Article

P2Y(12) receptor Upregulation in activated microglia is a gateway of p38 signaling and neuropathic pain

Department of Anatomy and Neuroscience, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.75). 04/2008; 28(11):2892-902. DOI: 10.1523/JNEUROSCI.5589-07.2008
Source: PubMed

ABSTRACT Microglia in the spinal cord may play an important role in the development and maintenance of neuropathic pain. A metabotropic ATP receptor, P2Y(12), has been shown to be expressed in spinal microglia constitutively and be involved in chemotaxis. Activation of p38 mitogen-activated protein kinase (MAPK) occurs in spinal microglia after nerve injury and may be related to the production of cytokines and other mediators, resulting in neuropathic pain. However, it remains unknown whether any type of P2Y receptor in microglia is involved in the activation of p38 MAPK and the pain behaviors after nerve injury. Using the partial sciatic nerve ligation (PSNL) model in the rat, we found that P2Y(12) mRNA and protein increased in the spinal cord and peaked at 3 d after PSNL. Double labeling studies revealed that cells expressing increased P2Y(12) mRNA and protein after nerve injury were exclusively microglia. Both pharmacological blockades by intrathecal administration of P2Y(12) antagonist and antisense knockdown of P2Y(12) expression suppressed the development of pain behaviors and the phosphorylation of p38 MAPK in spinal microglia after PSNL. The intrathecal infusion of the P2Y(12) agonist 2-(methythio) adenosine 5'-diphosphate trisodium salt into naive rats mimicked the nerve injury-induced activation of p38 in microglia and elevated pain behaviors. These data suggest a new mechanism of neuropathic pain, in which the increased P2Y(12) works as a gateway of the following events in microglia after nerve injury. Activation of this receptor by released ATP or the hydrolyzed products activate p38 MAPK pathway and may play a crucial role in the generation of neuropathic pain.

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    • "Next, we have attempted to identify the mechanism of action of P2Y 12 R antagonists for alleviating CFA-induced mechanical hyperalgesia in rats. Previous studies indicated an upregulation of P2Y 12 R mRNA in microglia cells of the spinal cord in neuropathic models using either semi-quantitative RT-PCR (Kobayashi et al., 2008) or in situ hybridization histochemistry (Kobayashi et al., 2008, 2012). In our experiments, a massive upregulation of P2Y 12 R mRNA was detected 48 h after CFA injection in the hind paw in parallel with the robust induction of the proinflammatory cytokine IL-1β, indicating a rapid cytokine response at the periphery. "
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    • "It seems there may be multiple activation states whereby microglia do change the manner with which they participate in neural plastic changes, but do not reach a morphologically activated phenotype. The p38 MAPK pathway can be activated by a host of molecules known to increase pain sensitivity, including the proinflammatory cytokines TNFí µí»¼ and IL-1í µí»½, CCL2 (also known as monocyte chemoattractant protein 1 (MCP-1)), fractalkine (CX3CL1), inducible nitric oxide synthase (iNOS), and matrix metalloprotease-9 (MMP-9) as well as the ATP receptors P2X4 and P2X7 [40] [41] [42] [43] [44] [45] [46] [47]. As shown in Figure 2, some of these microglial activators, such as ATP, CCL2, fractalkine, and MMP-9, could be released from primary afferent neurons [48] [49]. "
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    • "Two studies have revealed that P2Y12Rs are key regulators of neuropathic pain (Kobayashi et al., 2008; Tozaki-Saitoh et al., 2008). Intrathecally administered P2Y12R antagonists, such as MRS2395 and AR-C69931MX, and an antisense oligonucleotide for P2Y12R, significantly suppressed development of neuropathic pain after PNI (Kobayashi et al., 2008; Tozaki- Saitoh et al., 2008). A crucial finding was established in P2Y12R-knockout mice, which failed to show tactile allodynia (Tozaki-Saitoh et al., 2008). "
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