title: Analgesic efficacy of small-molecule angiotensin II type 2 receptor antagonists in a rat model of antiretroviral toxic polyneuropathy.
abstract: Individuals infected with the HIV and taking certain antiretroviral drugs to suppress viral replication have a high prevalence of neuropathic pain that is not alleviated by analgesic/adjuvant drugs that are often efficacious for the relief of other types of neuropathic pain. There is therefore a great need for new analgesics to alleviate the pain of antiretroviral toxic neuropathy (ATN). Small-molecule angiotensin II type 2 receptor (AT2R) antagonists, with ≥1000-fold selectivity over the angiotensin II type 1 receptor, produced analgesia in the chronic constriction injury of the sciatic nerve rat model of peripheral nerve trauma. Hence, the present study was designed to assess their analgesic efficacy in a rat model of ATN. The analgesic efficacy of small-molecule AT2R antagonists (EMA200 and EMA300) was assessed in a rat model of dideoxycytidine (ddC)-induced ATN. Single intraperitoneal bolus doses of EMA200 (0.3-10 mg/kg) induced dose-dependent analgesia in ddC-rats; the mean ED50 was 3.2 mg/kg. Twice-daily intraperitoneal administration of EMA300 at 30 mg/kg to ddC-rats for 3 days produced significant analgesia on days 2 and 3 of the treatment period. Therefore, small-molecule AT2R antagonists should be investigated further as novel analgesics for the relief of ATN.
authors: aCentre for Integrated Preclinical Drug Development bSchool of Pharmacy, The University of Queensland, Brisbane, Queensland, Australia cDepartment of Surgery and Cancer, Faculty of Medicine, Imperial College London, Chelsea and Westminster Hospital Campus, London, UK.
authors: Maree T
authors: MT
authors: Smith
authors: Tanya
authors: T
authors: Lau
authors: Victoria C J
authors: VC
authors: Wallace
authors: Bruce D
authors: BD
authors: Wyse
authors: Andrew S C
authors: AS
authors: Rice
mesh_terms: D000700:Analgesics / Q000494:pharmacology*; D057912:Angiotensin II Type 2 Receptor Blockers / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D019380:Anti-HIV Agents / Q000633:toxicity*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005106:Exploratory Behavior / Q000187:drug effects; D006358:Hot Temperature; D006930:Hyperalgesia / Q000139:chemically induced / Q000188:drug therapy; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology; D008297:Male; D009437:Neuralgia / Q000139:chemically induced / Q000188:drug therapy*; D011115:Polyneuropathies / Q000139:chemically induced / Q000150:complications / Q000188:drug therapy*; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D020426:Sciatic Neuropathy / Q000188:drug therapy; D013997:Time Factors; D014110:Touch; D016047:Zalcitabine / Q000633:toxicity*
chemical_list: D000700:Analgesics; D057912:Angiotensin II Type 2 Receptor Blockers; D019380:Anti-HIV Agents; D007093:Imidazoles; D011725:Pyridines; C063457:WL 19; C073402:PD 123319; D016047:Zalcitabine