Analgesic efficacy of small-molecule angiotensin II type 2 receptor antagonists in a rat model of antiretroviral toxic polyneuropathy

• Published in: Behavioural pharmacology Vol. 25; no. 2; p. 137
• Main Authors: Smith, Maree T, Lau, Tanya, Wallace, Victoria C J, Wyse, Bruce D, Rice, Andrew S C
• Format: Journal Article
• Language: English
• Published: England 01.04.2014
• Subjects: Analgesics - pharmacology; Angiotensin II Type 2 Receptor Blockers - chemistry; Angiotensin II Type 2 Receptor Blockers - pharmacology; Animals; Anti-HIV Agents - toxicity; Disease Models, Animal; Dose-Response Relationship, Drug; Exploratory Behavior - drug effects; Hot Temperature; Hyperalgesia - chemically induced; Hyperalgesia - drug therapy; Imidazoles - chemistry; Imidazoles - pharmacology; Male; Neuralgia - chemically induced; Neuralgia - drug therapy; Polyneuropathies - chemically induced; Polyneuropathies - complications; Polyneuropathies - drug therapy; Pyridines - chemistry; Pyridines - pharmacology; Rats; Rats, Sprague-Dawley; Rats, Wistar; Sciatic Neuropathy - drug therapy; Time Factors; Touch; Zalcitabine - toxicity
• ISSN: 1473-5849
• DOI: 10.1097/FBP.0000000000000025

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.