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 (α4β2* 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.
Footnotes
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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.
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M.I.D., C.F., and M.J.M. contributed equally to this work.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.106.112649.
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ABBREVIATIONS: nAChR, acetylcholine nicotinic receptor(s); WT, wild-type; BTX, bungarotoxin; %MPE, percentage of maximal possible effect; CL, confidence limit(s); ACh, acetylcholine; 4-OH-DMXB, 4-OH-dimethoxybenzylidine anabaseine.
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↵* Denotes other undetermined nicotinic subunits.
- Received August 17, 2006.
- Accepted March 16, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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