Role of Primary Afferents in Arthritis Induced Spinal Microglial Reactivity

Kwok, Charlie H.T.; Kohro, Yuta; Mousseau, Michael; O’Brien, Melissa; Matyas, John R.; McDougall, Jason J.

doi:10.3389/fimmu.2021.626884

Cited by 13 publications

(8 citation statements)

References 68 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…DRG (and spinal cord) changes have been recently recognized to be associated with pain chronicity in OA, especially at the advanced stage of disease [ 49 ]. More recent literature has documented profound molecular and cellular changes in the DRG of various OA models, including changes in neuronal excitability [ 50 ], intense proliferation and activation of microglia that mediate neuroinflammation, and neuronal damage [ 15 , 51 – 53 ], transcriptomic upregulation of the genes for neuroimmune interactions [ 54 ], sensitized PSN nociceptive voltage-gated ion channels [ 16 , 55 ] and mechanosensitive ion channels [ 42 ], and upregulated chemokine and cytokine production [ 56 ], all contributing interrelatedly in driving continuous neural sensitization after cessation of joint inflammation.…”

Section: Discussionmentioning

confidence: 99%

Selective block of sensory neuronal T-type/Cav3.2 activity mitigates neuropathic pain behavior in a rat model of osteoarthritis pain

Itson-Zoske

Shin

et al. 2022

Arthritis Res Ther

View full text Add to dashboard Cite

Background Peripheral and central nociceptive sensitization is a critical pathogenetic component in osteoarthritis (OA) chronic pain. T-type calcium channel 3.2 (CaV3.2) regulates neuronal excitability and plays important roles in pain processing. We previously identified that enhanced T-type/CaV3.2 activity in the primary sensory neurons (PSNs) of dorsal root ganglia (DRG) is associated with neuropathic pain behavior in a rat model of monosodium iodoacetate (MIA)-induced knee OA. PSN-specific T-type/CaV3.2 may therefore represent an important mediator in OA painful neuropathy. Here, we test the hypothesis that the T-type/CaV3.2 channels in PSNs can be rationally targeted for pain relief in MIA-OA. Methods MIA model of knee OA was induced in male and female rats by a single injection of 2 mg MIA into intra-knee articular cavity. Two weeks after induction of knee MIA-OA pain, recombinant adeno-associated viruses (AAV)-encoding potent CaV3.2 inhibitory peptide aptamer 2 (CaV3.2iPA2) that have been characterized in our previous study were delivered into the ipsilateral lumbar 4/5 DRG. Effectiveness of DRG-CaV3.2iPA2 treatment on evoked (mechanical and thermal) and spontaneous (conditioned place preference) pain behavior, as well as weight-bearing asymmetry measured by Incapacitance tester, in the arthritic limbs of MIA rats were evaluated. AAV-mediated transgene expression in DRG was determined by immunohistochemistry. Results AAV-mediated expression of CaV3.2iPA2 selective in the DRG-PSNs produced significant and comparable mitigations of evoked and spontaneous pain behavior, as well as normalization of weight-bearing asymmetry in both male and female MIA-OA rats. Analgesia of DRG-AAV-CaV3.2iPA1, another potent CaV3.2 inhibitory peptide, was also observed. Whole-cell current-clamp recordings showed that AAV-mediated CaV3.2iPA2 expression normalized hyperexcitability of the PSNs dissociated from the DRG of MIA animals, suggesting that CaV3.2iPA2 attenuated pain behavior by reversing MIA-induced neuronal hyperexcitability. Conclusions Together, our results add therapeutic support that T-type/CaV3.2 in primary sensory pathways contributes to MIA-OA pain pathogenesis and that CaV3.2iPAs are promising analgesic leads that, combined with AAV-targeted delivery in anatomically segmental sensory ganglia, have the potential for further development as a peripheral selective T-type/CaV3.2-targeting strategy in mitigating chronic MIA-OA pain behavior. Validation of the therapeutic potential of this strategy in other OA models may be valuable in future study.

show abstract

Section: Discussionmentioning

confidence: 99%

Selective block of sensory neuronal T-type/Cav3.2 activity mitigates neuropathic pain behavior in a rat model of osteoarthritis pain

Itson-Zoske

Shin

et al. 2022

Arthritis Res Ther

View full text Add to dashboard Cite

show abstract

“…Additionally, glial cells are robustly activated in injured or diseased states and are involved in a variety of neuropathological changes, including chronic pain [44]. It was reported that early activation of joint nociceptors after injury triggers spinal microglial activation [45]. Microglia release cytokines (such as TNF-α and IL-18), growth factors (such as BDNF), and ATP, which in turn stimulates astrocytes and neurons to induce central sensitization [46].…”

