Pituitary adenylate cyclase-activating polypeptide type 1 receptor signaling evokes long-lasting nociceptive behaviors through the activation of spinal astrocytes in mice

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• 作者：Tetsuya Ohnou^a ; ^b ; ¹ ; Masafumi Yokai^a ; ¹ ; Takashi Kurihara^a ; Maiko Hasegawa-Moriyama^b ; Takao Shimizu^a ; Kazuhiko Inoue^a ; Yuki Kambe^a ; Yuichi Kanmura^b ; Atsuro Miyata^a ; ^{amiyata@m3.kufm.kagoshima-u.ac.jp" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Pituitary adenylate cyclase-activating polypeptide (PACAP) ; PACAP type1 (PAC1) receptor (PAC1-R) ; Glial fibrillary acidic protein (GFAP) ; Extracellular signal-regulated kinase (ERK) ; c-Jun N-terminal kinase (JNK)
• 刊名：Journal of Pharmacological Sciences
• 出版年：2016
• 出版时间：April 2016
• 年：2016
• 卷：130
• 期：4
• 页码：194-203
• 全文大小：1942 K

文摘

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.