Microglial P2X4 receptors are essential for spinal neurons hyperexcitability and tactile allodynia in male and female neuropathic mice

Gilabert, Damien; Duveau, Alexia; Carracedo, Sara; Linck, Nathalie; Langla, Adeline; Muramatsu, Rieko; Koch-Nolte, Friedrich; Rassendren, François; Grutter, Thomas; Fossat, Pascal; Boué-Grabot, Eric; Ulmann, Lauriane

doi:10.1016/j.isci.2023.108110

Cited by 11 publications

(3 citation statements)

References 55 publications

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“…In contrast, Gilabert et al reported that spared nerve injury induced an increase of microglial number in the spinal dorsal horn and mechanical hypersensitivity, regardless of sex. 23) Additionally, our results demonstrate that dIoN-CCI increases the number and volume of microglia in the Sp5C, which were also suppressed by peri-neural treatment with anti-HMGB1 nAb in female as well as male mice. 7) Indeed, although it has been suggested that there are sex differences in microglial function, there is no definitive conclusion to this argument.…”

Section: Discussionmentioning

confidence: 55%

Perineural Treatment with High Mobility Group Box-1 Monoclonal Antibody Prevents Initiation of Pain-Like Behaviors in Female Mice with Trigeminal Neuropathy

Ma,

Nakamura,

Kochi

et al. 2024

Biological & Pharmaceutical Bulletin

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Post-traumatic trigeminal neuropathy (PTTN) is a type of chronic pain caused by damage to the trigeminal nerve. A previous study reported that pretreatment with anti-high mobility group box-1 (HMGB1) neutralizing antibodies (nAb) prevented the onset of PTTN following distal infraorbital nerve chronic constriction injury (dIoN-CCI) in male mice. Clinical evidence indicates a high incidence of PTTN in females. Although our previous study found that perineural HMGB1 is crucial in initiation of PTTN in male mice, it is currently unknown whether HMGB1 is also involved in the pathogenesis of PTTN in female mice. Therefore, in the current study, we examined the effect of anti-HMGB1 nAb on pain-like behavior in female mice following dIoN-CCI surgery. We found that dIoN-CCI surgery enhanced reactivity to mechanical and cold stimuli in female mice, which was suppressed by treatment with anti-HMGB1 nAb. Moreover, the increase in macrophages after dIoN-CCI was significantly attenuated by pretreatment with anti-HMGB1 nAb. Furthermore, anti-HMGB1 nAb treatment inhibited microglial activation in the trigeminal spinal tract nucleus. These data suggest that HMGB1 also plays a crucial role in the onset of PTTN after nerve injury in female mice. Thus, anti-HMGB1 nAb could be a novel therapeutic agent for inhibiting the onset of PTTN in female and male mice.

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Section: Discussionmentioning

confidence: 55%

Perineural Treatment with High Mobility Group Box-1 Monoclonal Antibody Prevents Initiation of Pain-Like Behaviors in Female Mice with Trigeminal Neuropathy

Ma,

Nakamura,

Kochi

et al. 2024

Biological & Pharmaceutical Bulletin

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“…Reactive microglia may also be a causal agent for ADHD-like symptoms in the spontaneously hypertensive rat model ( Zhang et al, 2022 ), although in other models (i.e., traumatic brain injury-induced ADHD-like conditions) microglia inhibition with minocycline did not affect impulsivity and attention deficits ( Pechacek et al, 2022 ). Although P2X4 was proposed as a male-biased microglial mediator of chronic pain ( Halievski et al, 2020 ), recent findings showed that microglial P2X4 is crucial for neuropathic pain, regardless of sex ( Gilabert et al, 2023 ). In agreement, sex comparisons in WT and P2X4KO mice did not reveal any differences between males and females in hyperactivity, impulsivity or sensory thresholds.…”

Section: Discussionmentioning

confidence: 99%

P2X4 signalling contributes to hyperactivity but not pain sensitization comorbidity in a mouse model of attention deficit/hyperactivity disorder

Bou Sader Nehme,

Sanchez-Sarasua,

Adel

et al. 2024

Front. Pharmacol.

