Nerve injury-activated microglia engulf myelinated axons in a P2Y12 signaling-dependent manner in the dorsal horn.
The mechanisms underlying neuropathic pain are poorly understood. However, several studies have implied a role for reactive microglia located in the dorsal horn in neuropathic pain. To clarify the roles of activated microglia in neuropathic pain, we investigated the interactions among microglia and other neural components in the dorsal horn using electron microscopy. Microglia were more abundantly localized in layers II-III of the dorsal horn than in other areas, and some of them adhered to and engulfed both injured and uninjured myelinated axons. This microglial engulfment was rarely observed in the normal dorsal horn, and the number of microglia attached to myelinated axons was markedly increased on postoperative day 7 on the operated side. However, after blocking the P2Y12 ATP receptor in microglia by intrathecal administration of its antagonist, AR-C69931MX, the increase in the number of microglia attached to myelinated axons, as well as the development of tactile allodynia, were markedly suppressed, although the number of activated microglia did not change remarkably. These results indicate that engulfment of myelinated axons by activated microglia via P2Y12 signaling in the dorsal horn may be a critical event in the pathogenesis of neuropathic pain.
Maeda
Mitsuyo
M
Department of Anatomy and Neurobiology, Graduate School of Medicine, Osaka City University, 1-4-3 Asahimachi, Abeno-Ku, Osaka 545-8585, Japan.
Tsuda
Makoto
M
Tozaki-Saitoh
Hidetoshi
H
Inoue
Kazuhide
K
Kiyama
Hiroshi
H
D000249:Adenosine Monophosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D002135:Calcium-Binding Proteins / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D007839:Functional Laterality; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D006930:Hyperalgesia / Q000188:drug therapy / Q000378:metabolism; D008297:Male; D008840:Microfilament Proteins; D017628:Microglia / Q000473:pathology* / Q000648:ultrastructure; D016253:Microscopy, Immunoelectron / Q000379:methods; D009413:Nerve Fibers, Myelinated / Q000473:pathology* / Q000648:ultrastructure; D009437:Neuralgia / Q000473:pathology*; D020671:Posterior Horn Cells / Q000473:pathology* / Q000648:ultrastructure; D058921:Purinergic P2Y Receptor Antagonists / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D058925:Receptors, Purinergic P2Y12 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013116:Spinal Cord / Q000473:pathology; D013127:Spinal Nerves / Q000473:pathology
C100745:Aif1 protein, rat; D002135:Calcium-Binding Proteins; D008840:Microfilament Proteins; D058921:Purinergic P2Y Receptor Antagonists; D058925:Receptors, Purinergic P2Y12; D000249:Adenosine Monophosphate; C117446:cangrelor