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MD-354 selectively antagonizes the antinociceptive effects of (−)nicotine in the mouse tail-flick assay

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Abstract

Rationale

(−)Nicotine produces antinociceptive effects in rodents. meta-Chlorophenylguanidine (MD-354), an analgesia-enhancing agent, binds at 5-HT3 and α2-adrenoceptors and potentiates the antinociceptive effects of an “inactive” dose of clonidine. The present study examined the actions of MD-354 on (−)nicotine-induced antinociception.

Materials and methods

Mouse tail-flick and other assays were employed.

Results

In the tail-flick assay, (−)nicotine (ED50 = 1.66 mg/kg) but not MD-354 produced dose-related antinociceptive effects. Administered in combination with (−)nicotine (2.5 mg/kg), MD-354 (AD50 = 3.4 mg/kg) did not potentiate, but effectively antagonized the antinociceptive actions of (−)nicotine. In a mouse hot-plate assay, MD-354 failed to modify (−)nicotine responses. In combination with a locomotor activity-suppressing dose of (−)nicotine, MD-354 (up to 17 mg/kg) failed to antagonize (−)nicotine-induced hypolocomotion. In a rat drug discrimination paradigm using (−)nicotine as training drug, MD-354 produced saline-appropriate responding; in combination with the training dose of (−)nicotine, MD-354 failed to antagonize the nicotine cue.

Conclusions

MD-354 selectively antagonizes the antinociceptive actions of (−)nicotine in the tail-flick, but not in the hot-plate assay, or either the motor effects, or discriminative stimulus effects of (−)nicotine. The most parsimonious explanation is that MD-354 might act as a negative allosteric modulator of α7 nACh receptors, and radioligand binding and functional data are provided to support this conclusion.

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Acknowledgments

We wish to acknowledge T. Bondareva for her assistance with the drug discrimination assay. HEK 293 cells stably expressing rat α7 nAChRs were generously provided by Dr. K. Kellar from Georgetown University.

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Authors and Affiliations

  1. Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, Box 980540, Richmond, VA, 23298-0540, USA

    Małgorzata Dukat, Anna Wesołowska, Genevieve Alley, Shawquia Young, Richard Young & Richard A. Glennon

  2. Department of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University, Richmond, VA, 23298, USA

    Galya R. Abdrakhmanova & Richard A. Glennon

  3. Pharmacology and Toxicology, Discovery Sciences, Research Triangle Institute, Research Triangle Park, NC, 27709, USA

    Hernán A. Navarro

Authors
  1. Małgorzata Dukat
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  2. Anna Wesołowska
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  3. Genevieve Alley
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  4. Shawquia Young
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  5. Galya R. Abdrakhmanova
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  6. Hernán A. Navarro
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  7. Richard Young
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  8. Richard A. Glennon
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Correspondence to Małgorzata Dukat.

Additional information

This study was supported in part by J-778 (MD) from the Jeffress Foundation.

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Dukat, M., Wesołowska, A., Alley, G. et al. MD-354 selectively antagonizes the antinociceptive effects of (−)nicotine in the mouse tail-flick assay. Psychopharmacology 210, 547–557 (2010). https://doi.org/10.1007/s00213-010-1857-0

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  • DOI: https://doi.org/10.1007/s00213-010-1857-0

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