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Introduction: Attention deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder characterized by hyperactivity, inattention, and impulsivity that often persist until adulthood. Frequent comorbid disorders accompany ADHD and two thirds of children diagnosed with ADHD also suffer from behavioural disorders and from alteration of sensory processing. We recently characterized the comorbidity between ADHD-like symptoms and pain sensitisation in a pharmacological mouse model of ADHD, and we demonstrated the implication of the anterior cingulate cortex and posterior insula. However, few studies have explored the causal mechanisms underlying the interactions between ADHD and pain. The implication of inflammatory mechanisms has been suggested but the signalling pathways involved have not been explored.Methods: We investigated the roles of purinergic signalling, at the crossroad of pain and neuroinflammatory pathways, by using a transgenic mouse line that carries a total deletion of the P2X4 receptor.Results: We demonstrated that P2X4 deletion prevents hyperactivity in the mouse model of ADHD. In contrast, the absence of P2X4 lowered thermal pain thresholds in sham conditions and did not affect pain sensitization in ADHD-like conditions. We further analysed microglia reactivity and the expression of inflammatory markers in wild type and P2X4KO mice. Our results revealed that P2X4 deletion limits microglia reactivity but at the same time exerts proinflammatory effects in the anterior cingulate cortex and posterior insula.Conclusion: This dual role of P2X4 could be responsible for the differential effects noted on ADHD-like symptoms and pain sensitization and calls for further studies to investigate the therapeutic benefit of targeting the P2X4 receptor in ADHD patients.

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“…We used male rats to investigate the modulation of microglial P2X 4 receptors by DAP in the present study. However, a recent study showed that microglia P2X 4 receptors are essential for both spinal neuron hyperexcitability and abnormal tactile pain in both male and female neuropathic mice [ 37 ]. This contradictory result may be due to differences in the breeding conditions of the mice tested.…”

Section: Discussionmentioning

confidence: 99%

Daphnetin Ameliorates Neuropathic Pain via Regulation of Microglial Responses and Glycerophospholipid Metabolism in the Spinal Cord

Liang,

Zhang,

Zhang

et al. 2024

Pharmaceuticals

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Neuropathic pain (NP) is a common type of chronic pain caused by a lesion or disease of the somatosensory nervous system. This condition imposes a considerable economic burden on society and patients. Daphnetin (DAP) is a natural product isolated from a Chinese medicinal herb with various pharmacological activities, such as anti-inflammatory and analgesic properties. However, the underlying mechanisms of these effects are not fully understood. In the present study, we aimed to investigate DAP’s anti-inflammatory and analgesic effects and explore the underlying mechanisms of action. The NP model was established as chronic constrictive injury (CCI) of the sciatic nerve, and pain sensitivity was evaluated by measuring the mechanical withdrawal threshold (MWT) and thermal withdrawal threshold (TWT). The activation of microglia in the spinal dorsal horn was measured via immunofluorescence staining. Protein levels were measured using a western blot assay. Using a mass-spectrometry proteomics platform and an LC-MS/MS-based metabolomics platform, proteins and metabolites in spinal cord tissues were extracted and analyzed. DAP treatment ameliorated the MWT and TWT in CCI rats. The expression of IL-1β, IL-6, and TNF-α was inhibited by DAP treatment in the spinal cords of CCI rats. Moreover, the activation of microglia was suppressed after DAP treatment. The elevation in the levels of P2X4, IRF8, IRF5, BDNF, and p-P38/P38 in the spinal cord caused by CCI was inhibited by DAP. Proteomics and metabolomics results indicated that DAP ameliorated the imbalance of glycerophospholipid metabolism in the spinal cords of CCI rats. DAP can potentially ameliorate NP by regulating microglial responses and glycerophospholipid metabolism in the CCI model. This study provides a pharmacological justification for using DAP in the management of NP.

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Microglial P2X4 receptors are essential for spinal neurons hyperexcitability and tactile allodynia in male and female neuropathic mice

Cited by 11 publications

References 55 publications

Perineural Treatment with High Mobility Group Box-1 Monoclonal Antibody Prevents Initiation of Pain-Like Behaviors in Female Mice with Trigeminal Neuropathy

Perineural Treatment with High Mobility Group Box-1 Monoclonal Antibody Prevents Initiation of Pain-Like Behaviors in Female Mice with Trigeminal Neuropathy

P2X4 signalling contributes to hyperactivity but not pain sensitization comorbidity in a mouse model of attention deficit/hyperactivity disorder

Daphnetin Ameliorates Neuropathic Pain via Regulation of Microglial Responses and Glycerophospholipid Metabolism in the Spinal Cord

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