A novel role of prostaglandin E2 in neuropathic pain: blockade of microglial migration in the spinal cord.
Neuropathic pain produced by damage to or dysfunction of the nervous system is a common and severely disabling state that affects millions of people worldwide. Recent evidence indicates that activated microglia are key cellular intermediaries in the pathogenesis of neuropathic pain and that ATP serves as the mediator. However, the in vivo mechanism underlying the retention of activated microglia in the injured region has not yet been completely elucidated. Prostaglandin E(2) (PGE(2)) is the principal proinflammatory prostanoid and plays versatile roles by acting via four PGE receptor subtypes, EP1-EP4. In the present study, we investigated the role of PGE(2) in spinal microglial activation in relation to neuropathic pain by using genetic and pharmacological methods. Mice deficient in microsomal prostaglandin E synthase-1 impaired the activation of microglia and the NMDA-nitric oxide (NO) cascade in spinal neurons in the dorsal horn and did not exhibit mechanical allodynia after peripheral nerve injury. The intrathecal injection of indomethacin, a nonsteroidal anti-inflammatory drug, ONO-8713, a selective EP1 antagonist, or 7-nitroindole, a neuronal NO synthase inhibitor, attenuated mechanical allodynia and the increase in activated microglia observed in the established neuropathic-pain state. We further demonstrated that ATP-induced microglial migration was blocked in vitro by PGE(2) via EP2 and by S-nitrosoglutathione, an NO donor. Taken together, the present study suggests that PGE(2) participated in the maintenance of neuropathic pain in vivo not only by activating spinal neurons, but also by retaining microglia in the central terminals of primary afferent fibers via EP2 subtype and via EP1-mediated NO production.
Department of Medical Chemistry, Kansai Medical University, Moriguchi, Japan.
Shunji
S
Kunori
Shinji
S
Matsumura
Emiko
E
Okuda-Ashitaka
Tayo
T
Katano
Laurent P
LP
Audoly
Yoshihiro
Y
Urade
Seiji
S
Ito
D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D002465:Cell Movement / Q000235:genetics / Q000502:physiology*; D002540:Cerebral Cortex / Q000166:cytology; D002934:Cinnamates / Q000494:pharmacology / Q000627:therapeutic use; D015232:Dinoprostone / Q000378:metabolism*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000235:genetics; D006930:Hyperalgesia / Q000188:drug therapy / Q000209:etiology; D007191:Indazoles / Q000494:pharmacology / Q000627:therapeutic use; D019746:Intramolecular Oxidoreductases / Q000172:deficiency; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D017628:Microglia / Q000187:drug effects / Q000502:physiology*; D009437:Neuralgia / Q000150:complications / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D009474:Neurons / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000494:pharmacology; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism; D000071876:Prostaglandin-E Synthases; D026422:S-Nitrosoglutathione / Q000494:pharmacology; D013116:Spinal Cord / Q000187:drug effects / Q000473:pathology*; D013127:Spinal Nerves / Q000293:injuries
D002934:Cinnamates; D004791:Enzyme Inhibitors; D007191:Indazoles; D020030:Nitric Oxide Donors; C411295:ONO 8713; D009569:Nitric Oxide; D026422:S-Nitrosoglutathione; D000255:Adenosine Triphosphate; D052248:Nitric Oxide Synthase Type I; D019746:Intramolecular Oxidoreductases; D000071876:Prostaglandin-E Synthases; D015232:Dinoprostone; C080122:7-nitroindazole