title: Involvement of p38 MAPK activation mediated through AT1 receptors on spinal astrocytes and neurons in angiotensin II- and III-induced nociceptive behavior in mice.
abstract: 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.
authors.affiliation: Department of Pharmacology, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai, 981-8558, Japan.
authors.forename: Wataru
authors.initials: W
authors.lastname: Nemoto
authors.affiliation: Department of Pharmacology, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai, 981-8558, Japan.
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Ogata
authors.affiliation: Department of Pharmacology, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai, 981-8558, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Nakagawasai
authors.affiliation: Department of Pharmacology, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai, 981-8558, Japan.
authors.forename: Fukie
authors.initials: F
authors.lastname: Yaoita
authors.affiliation: Department of Health Care Medical Research, Venture Business Laboratory, Kanazawa University, Kanazawa, 920-1192, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Tadano
authors.affiliation: Department of Pharmacology, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai, 981-8558, Japan. Electronic address: koichi@tohoku-pharm.ac.jp.
authors.forename: Koichi
authors.initials: K
authors.lastname: Tan-No
mesh_terms: D000804:Angiotensin II / Q000378:metabolism*; D000805:Angiotensin III / Q000378:metabolism*; D057911:Angiotensin Receptor Antagonists / Q000494:pharmacology; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D008159:Lumbar Vertebrae; D048670:MAP Kinase Kinase 4 / Q000037:antagonists & inhibitors / Q000378:metabolism; D008297:Male; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D059226:Nociceptive Pain / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism*; D044139:Receptor, Angiotensin, Type 2 / Q000378:metabolism; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D057911:Angiotensin Receptor Antagonists; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D000804:Angiotensin II; D000805:Angiotensin III; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4
keywords: AT1 receptors; Angiotensin II; Angiotensin III; Astrocyte; Intrathecal administration; Mice; Neuron; Nociceptive behavior; p38 MAPK