Involvement of p38 MAPK activation mediated through AT1 receptors on spinal astrocytes and neurons in angiotensin II- and III-induced nociceptive behavior in mice

• Published in: Neuropharmacology Vol. 99; pp. 221 - 231
• Main Authors: Nemoto, Wataru, Ogata, Yoshiki, Nakagawasai, Osamu, Yaoita, Fukie, Tadano, Takeshi, Tan-No, Koichi
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.12.2015
• Subjects: Angiotensin II; Angiotensin II - metabolism; Angiotensin III; Angiotensin III - metabolism; Angiotensin Receptor Antagonists - pharmacology; Animals; Astrocyte; Astrocytes - drug effects; Astrocytes - metabolism; Astrocytes - pathology; AT1 receptors; Disease Models, Animal; Intrathecal administration; Lumbar Vertebrae; Male; MAP Kinase Kinase 4 - antagonists & inhibitors; MAP Kinase Kinase 4 - metabolism; Mice; Neuron; Neurons - drug effects; Neurons - metabolism; Neurons - pathology; Nociceptive behavior; Nociceptive Pain - drug therapy; Nociceptive Pain - metabolism; Nociceptive Pain - pathology; p38 MAPK; p38 Mitogen-Activated Protein Kinases - antagonists & inhibitors; p38 Mitogen-Activated Protein Kinases - metabolism; Phosphorylation; Receptor, Angiotensin, Type 1 - metabolism; Receptor, Angiotensin, Type 2 - metabolism; Spinal Cord - drug effects; Spinal Cord - metabolism; Spinal Cord - pathology; Nociceptive behavior; Angiotensin III; DMSO; JNK; HRP; ID50; Angiotensin II; NDS; AT1; Iba-1; AT2; AT1 receptors; ACE; IR; i.p; Astrocyte; MAPK; p38 MAPK; Intrathecal administration; LAA; i.t; GFAP; ECL; Neuron; NeuN; Mice; Ang; NGS; ERK
• ISSN: 0028-3908; 1873-7064
• DOI: 10.1016/j.neuropharm.2015.07.022

We have previously demonstrated the possibility that angiotensin (Ang) II and its N-terminal metabolite Ang (1–7) act as neurotransmitters and/or neuromodulators in the spinal transmission of nociceptive information. Ang III, which is a C-terminal metabolite of Ang II, can also act on AT1 receptors, but its role in spinal nociceptive transmission remains unclear. Therefore, we examined the role of Ang III on the spinal nociceptive system in comparison with that of Ang II. Intrathecal (i.t.) administration of Ang III into mice produced a nociceptive behavior, which was dose-dependently inhibited by the co-administration of the AT1 receptor antagonist losartan and the p38 MAPK inhibitor SB203580, but not by the AT2 receptor antagonist PD123319, MEK1/2 inhibitor U0126 and JNK inhibitor SP600125. In addition, Ang III increased the phosphorylation of p38 MAPK in the dorsal lumbar spinal cord, which was inhibited by losartan. These effects were similar to those of observed with Ang II. The nociceptive behavior produced by Ang II or III was also attenuated by the administration of the astrocytic inhibitor l-α-aminoadipic acid, but not by the microglial inhibitor minocycline. Double immunohistochemical staining showed that spinal AT1 receptors were expressed on neurons and astrocytes, and that i.t. administration of either Ang II or III phosphorylated p38 MAPK in both spinal astrocytes and neurons. These results indicate that Ang III produces nociceptive behavior similar to Ang II, and suggest that the phosphorylation of p38 MAPK mediated through AT1 receptors on spinal astrocytes and neurons contributes to Ang II- and III-induced nociceptive behavior. •Angiotensin (Ang) III produced a nociceptive behavior via spinal AT1 receptors.•Ang III phosphorylated spinal p38 MAPK, which led to nociceptive behavior.•Ang II and III phosphorylated both spinal astrocytic and neuronal p38 MAPK.•AT1 receptors were expressed in both astrocytes and neurons in the spinal cord.•Astrocytic inhibitor inhibited Ang II- and III-induced nociceptive behavior.