Functional Characterization of Ovine Dorsal Root Ganglion Neurons Reveal Peripheral Sensitization after Osteochondral Defect

Chakrabarti, Sampurna; Ai, Minji; Wong, Katherine; Newell, Karin; Henson, Frances; Smith, Ewan St. John

doi:10.1523/eneuro.0237-21.2021

Cited by 5 publications

(6 citation statements)

References 26 publications

(54 reference statements)

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“…Sensory neuron sensitization is known to underlie the pain-related behavioral changes that occur in rat OA ( 56 ) and sensory neuron hyperexcitability is also common to mouse and sheep models of joint pain ( 13 , 41 , 57 ). Thus, we performed electrophysiological characterization of retrograde labelled, knee-innervating neurons and observed depolarization of the RMP and lowering of the AP threshold in knee-innervating neurons isolated from DMM mice compared to those isolated from sham mice, effects that were not observed in neurons isolated from DMM mice treated with MSCs or MSC-EVs (Fig.…”

Section: Discussionmentioning

confidence: 99%

Human mesenchymal stem cells and derived extracellular vesicles reduce sensory neuron hyperexcitability and pain-related behaviors in a mouse model of osteoarthritis

Hotham

Pattison

et al. 2022

Preprint

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Osteoarthritis (OA) is a common degenerative joint disease characterized by joint pain and stiffness. In humans, mesenchymal stem cells (MSCs) and derived extracellular vesicles (MSC-EVs) have been reported to alleviate pain in knee OA. Here, we used the destabilization of the medial meniscus (DMM) mouse model of OA to investigate mechanisms by which MSCs and MSC-EVs influence pain-related behavior. We found that MSC and MSC-EV treated DMM mice displayed improved OA pain-related behavior (i.e. locomotion, digging and sleep) compared to untreated DMM mice. Improved behavior was not the result of reduced joint damage, but rather knee-innervating sensory neurons from MSC and MSC-EV treated mice did not display the hyperexcitability observed in untreated DMM mice. Furthermore, we found that MSC-EVs normalize sensory neuron hyperexcitability induced by nerve growth factor in vitro. Our study suggests that MSCs and MSC-EVs may reduce pain in OA by direct action on peripheral sensory neurons.

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Section: Discussionmentioning

confidence: 99%

Human mesenchymal stem cells and derived extracellular vesicles reduce sensory neuron hyperexcitability and pain-related behaviors in a mouse model of osteoarthritis

Hotham

Pattison

et al. 2022

Preprint

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“…Pre-clinical chronic pain research has predominantly utilized small animal models. However, there is growing interest in production animal species focusing on developing larger animal models of neuropathic pain for translational studies ( Wilkes et al, 2012 ; Reddy et al, 2018 ; Chakrabarti et al, 2021 ). Additionally, a greater understanding of the neuroimmune contribution to chronic pain in rodents and humans is providing insight into this condition and creating new measurement techniques and treatment opportunities that may also be applicable in livestock.…”

Section: Measuring Pain In Livestockmentioning

confidence: 99%

“…Livestock may be promising translational models of naturally occurring painful conditions in humans ( Herzberg and Bustamante, 2021 ). Sheep are already proving to be useful models of human disease due to their larger size compared to typical rodent models and similar anatomy and histomorphology of regions of interest to human disease, such as the stifle ( Chakrabarti et al, 2021 ) and peripheral nerves ( Alvites et al, 2021 ). Chakrabarti et al (2021) surgically created osteochondral defects on the femoral condyle of the stifle in sheep and demonstrated increased excitability of the ipsilateral dorsal root ganglions consistent with known neural correlates of pain.…”

Section: Neuroimmune Interface In Livestockmentioning

confidence: 99%

“…Sheep are already proving to be useful models of human disease due to their larger size compared to typical rodent models and similar anatomy and histomorphology of regions of interest to human disease, such as the stifle ( Chakrabarti et al, 2021 ) and peripheral nerves ( Alvites et al, 2021 ). Chakrabarti et al (2021) surgically created osteochondral defects on the femoral condyle of the stifle in sheep and demonstrated increased excitability of the ipsilateral dorsal root ganglions consistent with known neural correlates of pain. Despite this neurological evidence of peripheral hypersensitivity, the sheep showed no evidence of clinical lameness at the time of slaughter 2-6 weeks after the lesion was created.…”

