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: Maree T Smith, Tanya Lau, Victoria C J Wallace, Bruce D Wyse, Andrew S C Rice
• Journal: Behavioural pharmacology (Behav Pharmacol) Vol. 25 Issue 2 Pg. 137-46 (Apr 2014) ISSN: 1473-5849 [Electronic] England
• PMID: 24525712 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Analgesics
• Angiotensin II Type 2 Receptor Blockers
• Anti-HIV Agents
• Imidazoles
• Pyridines
• WL 19
• PD 123319
• Zalcitabine

Topics

• Analgesics (pharmacology)
• Angiotensin II Type 2 Receptor Blockers (chemistry, pharmacology)
• Animals
• Anti-HIV Agents (toxicity)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Exploratory Behavior (drug effects)
• Hot Temperature
• Hyperalgesia (chemically induced, drug therapy)
• Imidazoles (chemistry, pharmacology)
• Male
• Neuralgia (chemically induced, drug therapy)
• Polyneuropathies (chemically induced, complications, drug therapy)
• Pyridines (chemistry, pharmacology)
• Rats
• Rats, Sprague-Dawley
• Rats, Wistar
• Sciatic Neuropathy (drug therapy)
• Time Factors
• Touch
• Zalcitabine (toxicity)