title: Pituitary adenylate cyclase-activating polypeptide type 1 receptor signaling evokes long-lasting nociceptive behaviors through the activation of spinal astrocytes in mice.
abstract: Intrathecal (i.t.) administration of pituitary adenylate cyclase-activating polypeptide (PACAP) induces long-lasting nociceptive behaviors for more than 60 min in mice, while the involvement of PACAP type1 receptor (PAC1-R) has not been clarified yet. The present study investigated signaling mechanisms of the PACAP-induced prolonged nociceptive behaviors. Single i.t. injection of a selective PAC1-R agonist, maxadilan (Max), mimicked nociceptive behaviors in a dose-dependent manner similar to PACAP. Pre- or post-treatment of a selective PAC1-R antagonist, max.d.4, significantly inhibited the nociceptive behaviors by PACAP or Max. Coadministration of a protein kinase A inhibitor, Rp-8-Br-cAMPS, a mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase inhibitor, PD98059 or a c-Jun N-terminal kinase (JNK) inhibitor, SP600125, significantly inhibited the nociceptive behaviors by Max. Immunohistochemistry and immunoblotting analysis revealed that spinal administration of Max-induced ERK phosphorylation and JNK phosphorylation, and also augmented an astrocyte marker, glial fibrillary acidic protein in mouse spinal cord. Furthermore, an astroglial toxin, l-α-aminoadipate, significantly attenuated the development of the nociceptive behaviors and ERK phosphorylation by Max. These results suggest that the activation of spinal PAC1-R induces long-lasting nociception through the interaction of neurons and astrocytes.
authors.affiliation: Department of Pharmacology, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima City, Kagoshima 890-8544, Japan; Department of Anesthesiology and Critical Care Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima City, Kagoshima 890-8544, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Ohnou
authors.affiliation: Department of Pharmacology, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima City, Kagoshima 890-8544, Japan.
authors.forename: Masafumi
authors.initials: M
authors.lastname: Yokai
authors.affiliation: Department of Pharmacology, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima City, Kagoshima 890-8544, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kurihara
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima City, Kagoshima 890-8544, Japan.
authors.forename: Maiko
authors.initials: M
authors.lastname: Hasegawa-Moriyama
authors.affiliation: Department of Pharmacology, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima City, Kagoshima 890-8544, Japan.
authors.forename: Takao
authors.initials: T
authors.lastname: Shimizu
authors.affiliation: Department of Pharmacology, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima City, Kagoshima 890-8544, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Inoue
authors.affiliation: Department of Pharmacology, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima City, Kagoshima 890-8544, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Kambe
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima City, Kagoshima 890-8544, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Kanmura
authors.affiliation: Department of Pharmacology, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima City, Kagoshima 890-8544, Japan. Electronic address: amiyata@m3.kufm.kagoshima-u.ac.jp.
authors.forename: Atsuro
authors.initials: A
authors.lastname: Miyata
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000502:physiology*; D001522:Behavior, Animal / Q000502:physiology*; D008297:Male; D008815:Mice, Inbred Strains; D059225:Nociception / Q000502:physiology*; D051237:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I / Q000502:physiology*; D015398:Signal Transduction; D013116:Spinal Cord / Q000166:cytology* / Q000502:physiology*
chemical_list: D051237:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I
keywords: Extracellular signal-regulated kinase (ERK); Glial fibrillary acidic protein (GFAP); PACAP type1 (PAC(1)) receptor (PAC(1)-R); Pituitary adenylate cyclase-activating polypeptide (PACAP); c-Jun N-terminal kinase (JNK)