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NEUROPHARMACOLOGY

Genetic Approaches Identify Differential Roles for ₄₂^* Nicotinic Receptors in Acute Models of Antinociception in Mice

Department of Pharmacology and Toxicology, Medical College of Virginia, Virginia Commonwealth University, Richmond, Virginia (M.I.D., B.R.M.); Institute for Behavioral Genetics, University of Colorado, Boulder, Colorado (M.J.M., A.C.C.); and Division of Biology, California Institute of Technology, Pasadena, California (C.F., P.D., C.L., H.A.L.)

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 ₄ 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 (₄₂^* subtypes), but not in ¹²⁵I--bungarotoxin binding (₇^* subtypes), were observed. Significant negative correlations between cytisine-sensitive [¹²⁵I]epibatidine binding and nicotine ED₅₀ for both tests were noted. Our results indicate that ₄₂^* acetylcholine nicotinic receptors (nAChR) are important in mediating nicotine analgesia in supraspinal responses, while also showing that ₄₂^*-nAChR and at least one other nAChR subtype appear to modulate spinal actions.

Address correspondence to: M. Imad Damaj, Department of Pharmacology and Toxicology, Medical College of Virginia Campus, Virginia Commonwealth University, Box 980613, Richmond, VA 23298-0613. E-mail: mdamaj{at}hsc.vcu.edu

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