Section: Neuroimmune Interface In Livestockmentioning

confidence: 99%

“…Despite this neurological evidence of peripheral hypersensitivity, the sheep showed no evidence of clinical lameness at the time of slaughter 2-6 weeks after the lesion was created. This suggests that early osteochondral defects which can progress to painful osteoarthritis in humans ( Chakrabarti et al, 2021 ) may be missed in sheep. Further investigation of this is warranted to target early treatment and prevention of osteoarthritis in sheep and benefit human patients as well.…”

Section: Neuroimmune Interface In Livestockmentioning

confidence: 99%

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The Neuroimmune Interface and Chronic Pain Through the Lens of Production Animals

et al. 2022

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Communication between the central nervous system (CNS) and the immune system has gained much attention for its fundamental role in the development of chronic and pathological pain in humans and rodent models. Following peripheral nerve injury, neuroimmune signaling within the CNS plays an important role in the pathophysiological changes in pain sensitivity that lead to chronic pain. In production animals, routine husbandry procedures such as tail docking and castration, often involve some degree of inflammation and peripheral nerve injury and consequently may lead to chronic pain. Our understanding of chronic pain in animals is limited by the difficulty in measuring this pathological pain state. In light of this, we have reviewed the current understanding of chronic pain in production animals. We discuss our ability to measure pain and the implications this has on animal welfare and production outcomes. Further research into the neuroimmune interface in production animals will improve our fundamental understanding of chronic pain and better inform human clinical pain management and animal husbandry practices and interventions.

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Role of Human Mesenchymal Stem Cells and Derived Extracellular Vesicles in Reducing Sensory Neuron Hyperexcitability and Pain Behaviors in Murine Osteoarthritis

Hotham

Pattison

et al. 2022

Arthritis & Rheumatology

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Objective Mesenchymal stem/stromal cells (MSCs) and MSC‐derived extracellular vesicles (MSC‐EVs) have been reported to alleviate pain in patients with knee osteoarthritis (OA). We undertook this study to determine whether MSCs and/or MSC‐EVs reduce OA pain through influencing sensory neuron excitability in OA joints. Methods We induced knee OA in adult male C57BL/6J mice through destabilization of the medial meniscus (DMM) surgery. Mice were sorted into 4 experimental groups with 9 mice per group as follows: unoperated sham, untreated DMM, DMM plus MSC treatment, and DMM plus MSC‐EV treatment. Treated mice received either MSCs at week 14 postsurgery or MSC‐EVs at weeks 12 and 14 postsurgery. Mouse behavior was evaluated by digging and rotarod tests and the Digital Ventilated Cage system. At week 16, mouse knee joints were harvested for histology, and dorsal root ganglion (DRG) neurons were isolated for electrophysiology. Furthermore, we induced hyperexcitability in DRG neurons in vitro using nerve growth factor (NGF) then treated these neurons with or without MSC‐EVs and evaluated neuron excitability. Results MSC‐ and MSC‐EV–treated DMM‐operated mice did not display pain‐related behavior changes (in locomotion, digging, and sleep) that occurred in untreated DMM‐operated mice. The absence of pain‐related behaviors in MSC‐ and MSC‐EV–treated mice was not the result of reduced joint damage but rather a lack of knee‐innervating sensory neuron hyperexcitability that was observed in untreated DMM‐operated mice. Furthermore, we found that NGF‐induced sensory neuron hyperexcitability is prevented by MSC‐EV treatment (P < 0.05 versus untreated NGF‐sensitized neurons when comparing action potential threshold). Conclusion MSCs and MSC‐EVs may reduce pain in OA by direct action on peripheral sensory neurons.

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Functional Characterization of Ovine Dorsal Root Ganglion Neurons Reveal Peripheral Sensitization after Osteochondral Defect

Abstract: TitleFunctional characterization of ovine dorsal root ganglion neurons reveal peripheral sensitization after osteochondral defect.

Cited by 5 publications

References 26 publications

Human mesenchymal stem cells and derived extracellular vesicles reduce sensory neuron hyperexcitability and pain-related behaviors in a mouse model of osteoarthritis

Human mesenchymal stem cells and derived extracellular vesicles reduce sensory neuron hyperexcitability and pain-related behaviors in a mouse model of osteoarthritis

The Neuroimmune Interface and Chronic Pain Through the Lens of Production Animals

Role of Human Mesenchymal Stem Cells and Derived Extracellular Vesicles in Reducing Sensory Neuron Hyperexcitability and Pain Behaviors in Murine Osteoarthritis

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