Analgesic and toxic effects of ABT-594 resemble epibatidine and nicotine in rats.

Abstract

The present study directly compared the antinociceptive and toxic effects of the neuronal nicotinic receptor agonist ABT-594 ((R)-5-(2-azetidinylmethoxy)-2-chloropyridine) with (-)-nicotine and (+)-epibatidine. Like (-)-nicotine (0.8 and 1.6 mg/kg s.c.) and (+)-epibatidine (0.005 and 0.01 mg/kg s.c.), ABT-594 (0.05 and 0.1 mg/kg s.c.) increased response latencies in the hot-plate test in rats, indicating that it has antinociceptive activity. In contrast to (-)-nicotine and (+)-epibatidine, ABT-594 did not cause rotarod impairment at antinociceptive doses but did cause hypothermia and life-threatening adverse effects including seizures. ABT-594 (0.01 and 0.1 mg/kg i.v.) also produced a dose-dependent increase in blood pressure resembling that observed with (-)-nicotine (0.03, 0.1 and 0. 03 mg/kg i.v.) and (+)-epibatidine (0.001 and 0.003 mg/kg i.v.). Both the antinociceptive and toxic effects (convulsions and hypertension) were abolished by pretreatment with the brain penetrant neuronal nAChR antagonist mecamylamine (1 mg/kg s.c.; i.v. for cardiovascular studies), demonstrating that these actions of ABT-594 were mediated via activation of neuronal nicotinic receptors. Continuous infusion of ABT-594 (0.2 mg/kg per day s.c.) to rats for 7 days followed by challenge with mecamylamine (1 mg/kg i.p.) induced a nicotine-like abstinence syndrome suggesting that ABT-594 has nicotine-like dependence liability. These findings indicate that the acute safety profile of ABT-594 is not significantly improved over other nicotinic analgesics.

• Authors: S Boyce, J K Webb, S L Shepheard, M G N Russell, R G Hill, N M J Rupniak
• Journal: Pain (Pain) Vol. 85 Issue 3 Pg. 443-450 (Apr 2000) ISSN: 0304-3959 [Print] United States
• PMID: 10781917 (Publication Type: Comparative Study, Journal Article)

Chemical References

• 5-(2-azetidinylmethoxy)-2-chloropyridine
• Analgesics, Non-Narcotic
• Azetidines
• Bridged Bicyclo Compounds, Heterocyclic
• Nicotinic Agonists
• Nicotinic Antagonists
• Pyridines
• Mecamylamine
• Nicotine
• epibatidine

Topics

• Analgesics, Non-Narcotic (antagonists & inhibitors, pharmacology, toxicity)
• Animals
• Azetidines (antagonists & inhibitors, pharmacology, toxicity)
• Behavior, Animal (drug effects)
• Body Temperature (drug effects)
• Bridged Bicyclo Compounds, Heterocyclic (antagonists & inhibitors, pharmacology, toxicity)
• Hot Temperature
• Hypertension (chemically induced)
• Male
• Mecamylamine (pharmacology)
• Nicotine (antagonists & inhibitors, pharmacology, toxicity)
• Nicotinic Agonists (pharmacology, toxicity)
• Nicotinic Antagonists (pharmacology)
• Pain Measurement (drug effects)
• Postural Balance (drug effects)
• Pyridines (antagonists & inhibitors, pharmacology, toxicity)
• Rats
• Rats, Sprague-Dawley
• Reaction Time (drug effects)
• Seizures (chemically induced, prevention & control)
• Substance-Related Disorders (psychology)