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Microglial P2Y12 receptors regulate microglial activation and surveillance during neuropathic pain
Nan Gu1, Ukpong B Eyo2, Madhuvika Murugan2
1Department of Anesthesiology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi Province 710032, PR China; Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ 08854, USA.
Abstract:
Microglial cells are critical in the pathogenesis of neuropathic pain and several microglial receptors have been proposed to mediate this process. Of these receptors, the P2Y12 receptor is a unique purinergic receptor that is exclusively expressed by microglia in the central nervous system (CNS). In this study, we set forth to investigate the role of P2Y12 receptors in microglial electrophysiological and morphological (static and dynamic) activation during spinal nerve transection (SNT)-induced neuropathic pain in mice. First, we found that a genetic deficiency of the P2Y12 receptor (P2Y12(-/-) mice) ameliorated pain hypersensitivities during the initiation phase of neuropathic pain. Next, we characterised both the electrophysiological and morphological properties of microglia in the superficial spinal cord dorsal horn following SNT injury. We show dramatic alterations including a peak at 3days post injury in microglial electrophysiology while high resolution two-photon imaging revealed significant changes of both static and dynamic microglial morphological properties by 7days post injury. Finally, in P2Y12(-/-) mice, these electrophysiological and morphological changes were ameliorated suggesting roles for P2Y12 receptors in SNT-induced microglial activation. Our results therefore indicate that P2Y12 receptors regulate microglial electrophysiological as well as static and dynamic microglial properties after peripheral nerve injury, suggesting that the microglial P2Y12 receptor could be a potential therapeutic target for the treatment of neuropathic pain.
Insights
The P2Y12 receptor, found exclusively on microglia, plays a key role in neuropathic pain. Blocking this receptor in mice reduced pain and altered microglial activation, suggesting it as a therapeutic target.
Area of Science:
- Neuroscience
- Immunology
- Pain Research
Background:
- Microglial cells are crucial in neuropathic pain development.
- The P2Y12 receptor is uniquely expressed by microglia in the central nervous system (CNS).
Purpose of the Study:
- To investigate the role of P2Y12 receptors in microglial activation during spinal nerve transection (SNT)-induced neuropathic pain.
- To assess the impact of P2Y12 deficiency on pain hypersensitivity and microglial electrophysiological and morphological changes.
Main Methods:
- Utilized P2Y12 receptor-deficient mice (P2Y12(-/-)) and wild-type littermates.
- Induced neuropathic pain via spinal nerve transection (SNT).
- Assessed pain behaviors, microglial electrophysiology, and high-resolution two-photon imaging of microglial morphology (static and dynamic).
Main Results:
- P2Y12 deficiency ameliorated pain hypersensitivity during the initiation phase of neuropathic pain.
- SNT induced significant alterations in microglial electrophysiology (peaking at 3 days post-injury) and morphology (static and dynamic changes by 7 days post-injury).
- These SNT-induced microglial changes were ameliorated in P2Y12(-/-) mice.
Conclusions:
- P2Y12 receptors are critical regulators of microglial electrophysiological and morphological activation following peripheral nerve injury.
- Targeting microglial P2Y12 receptors may offer a novel therapeutic strategy for treating neuropathic pain.
