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Research ArticleArticle

Differences Between the Antinociceptive Effects of the Cholinergic Channel Activators A-85380 and (±)-Epibatidine in Rats

Peter Curzon, Arthur L. Nikkel, Anthony W. Bannon, Stephen P. Arneric and Michael W. Decker
Journal of Pharmacology and Experimental Therapeutics December 1998, 287 (3) 847-853;
Peter Curzon
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Arthur L. Nikkel
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Anthony W. Bannon
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Stephen P. Arneric
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Michael W. Decker
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Abstract

(±)-Epibatidine (EPIB) and A-85380 are nicotinic acetylcholine receptor (nAChR) agonists that bind to the agonist ([3H]cytisine) binding site with 40 to 50 pM affinity but have different affinities in nAChR subtype selective functional receptor assays. In vivo EPIB was more (23-fold) potent than A-85380 in reducing open field activity and more (12-fold) potent in reducing nociception in the formalin test of persistent chemical pain. In the rat hot box test of thermal acute pain, both compounds produced antinociception, as indicated by an increase in the paw withdrawal latency, however EPIB was a ∼33-fold more potent than A-85380 (ED50 = 0.004 and 0.11 μmol/kg, i.p., respectively). The systemic effects of both nAChR agonists were blocked by central (i.c.v.) administration of the nAChR antagonist chlorisondamine suggesting a central site of action for these compounds. Injections of EPIB (0.0013 to 0.013 nmol) and A-85380 (0.013 to 0.13 nmol) directly into the nucleus raphe magnus (NRM) were also effective in the hot box and could be blocked by coadministration of the nAChR antagonists chlorisondamine (0.23 nmol) or mecamylamine (0.8 nmol). The NRM was found to be critical for the antinociceptive effects of systemic EPIB but not for A-85380 in that NRM injections of either mecamylamine (0.8 nmol) or lidocaine (74 nmol) blocked the antinociceptive effects of systemic (i.p.) EPIB but not those of A-85380. These results suggest that A-85380 may act at multiple sites both within and outside the NRM, whereas EPIB acts largelyvia descending inhibitory pathways arising from the NRM.

Footnotes

  • Send reprint requests to: Peter Curzon, Neurological and Urological Diseases Research, Pharmaceutical Products Division, Abbott Laboratories, Building AP9A-LL (D-47W), Abbott Park, IL 60064-3500. E-mail: peter.curzon{at}abbott.com

  • Abbreviations:
    EPIB
    (±)-epibatidine
    CHLOR
    chlorisondamine
    i.c.v.
    intracerebral ventricular
    LIDO
    lidocaine
    MEC
    mecamylamine
    nAChR
    nicotinic acetylcholine receptor
    NRM
    nucleus raphe magnus
    • Received April 9, 1998.
    • Accepted July 10, 1998.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 287, Issue 3
1 Dec 1998
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Research ArticleArticle

Differences Between the Antinociceptive Effects of the Cholinergic Channel Activators A-85380 and (±)-Epibatidine in Rats

Peter Curzon, Arthur L. Nikkel, Anthony W. Bannon, Stephen P. Arneric and Michael W. Decker
Journal of Pharmacology and Experimental Therapeutics December 1, 1998, 287 (3) 847-853;

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Research ArticleArticle

Differences Between the Antinociceptive Effects of the Cholinergic Channel Activators A-85380 and (±)-Epibatidine in Rats

Peter Curzon, Arthur L. Nikkel, Anthony W. Bannon, Stephen P. Arneric and Michael W. Decker
Journal of Pharmacology and Experimental Therapeutics December 1, 1998, 287 (3) 847-853;
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