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

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. © 2016 the authors.