title: Involvement of Spinal Angiotensin II System in Streptozotocin-Induced Diabetic Neuropathic Pain in Mice.
abstract: Renin-angiotensin system (RAS) activity increases under hyperglycemic states, and is thought to be involved in diabetic complications. We previously demonstrated that angiotensin (Ang) II, a main bioactive component of the RAS, might act as a neurotransmitter and/or neuromodulator in the transmission of nociceptive information in the spinal cord. Here, we examined whether the spinal Ang II system is responsible for diabetic neuropathic pain induced by streptozotocin (STZ). Tactile allodynia was observed concurrently with an increase in blood glucose levels the day after mice received STZ (200 mg/kg, i.v.) injections. Tactile allodynia on day 14 was dose-dependently inhibited by intrathecal administration of losartan, an Ang II type 1 (AT1) receptor antagonist, but not by PD123319, an AT2 receptor antagonist. In the lumbar dorsal spinal cord, the expression of Ang II, Ang converting enzyme (ACE), and phospho-p38 mitogen-activated protein kinase (MAPK) were all significantly increased on day 14 after STZ injection compared with vehicle-treated controls, whereas no differences were observed among AT1 receptors or angiotensinogen levels. Moreover, the increase in phospho-p38 MAPK was significantly inhibited by intrathecal administration of losartan. These results indicate that the expression of spinal ACE increased in STZ-induced diabetic mice, which in turn led to an increase in Ang II levels and tactile allodynia. This increase in spinal Ang II was accompanied by the phosphorylation of p38 MAPK, which was shown to be mediated by AT1 receptors.
authors.affiliation: Department of Pharmacology, Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, Aoba-ku, Sendai, Japan (Y.O., W.N., O.N., R.Y., K.T.-N.); Department of Health Care Medical Research, Venture Business Laboratory, Kanazawa University, Kanazawa, Japan (T.T.).
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Ogata
authors.affiliation: Department of Pharmacology, Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, Aoba-ku, Sendai, Japan (Y.O., W.N., O.N., R.Y., K.T.-N.); Department of Health Care Medical Research, Venture Business Laboratory, Kanazawa University, Kanazawa, Japan (T.T.).
authors.forename: Wataru
authors.initials: W
authors.lastname: Nemoto
authors.affiliation: Department of Pharmacology, Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, Aoba-ku, Sendai, Japan (Y.O., W.N., O.N., R.Y., K.T.-N.); Department of Health Care Medical Research, Venture Business Laboratory, Kanazawa University, Kanazawa, Japan (T.T.).
authors.forename: Osamu
authors.initials: O
authors.lastname: Nakagawasai
authors.affiliation: Department of Pharmacology, Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, Aoba-ku, Sendai, Japan (Y.O., W.N., O.N., R.Y., K.T.-N.); Department of Health Care Medical Research, Venture Business Laboratory, Kanazawa University, Kanazawa, Japan (T.T.).
authors.forename: Ryota
authors.initials: R
authors.lastname: Yamagata
authors.affiliation: Department of Pharmacology, Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, Aoba-ku, Sendai, Japan (Y.O., W.N., O.N., R.Y., K.T.-N.); Department of Health Care Medical Research, Venture Business Laboratory, Kanazawa University, Kanazawa, Japan (T.T.).
authors.forename: Takeshi
authors.initials: T
authors.lastname: Tadano
authors.affiliation: Department of Pharmacology, Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, Aoba-ku, Sendai, Japan (Y.O., W.N., O.N., R.Y., K.T.-N.); Department of Health Care Medical Research, Venture Business Laboratory, Kanazawa University, Kanazawa, Japan (T.T.) koichi@tohoku-mpu.ac.jp.
authors.forename: Koichi
authors.initials: K
authors.lastname: Tan-No
mesh_terms: D000804:Angiotensin II / Q000378:metabolism*; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000150:complications* / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D006930:Hyperalgesia / Q000150:complications; D007267:Injections; D008159:Lumbar Vertebrae / Q000201:enzymology / Q000473:pathology; D008297:Male; D051379:Mice; D009437:Neuralgia / Q000097:blood / Q000150:complications* / Q000378:metabolism*; D007703:Peptidyl-Dipeptidase A / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000235:genetics; D013116:Spinal Cord / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D066148:Spinal Cord Dorsal Horn / Q000378:metabolism / Q000473:pathology; D013311:Streptozocin; D013997:Time Factors; D014110:Touch; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D015415:Biomarkers; D001786:Blood Glucose; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D000804:Angiotensin II; D013311:Streptozocin; D048051:p38 Mitogen-Activated Protein Kinases; D007703:Peptidyl-Dipeptidase A