title: Distinct time courses of microglial and astrocytic hyperactivation and the glial contribution to pain hypersensitivity in a facial cancer model.
abstract: Although recent evidence suggests that central glial hyperactivation is involved in cancer-induced persistent pain, the time course of this hyperactivation and the glial contribution to pain hypersensitivity remain unclear. The present study investigated the time-dependent spatial changes of microglial and astrocytic hyperactivation in the trigeminocervical complex, which consists of the medullary (MDH) and upper cervical (UCDH) dorsal horns, and pain-related behaviors in a rat facial cancer model in which Walker 256B-cells are inoculated into the vibrissal pad. In this model, the tumors grew within the vibrissal pad, from which sensory nerve fibers project into the MDH, but did not expand into the infraorbital region, from which fibers project into the UCDH. Nevertheless, mechanical allodynia and thermal hyperalgesia were observed not only in the vibrissal pad but also in the infraorbital region. Western blotting and immunofluorescence studies indicated that microglia were widely activated in the trigeminocervical complex on day 4 and gradually inactivated by day 11. In contrast, astrocytes were only activated in the MDH on day 4; the hyperactivation later expanded into the UCDH. Daily administration of the glial hyperactivation inhibitor propentofylline beginning on day 4 suppressed the glial hyperactivation on later days. Propentofylline treatment largely prevented allodynia/hyperalgesia in the infraorbital region beginning on day 5, although established allodynia/hyperalgesia in the vibrissal pad was less sensitive to the treatment. These results suggest that central glial hyperactivation, transient microglial hyperactivation and persistent astrocytic hyperactivation, contributes to the development of pain hypersensitivity but not to the maintenance of pain in this model.
authors.affiliation: Department of Biosciences, Kyushu Dental College, 2-6-1 Manazuru, Kitakyushu, 803-8580, Japan.
authors.forename: Teppei
authors.initials: T
authors.lastname: Sago
authors.forename: Kentaro
authors.initials: K
authors.lastname: Ono
authors.forename: Nozomu
authors.initials: N
authors.lastname: Harano
authors.forename: Kazumi
authors.initials: K
authors.lastname: Furuta-Hidaka
authors.forename: Suzuro
authors.initials: S
authors.lastname: Hitomi
authors.forename: Masahito
authors.initials: M
authors.lastname: Nunomaki
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Yoshida
authors.forename: Shunji
authors.initials: S
authors.lastname: Shiiba
authors.forename: Osamu
authors.initials: O
authors.lastname: Nakanishi
authors.forename: Kou
authors.initials: K
authors.lastname: Matsuo
authors.forename: Kiyotoshi
authors.initials: K
authors.lastname: Inenaga
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000502:physiology*; D002296:Carcinosarcoma / Q000150:complications; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005153:Facial Neoplasms / Q000150:complications; D005157:Facial Pain / Q000473:pathology* / Q000503:physiopathology*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006930:Hyperalgesia / Q000473:pathology*; D008297:Male; D017628:Microglia / Q000502:physiology*; D009368:Neoplasm Transplantation; D010147:Pain Measurement; D017288:Pain Threshold / Q000502:physiology*; D011601:Psychophysics; D051381:Rats; D017208:Rats, Wistar; D014162:Transfection
chemical_list: D005904:Glial Fibrillary Acidic Protein; D049452:Green Fluorescent Proteins