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

J Pharmacol Sci. 2016 Apr;130(4):194-203. doi: 10.1016/j.jphs.2016.01.008. Epub 2016 Feb 3.

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.

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).

MeSH terms

  • Animals
  • Astrocytes / physiology*
  • Behavior, Animal / physiology*
  • Male
  • Mice, Inbred Strains
  • Nociception / physiology*
  • Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I / physiology*
  • Signal Transduction*
  • Spinal Cord / cytology*
  • Spinal Cord / physiology*

Substances

  • Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I