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Abstract
Peripheral nerve injury causes neuropathic pain and microglia activation. P2Y12 receptors on microglia are thought to be a key player in the surveillance of the local environment, but whether or how these receptors are engaged in the cross-talk between microglia and neurons of the dorsal horn remain ambiguous. Using a rodent model of nerve injury-induced pain, we investigated the roles of P2Y12 in microglia activation, excitatory synaptic transmission, and nociceptive allodynia. We found that spinal nerve ligation (SNL) significantly increased the level of P2Y12 receptors specifically in the microglia of the ipsilateral dorsal horn. Injections of P2Y12 antagonists (MRS2395 or clopidogrel) attenuated microglia activation and increased the paw withdrawal latency in response to thermal stimuli on the ipsilateral side without affecting the basal threshold on the contralateral side. These effects on pain behaviors were replicated in P2Y12 knockout mice. Patch-clamp recordings further revealed that partial sciatic nerve ligation (PSNL)-induced excessive miniature excitatory postsynaptic currents (mEPSCs) were significantly attenuated in P2Y12 knockout mice. Moreover, we found that SNL activates the GTP-RhoA/ROCK2 signaling pathway and elevates the level of phosphorylated p38 mitogen-activated protein kinase (MAPK), which was inhibited by the P2Y12 antagonist. The phosphorylation of p38 MAPK was inhibited by a ROCK inhibitor, but not vice versa, suggesting that p38 MAPK is downstream of ROCK activation. Our findings suggest that nerve injury engages the P2Y12 receptor-dependent GTP-RhoA/ROCK2 signaling pathway to upregulate excitatory synaptic transmission in the dorsal horn. This cross-talk ultimately participates in the manifestation of nociceptive allodynia, implicating P2Y12 receptor as a potential target for alleviating neuropathic pain.
Highlights
Nerve injury-induced neuropathic pain involves painful responses evoked by normally innocuous tactile stimuli, and it is one of the most challenging clinical problems[1]
Analysis of different time points revealed that the P2Y12 expression was increased from day 3 to 14 after spinal nerve ligation (SNL) surgery compared to the expression in the sham group (Fig. 1a, b)
MRS2395 and clopidogrel inhibited the development of tactile allodynia and thermal hyperalgesia induced by SNL surgery
Summary
Nerve injury-induced neuropathic pain involves painful responses evoked by normally innocuous tactile stimuli, and it is one of the most challenging clinical problems[1]. The currently available therapeutics for this pathological pain are relatively limited. Microglia play an important role in the process of pathological pain. As potent stimulators of microglia, extracellular nucleotides caught our attention[2]. They play roles in various functions by activating purinergic receptors expressed in microglia[3]. In the pathological course of nerve injury, ATP can be released or leaked from a variety of sources, such as primary afferent terminals, dorsal horn neurons, and spinal astrocytes[4]. The release or leakage of ATP after nerve injury can activate the neighboring microglia
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