Section: Discussionmentioning

confidence: 99%

Neuronal CRMP2 phosphorylation inhibition by the flavonoid, naringenin, contributes to the reversal of spinal sensitization and arthritic pain improvement

et al. 2022

View full text Add to dashboard Cite

Background Rheumatoid arthritis patients usually suffer from arthritic chronic pain. However, due to an incomplete understanding of the mechanisms underlying autoimmune disorders, the management of arthritic pain is unsatisfactory. Here, we investigated the analgesic effect and underlying mechanism of the natural flavonoid naringenin (NAR) in collagen-induced arthritis (CIA) pain. Methods NAR was injected (i.p.) once per day for 42 days after initial immunization, and rats were sacrificed on the 28th (the 21st day after final immunization, PID 21) and 42nd days (PID 35). The inflammatory factors, central sensitization indicators, and CRMP2 phosphorylation, as well as the anti-rheumatoid activity and analgesic effect of NAR, were further investigated. Results We found that NAR decreased the arthritis score and paw swelling, as well as the mechanical and thermal pain. The immunofluorescence results also showed a dose dependent effect of NAR on reducing the expressions of spinal cFos, IBA-1, and GFAP on the 28th (PID 21) and 42nd day (PID 35). NAR decreased the phosphorylation of CRMP2 S522 and the expression of the kinase CDK5 in the spinal dorsal horn, but pCRMP2 Y479 was unchanged. In addition, CRMP2 was co-localized with NEUN, but not IBA-1 or GFAP, indicating the involvement of neural CRMP2 phosphorylation in CIA-related pain. Finally, CRMP2 S522 phosphorylation selective inhibitor (S)-lacosamide also alleviated arthritic pain. Conclusions Taken together, our results demonstrate that NAR alleviates inflammation and chronic pain in CIA model, which might be related to its inhibition of neuronal CRMP2 S522 phosphorylation, potentially mitigating the central sensitization. Our study provide evidence for the potential use of NAR as non-opioid-dependent analgesia in arthritic pain.

show abstract

“…No animals exceeded these limits. The MIA dose was based on previous studies 25 , 40 and on a pilot study (Figure S1, http://links.lww.com/PR9/A224 ). Intra-articular injection of 2 mg/50 µL of MIA produced robust pain behavior and OA-like knee pathology in young adult female Sprague-Dawley rats, while a 1 mg dose produced variable joint pathology without significant pain behavior.…”

Section: Methodsmentioning

confidence: 99%

“…No animals exceeded these limits. The MIA dose was based on previous studies 25,40 and on a pilot study (Figure S1, http://links. lww.com/PR9/A224).…”

Section: Induction Of the Monosodium Iodoacetate Model Of Osteoarthri...mentioning

confidence: 99%

Sustained morphine exposure alters spinal NMDA receptor and astrocyte expression and exacerbates chronic pain behavior in female rats

Gonçalves,

Woodhams,

et al. 2024

PR9

View full text Add to dashboard Cite

Introduction: Sustained opioid use has long-term negative impacts on future pain experience, particularly in women. This study aimed to investigate the underlying spinal neurobiology of this clinical observation in an experimental model of joint pain. Objectives: In this study, we tested the hypothesis that sustained opioid treatment exacerbates chronic pain responses and alters spinal cord dorsal horn astrogliosis and the expression of GluN2B-containing N-methyl-d-aspartate receptors in female rats. Methods: Subcutaneous morphine (3 mg/kg) or saline was administered twice daily for 1 week before inducing a model of joint knee pain (intra-articular injection of 2 mg of monosodium iodoacetate [MIA]) in adult female Sprague-Dawley rats, with pain-free controls receiving 50 µL of saline. Pain behavior (weight-bearing and mechanical paw withdrawal thresholds) was measured at baseline and at intervals thereafter. Twice-daily morphine/saline treatment was continued for up to 3 weeks after intra-articular injections, and spinal cord tissue was collected for Western blot analyses. Results: Area under the curve analysis of weight-bearing asymmetry confirmed a significant exacerbation of pain behavior in the morphine/MIA group, compared with the saline/MIA group (F(3,18) = 46.3, P < 0.0001), despite comparable joint damage in both groups. Sustained morphine treatment was associated with significant elevations in dorsal horn expression of astrocytic glial fibrillary acidic protein (27 ± 5% increase) and neuronal GluN2B (80 ± 30% increase), but not microglial IBA1, irrespective of the model of joint pain. Conclusion: These data suggest that sustained morphine treatment in female rats drives spinal cord plasticity, including spinal astrogliosis and the expression of GluN2B-containing N-methyl-d-aspartate receptors, priming the dorsal horn to incoming sensory inputs and producing exacerbated pain responses.

show abstract

Role of Primary Afferents in Arthritis Induced Spinal Microglial Reactivity

Cited by 13 publications

References 68 publications

Selective block of sensory neuronal T-type/Cav3.2 activity mitigates neuropathic pain behavior in a rat model of osteoarthritis pain

Selective block of sensory neuronal T-type/Cav3.2 activity mitigates neuropathic pain behavior in a rat model of osteoarthritis pain

Neuronal CRMP2 phosphorylation inhibition by the flavonoid, naringenin, contributes to the reversal of spinal sensitization and arthritic pain improvement

Sustained morphine exposure alters spinal NMDA receptor and astrocyte expression and exacerbates chronic pain behavior in female rats

Contact Info

Product

Resources

About