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RhoA/ROCK pathway mediates p38 MAPK activation and morphological changes downstream of P2Y12/13 receptors in spinal microglia in neuropathic pain.
Glia. 2015 Feb; 63(2):216-28.GLIA

Abstract

Recent studies have indicated an important role of ATP receptors in spinal microglia, such as P2Y12 or P2Y13, in the development of chronic pain. However, intracellular signaling cascade of these receptors have not been clearly elucidated. We found that intrathecal injection of 2-(methylthio)adenosine 5'-diphosphate (2Me-SADP) induced mechanical hypersensitivity and p38 mitogen-activated protein kinase (MAPK) phosphorylation in the spinal cord. Intrathecal administration of P2Y12/P2Y13 antagonists and Rho-associated coiled-coil-containing protein kinase (ROCK) inhibitor H1152 suppressed not only p38 MAPK phosphorylation, but also mechanical hypersensitivity induced by 2Me-SADP. In the rat peripheral nerve injury model, intrathecal administration of antagonists for the P2Y12/P2Y13 receptor suppressed activation of p38 MAPK in the spinal cord. In addition, subarachnoidal injection of H1152 also attenuated nerve injury-induced spinal p38 MAPK phosphorylation and neuropathic pain behavior, suggesting an essential role of ROCK in nerve injury-induced p38 MAPK activation. We also found that the antagonists of the P2Y12/P2Y13 receptor and H1152 had inhibitory effects on the morphological changes of microglia such as retraction of processes in both 2Me-SADP and nerve injured rats. In contrast these treatments had no effect on the number of Iba1-positive cells in the nerve injury model. Collectively, our results have demonstrated roles of ROCK in the spinal microglia that is involved in p38 MAPK activation and the morphological changes. Inhibition of ROCK signaling may offer a novel target for the development of a neuropathic pain treatment.

Authors+Show Affiliations

Department of Anatomy and Neuroscience, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan; Department of Otolaryngology, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25130721

Citation

Tatsumi, Emiko, et al. "RhoA/ROCK Pathway Mediates P38 MAPK Activation and Morphological Changes Downstream of P2Y12/13 Receptors in Spinal Microglia in Neuropathic Pain." Glia, vol. 63, no. 2, 2015, pp. 216-28.
Tatsumi E, Yamanaka H, Kobayashi K, et al. RhoA/ROCK pathway mediates p38 MAPK activation and morphological changes downstream of P2Y12/13 receptors in spinal microglia in neuropathic pain. Glia. 2015;63(2):216-28.
Tatsumi, E., Yamanaka, H., Kobayashi, K., Yagi, H., Sakagami, M., & Noguchi, K. (2015). RhoA/ROCK pathway mediates p38 MAPK activation and morphological changes downstream of P2Y12/13 receptors in spinal microglia in neuropathic pain. Glia, 63(2), 216-28. https://doi.org/10.1002/glia.22745
Tatsumi E, et al. RhoA/ROCK Pathway Mediates P38 MAPK Activation and Morphological Changes Downstream of P2Y12/13 Receptors in Spinal Microglia in Neuropathic Pain. Glia. 2015;63(2):216-28. PubMed PMID: 25130721.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - RhoA/ROCK pathway mediates p38 MAPK activation and morphological changes downstream of P2Y12/13 receptors in spinal microglia in neuropathic pain. AU - Tatsumi,Emiko, AU - Yamanaka,Hiroki, AU - Kobayashi,Kimiko, AU - Yagi,Hideshi, AU - Sakagami,Masafumi, AU - Noguchi,Koichi, Y1 - 2014/08/14/ PY - 2014/03/26/received PY - 2014/08/04/accepted PY - 2014/8/19/entrez PY - 2014/8/19/pubmed PY - 2015/8/20/medline KW - P2 receptors KW - chronic pain KW - glial activation KW - intracellular signaling cascade KW - peripheral nerve injury SP - 216 EP - 28 JF - Glia JO - Glia VL - 63 IS - 2 N2 - Recent studies have indicated an important role of ATP receptors in spinal microglia, such as P2Y12 or P2Y13, in the development of chronic pain. However, intracellular signaling cascade of these receptors have not been clearly elucidated. We found that intrathecal injection of 2-(methylthio)adenosine 5'-diphosphate (2Me-SADP) induced mechanical hypersensitivity and p38 mitogen-activated protein kinase (MAPK) phosphorylation in the spinal cord. Intrathecal administration of P2Y12/P2Y13 antagonists and Rho-associated coiled-coil-containing protein kinase (ROCK) inhibitor H1152 suppressed not only p38 MAPK phosphorylation, but also mechanical hypersensitivity induced by 2Me-SADP. In the rat peripheral nerve injury model, intrathecal administration of antagonists for the P2Y12/P2Y13 receptor suppressed activation of p38 MAPK in the spinal cord. In addition, subarachnoidal injection of H1152 also attenuated nerve injury-induced spinal p38 MAPK phosphorylation and neuropathic pain behavior, suggesting an essential role of ROCK in nerve injury-induced p38 MAPK activation. We also found that the antagonists of the P2Y12/P2Y13 receptor and H1152 had inhibitory effects on the morphological changes of microglia such as retraction of processes in both 2Me-SADP and nerve injured rats. In contrast these treatments had no effect on the number of Iba1-positive cells in the nerve injury model. Collectively, our results have demonstrated roles of ROCK in the spinal microglia that is involved in p38 MAPK activation and the morphological changes. Inhibition of ROCK signaling may offer a novel target for the development of a neuropathic pain treatment. SN - 1098-1136 UR - https://www.unboundmedicine.com/medline/citation/25130721/RhoA/ROCK_pathway_mediates_p38_MAPK_activation_and_morphological_changes_downstream_of_P2Y12/13_receptors_in_spinal_microglia_in_neuropathic_pain_ L2 - https://doi.org/10.1002/glia.22745 DB - PRIME DP - Unbound Medicine ER -