◽  
Neural Remodeling ◽  
Over Time

Background:Many humans suffering with chronic pain have no clinical evidence of a lesion or disease. They are managed with a morass of drugs and invasive procedures. Opiates usually become less effective over time. In many, their persistent pain occurs after the healing of a soft tissue injury. Current animal models of neuropathic pain typically create direct neural damage with open surgeries using ligatures, neurectomies, chemicals or other forms of deliberate trauma. However, we have observed clinically that after an injury in humans, the naturally occurring process of tissue repair can cause chronic neural pain.Methods:We demonstrate how the refined biomimetic NeuroDigm GEL™ Model, in the mature male rat, gradually induces neuropathic pain behavior with a nonsurgical percutaneous implant of tissue-derived hydrogel in the musculo-fascial tunnel of the distal tibial nerve. Morphine, Celecoxib, Gabapentin and Duloxetine were each screened in the model three times each over 5 months after pain behaviors developed. A pilot study followed in which recombinant human erythropoietin was applied to the GEL neural procedure site.Results:The GEL Model gradually developed neuropathic pain behavior lasting months. Morphine, initially effective, had less analgesia over time. Celecoxib produced no analgesia, while gabapentin and duloxetine at low doses had profound analgesia at all times tested. The injected erythropoietin markedly decreased bilateral pain behavior that had been present for over 4 months. Histology revealed a site of focal neural remodeling, with neural regeneration, as in human biopsies.Conclusion:The refined NeuroDigm GEL™ Model induces localized neural remodeling resulting in robust neuropathic pain behavior. The analgesics responses in this model reflect known responses of humans with neuropathic pain. The targeted recombinant human erythropoietin appears to heal the ectopic focal neural site, as demonstrated by the extinguishing of neuropathic pain behavior present for over 4 months.

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

F1000Research ◽  
2017 ◽  
Vol 5 ◽  
pp. 2516 ◽  
Author(s):  
Mary R. Hannaman ◽  
Douglas A. Fitts ◽  
Rose M. Doss ◽  
David E. Weinstein ◽  
Joseph L. Bryant
Keyword(s):  
Neuropathic Pain ◽  
Recombinant Human Erythropoietin ◽  
Tibial Nerve ◽  
Soft Tissue Injury ◽  
Persistent Pain ◽  
Pain Behavior ◽  
Neural Regeneration ◽  
Human Erythropoietin ◽  
Objective Evidence ◽  
Over Time

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.

scholarly journals Nuclear Factor κB-COX2 Pathway Activation in Non-myelinating Schwann Cells Is Necessary for the Maintenance of Neuropathic Pain in vivo

2022 ◽  
Vol 15 ◽  
Author(s):  
Alison Xiaoqiao Xie ◽  
Sarah Taves ◽  
Ken McCarthy
Keyword(s):  
Chronic Pain ◽  
Neuropathic Pain ◽  
Schwann Cells ◽  
Nerve Injury ◽  
Glial Cells ◽  
Nuclear Factor Κb ◽  
Pain Behavior ◽  
Nuclear Factor ◽  
Nociceptive Neurons

Chronic neuropathic pain leads to long-term changes in the sensitivity of both peripheral and central nociceptive neurons. Glial fibrillary acidic protein (GFAP)-positive glial cells are closely associated with the nociceptive neurons including astrocytes in the central nervous system (CNS), satellite glial cells (SGCs) in the sensory ganglia, and non-myelinating Schwann cells (NMSCs) in the peripheral nerves. Central and peripheral GFAP-positive cells are involved in the maintenance of chronic pain through a host of inflammatory cytokines, many of which are under control of the transcription factor nuclear factor κB (NFκB) and the enzyme cyclooxygenase 2 (COX2). To test the hypothesis that inhibiting GFAP-positive glial signaling alleviates chronic pain, we used (1) a conditional knockout (cKO) mouse expressing Cre recombinase under the hGFAP promoter and a floxed COX2 gene to inactivate the COX2 gene specifically in GFAP-positive cells; and (2) a tet-Off tetracycline transactivator system to suppress NFκB activation in GFAP-positive cells. We found that neuropathic pain behavior following spared nerve injury (SNI) significantly decreased in COX2 cKO mice as well as in mice with decreased glial NFκB signaling. Additionally, experiments were performed to determine whether central or peripheral glial NFκB signaling contributes to the maintenance of chronic pain behavior following nerve injury. Oxytetracycline (Oxy), a blood-brain barrier impermeable analog of doxycycline was employed to restrict transgene expression to CNS glia only, leaving peripheral glial signaling intact. Signaling inactivation in central GFAP-positive glia alone failed to exhibit the same analgesic effects as previously observed in animals with both central and peripheral glial signaling inhibition. These data suggest that the NFκB-COX2 signaling pathway in NMSCs is necessary for the maintenance of neuropathic pain in vivo.

Operant Management of Chronic Pain Behavior

1978 ◽  
Vol 23 (7) ◽  
pp. 533-534
Author(s):  
SAMUEL F. DWORKIN
Keyword(s):  
Chronic Pain ◽  
Pain Behavior

scholarly journals The Safety and Effect of Local Botulinumtoxin A Injections for Long-Term Management of Chronic Pain in Post-Herpetic Neuralgia: Literature Review and Cases Report Treated with Incobotulinumtoxin A

2021 ◽  
Vol 11 (8) ◽  
pp. 758
Author(s):  
Songjin Ri ◽  
Anatol Kivi ◽  
Jörg Wissel
Keyword(s):  
Chronic Pain ◽  
Neuropathic Pain ◽  
Adverse Events ◽  
Case Reports ◽  
Pain Reduction ◽  
Post Herpetic Neuralgia ◽  
Botulinumtoxin A ◽  
Incobotulinumtoxin A ◽  
Term Management

There are few reports on the safety and effectiveness of long-term botulinumtoxin A (BoNT A) therapy in severe chronic pain of post-herpetic neuralgia (PHN). The literature was searched with the term “neuropathic pain” and “botulinum” on PubMed (up to 29 February 2020). Pain was assessed with the Visual Analogue Scale (VAS) before and after BoNT A therapy. A total of 10 clinical trials and six case reports including 251 patients with PHN were presented. They showed that BoNT A therapy had significant pain reduction (up to 30–50%) and improvement in quality of life. The effect duration seems to be correlated with BoNT A doses injected per injection site. Intervals between BoNT A injections were 10–14 weeks. No adverse events were reported in cases and clinical studies, even in the two pregnant women, whose babies were healthy. The repeated (≥6 times) intra/subcutaneous injections of incobotulinumtoxin A (Xeomin®, Merz Pharmaceuticals, Germany) over the two years of our three cases showed marked pain reduction and no adverse events. Adjunctive local BoNT A injection is a promising option for severe PHN, as a safe and effective therapy in long-term management for chronic neuropathic pain. Its effect size and -duration seem to be depended on the dose of BoNT A injected per each point.

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