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Genetic Approaches Identify Differential Roles for α₄β₂* Nicotinic Receptors in Acute Models of Antinociception in Mice

Damaj, M. I. and Fonck, C. and Marks, M. J. and Deshpande, P. and Labarca, C. and Lester, H. A. and Collins, A. C. and Martin, B. R. (2007) Genetic Approaches Identify Differential Roles for α₄β₂* Nicotinic Receptors in Acute Models of Antinociception in Mice. Journal of Pharmacology and Experimental Therapeutics, 321 (3). pp. 1161-1169. ISSN 0022-3565. doi:10.1124/jpet.106.112649. https://resolver.caltech.edu/CaltechAUTHORS:20200427-083757686

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Abstract

The effects of nicotine on the tail-flick and hot-plate tests were determined to identify nicotinic receptor subtypes responsible for spinally and supraspinally mediated nicotine analgesia in knockin mice expressing hypersensitive α4 nicotinic receptors (L9′S), in seven inbred mouse strains (C57BL/6, DBA/2, A/2, CBA/2, BALB/cByJ, C3H/HeJ, and 129/SvEv), and in two F1 hybrids (B6CBAF1 and B6D2F1). L9′S heterozygotes were ∼6-fold more sensitive to the antinociceptive effects of nicotine than the wild-type controls in the hot-plate test but not in the tail-flick assay. Large differences in the effects of nicotine were also observed with both tests for the seven mouse strains. A/J and 129 mice were 6- to 8-fold more sensitive than CBA and BALB mice. In addition, B6CBAF1 hybrid mice were even less sensitive than CBA mice. Nicotinic binding sites were measured in three spinal cord regions and the hindbrain of the inbred strains. Significant differences in cytisine-sensitive, high affinity [¹²⁵I]epibatidine binding site levels (α₂β₂* subtypes), but not in ¹²⁵I-α-bungarotoxin binding (α7* subtypes), were observed. Significant negative correlations between cytisine-sensitive [¹²⁵I]epibatidine binding and nicotine ED50 for both tests were noted. Our results indicate that α₄β₂* acetylcholine nicotinic receptors (nAChR) are important in mediating nicotine analgesia in supraspinal responses, while also showing that α₄β₂*-nAChR and at least one other nAChR subtype appear to modulate spinal actions.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1124/jpet.106.112649DOIArticle
ORCID:
AuthorORCID
Lester, H. A.0000-0002-5470-5255
Additional Information:© 2007 by The American Society for Pharmacology and Experimental Therapeutics. Received August 17, 2006; accepted March 16, 2007. This work was supported by National Institute on Drug Abuse Grants DA-12610, DA-0527, DA-03194, and DA-17279, by the National Institute of Mental Health (MH-49176), and by the California Tobacco-Related Disease Research Program.
Funders:
Funding AgencyGrant Number
NIHDA-12610
NIHDA-0527
NIHDA-03194
NIHDA-17279
NIHMH-49176
California Tobacco-Related Disease Research ProgramUNSPECIFIED
Issue or Number:3
DOI:10.1124/jpet.106.112649
Record Number:CaltechAUTHORS:20200427-083757686
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20200427-083757686
Official Citation:Genetic Approaches Identify Differential Roles for α4β2* Nicotinic Receptors in Acute Models of Antinociception in Mice. M. I. Damaj, C. Fonck, M. J. Marks, P. Deshpande, C. Labarca, H. A. Lester, A. C. Collins and B. R. Martin. Journal of Pharmacology and Experimental Therapeutics June 1, 2007, 321 (3) 1161-1169; DOI: https://doi.org/10.1124/jpet.106.112649
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:102785
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:27 Apr 2020 15:59
Last Modified:16 Nov 2021 18:15

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