Maladaptive changes in the homeostasis of AEA-TRPV1/CB1R induces pain-related hyperactivity of nociceptors after spinal cord injury
Abstract Background Neuropathic pain resulting from spinal cord injury (SCI) is associated with persistent hyperactivity of primary nociceptors. Anandamide (AEA) has been reported to modulate neuronal excitability and synaptic transmission through activation of cannabinoid type-1 receptors (CB1Rs) a...
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BMC
2025-01-01
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| Series: | Cell & Bioscience |
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| Online Access: | https://doi.org/10.1186/s13578-025-01345-6 |
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| author | JiaQi Hu WenYong Fan Yue Xu XiaoFei Li HaoYang Zhang Shun Li Lei Xue |
| author_facet | JiaQi Hu WenYong Fan Yue Xu XiaoFei Li HaoYang Zhang Shun Li Lei Xue |
| author_sort | JiaQi Hu |
| collection | DOAJ |
| description | Abstract Background Neuropathic pain resulting from spinal cord injury (SCI) is associated with persistent hyperactivity of primary nociceptors. Anandamide (AEA) has been reported to modulate neuronal excitability and synaptic transmission through activation of cannabinoid type-1 receptors (CB1Rs) and transient receptor potential vanilloid 1 (TRPV1). However, the role of AEA and these receptors in the hyperactivity of nociceptors after SCI remains unclear. Results In this study, we investigated the effects of AEA and its receptors on the hyperexcitability of mouse dorsal root ganglion (DRG) neurons after SCI. Using a whole-cell patch-clamp technique, we found that the timing of SCI-induced hyperexcitability in nociceptors paralleled an increase in the endocannabinoid AEA content. The expression of TRPV1 and CB1R was also upregulated at different time points after SCI. High-dose extracellular administration of AEA increased the excitability of naive DRG neurons, leading to the transition from a rapidly accommodating (RA) hypoexcitable state to a highly excitable non-accommodating (NA) state. These AEA-induced transitions were facilitated by increased TRPV1 transcription. Pharmacological and Ca2+ imaging experiments revealed that AEA induced hyperexcitability in nociceptors after SCI via the AEA-TRPV1-Ca2+ pathway, whereas activation of CB1Rs reduced SCI-induced hyperexcitability and maintained cytosolic Ca2+ concentration ([Ca2+]cyto) at low levels in the early stages of SCI. As the AEA and TRPV1 levels increased after SCI, adaptive neuroprotection transitioned to a maladaptive hyperactive state, leading to sustained pain. Conclusions Taken together, this study provides new insights into how endocannabinoids regulate nociceptor activity after SCI, offering potential targets for the treatment of neuropathic pain. |
| format | Article |
| id | doaj-art-59a497e093dd47b88f16e3c6090eed0d |
| institution | Kabale University |
| issn | 2045-3701 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Cell & Bioscience |
| spelling | doaj-art-59a497e093dd47b88f16e3c6090eed0d2025-01-12T12:41:27ZengBMCCell & Bioscience2045-37012025-01-0115111910.1186/s13578-025-01345-6Maladaptive changes in the homeostasis of AEA-TRPV1/CB1R induces pain-related hyperactivity of nociceptors after spinal cord injuryJiaQi Hu0WenYong Fan1Yue Xu2XiaoFei Li3HaoYang Zhang4Shun Li5Lei Xue6State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan UniversityDepartment of Physiology and Neurobiology, School of Life Sciences, Fudan UniversityState Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan UniversityState Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan UniversityState Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan UniversityCenter for Rehabilitation Medicine, Department of Pain Management, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical CollegeState Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan UniversityAbstract Background Neuropathic pain resulting from spinal cord injury (SCI) is associated with persistent hyperactivity of primary nociceptors. Anandamide (AEA) has been reported to modulate neuronal excitability and synaptic transmission through activation of cannabinoid type-1 receptors (CB1Rs) and transient receptor potential vanilloid 1 (TRPV1). However, the role of AEA and these receptors in the hyperactivity of nociceptors after SCI remains unclear. Results In this study, we investigated the effects of AEA and its receptors on the hyperexcitability of mouse dorsal root ganglion (DRG) neurons after SCI. Using a whole-cell patch-clamp technique, we found that the timing of SCI-induced hyperexcitability in nociceptors paralleled an increase in the endocannabinoid AEA content. The expression of TRPV1 and CB1R was also upregulated at different time points after SCI. High-dose extracellular administration of AEA increased the excitability of naive DRG neurons, leading to the transition from a rapidly accommodating (RA) hypoexcitable state to a highly excitable non-accommodating (NA) state. These AEA-induced transitions were facilitated by increased TRPV1 transcription. Pharmacological and Ca2+ imaging experiments revealed that AEA induced hyperexcitability in nociceptors after SCI via the AEA-TRPV1-Ca2+ pathway, whereas activation of CB1Rs reduced SCI-induced hyperexcitability and maintained cytosolic Ca2+ concentration ([Ca2+]cyto) at low levels in the early stages of SCI. As the AEA and TRPV1 levels increased after SCI, adaptive neuroprotection transitioned to a maladaptive hyperactive state, leading to sustained pain. Conclusions Taken together, this study provides new insights into how endocannabinoids regulate nociceptor activity after SCI, offering potential targets for the treatment of neuropathic pain.https://doi.org/10.1186/s13578-025-01345-6Spinal cord injuryAnandamideDRGAction potentialsHyperexcitability |
| spellingShingle | JiaQi Hu WenYong Fan Yue Xu XiaoFei Li HaoYang Zhang Shun Li Lei Xue Maladaptive changes in the homeostasis of AEA-TRPV1/CB1R induces pain-related hyperactivity of nociceptors after spinal cord injury Cell & Bioscience Spinal cord injury Anandamide DRG Action potentials Hyperexcitability |
| title | Maladaptive changes in the homeostasis of AEA-TRPV1/CB1R induces pain-related hyperactivity of nociceptors after spinal cord injury |
| title_full | Maladaptive changes in the homeostasis of AEA-TRPV1/CB1R induces pain-related hyperactivity of nociceptors after spinal cord injury |
| title_fullStr | Maladaptive changes in the homeostasis of AEA-TRPV1/CB1R induces pain-related hyperactivity of nociceptors after spinal cord injury |
| title_full_unstemmed | Maladaptive changes in the homeostasis of AEA-TRPV1/CB1R induces pain-related hyperactivity of nociceptors after spinal cord injury |
| title_short | Maladaptive changes in the homeostasis of AEA-TRPV1/CB1R induces pain-related hyperactivity of nociceptors after spinal cord injury |
| title_sort | maladaptive changes in the homeostasis of aea trpv1 cb1r induces pain related hyperactivity of nociceptors after spinal cord injury |
| topic | Spinal cord injury Anandamide DRG Action potentials Hyperexcitability |
| url | https://doi.org/10.1186/s13578-025-01345-6 |
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