| Analgesic and toxic effects of ABT-594 resemble epibatidine and nicotine in rats. | |
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MedLine Citation:
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PMID: 10781917 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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S Boyce; J K Webb; S L Shepheard; M G Russell; R G Hill; N M Rupniak |
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Publication Detail:
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Type: Comparative Study; Journal Article |
Journal Detail:
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Title: Pain Volume: 85 ISSN: 0304-3959 ISO Abbreviation: Pain Publication Date: 2000 Apr |
Date Detail:
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Created Date: 2000-06-21 Completed Date: 2000-06-21 Revised Date: 2008-11-21 |
Medline Journal Info:
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Nlm Unique ID: 7508686 Medline TA: Pain Country: NETHERLANDS |
Other Details:
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Languages: eng Pagination: 443-50 Citation Subset: IM |
Affiliation:
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Merck Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Terlings Park, Eastwick Road, Harlow, UK. susan_boyce@merck.com |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Analgesics, Non-Narcotic
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antagonists & inhibitors,
pharmacology*,
toxicity* Animals Azetidines / antagonists & inhibitors, pharmacology*, toxicity Behavior, Animal / drug effects Bicyclo Compounds, Heterocyclic / antagonists & inhibitors, pharmacology*, toxicity* Body Temperature / drug effects 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 |
| Chemical | |
Reg. No./Substance:
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0/5-(2-azetidinylmethoxy)-2-chloropyridine; 0/Analgesics, Non-Narcotic; 0/Azetidines; 0/Bicyclo Compounds, Heterocyclic; 0/Nicotinic Agonists; 0/Nicotinic Antagonists; 0/Pyridines; 140111-52-0/epibatidine; 54-11-5/Nicotine; 60-40-2/Mecamylamine |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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