title: COX-1-dependent prostaglandin D2 in microglia contributes to neuropathic pain via DP2 receptor in spinal neurons.
abstract: Cyclooxygenase (COX) enzyme synthesizes prostaglandins (PGs) from arachidonic acid and exists as two major isozymes, COX-1 and COX-2. The crucial role of prostaglandins in the pathogenesis of inflammatory pain in peripheral tissue and the spinal cord has been established; however its expression dynamics after peripheral nerve injury and its role in neuropathic pain are not clear. In this study, we examined the detailed expression patterns of genes for COX, PGD2 and thromboxane A2 synthases and their receptors in the spinal cord. Furthermore, we explored the altered gene expression of these molecules using the spared nerve injury (SNI) model. We also examined whether these molecules have a role in the development or maintenance of neuropathic pain. We found a number of interesting results in this study, the first was that COX-1 was constitutively expressed in the spinal cord and up-regulated in microglia located in laminae I-II after nerve injury. Second, COX-2 mRNA expression was induced in blood vessels after nerve injury. Third, TXA2 synthase and hematopoietic PGD synthase mRNAs were dramatically increased in the microglia after nerve injury. Finally, we found that intrathecal injection of a COX-1 inhibitor and DP2 receptor antagonist significantly attenuated the mechanical allodynia. Our findings indicate that PGD2 produced by microglia is COX-1 dependent, and that neurons in the spinal cord can receive PGD2 from microglia following peripheral nerve injury. We believe that PGD2 signaling via DP2 signaling pathway from microglia to neurons is one of the triggering factors for mechanical allodynia in this neuropathic pain model.
authors.affiliation: Department of Anatomy and Neuroscience, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan.
authors.forename: Hirosato
authors.initials: H
authors.lastname: Kanda
authors.forename: Kimiko
authors.initials: K
authors.lastname: Kobayashi
authors.forename: Hiroki
authors.initials: H
authors.lastname: Yamanaka
authors.forename: Koichi
authors.initials: K
authors.lastname: Noguchi
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D051545:Cyclooxygenase 1 / Q000235:genetics / Q000378:metabolism*; D006930:Hyperalgesia / Q000235:genetics / Q000378:metabolism; D008297:Male; D017628:Microglia / Q000378:metabolism*; D009437:Neuralgia / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D010147:Pain Measurement; D015230:Prostaglandin D2 / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism*; D011982:Receptors, Prostaglandin / Q000235:genetics / Q000378:metabolism*; D013116:Spinal Cord / Q000378:metabolism
chemical_list: D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin; D051545:Cyclooxygenase 1; D015230:Prostaglandin D2; C036293:prostaglandin D2 receptor