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

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 ␣ 4 nicotinic receptors (L9ЈS), 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). L9ЈS heterozygotes were ϳ6-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 [

Chronic Nicotine Cell Specifically Upregulates Functional α4* Nicotinic Receptors: Basis for Both Tolerance in Midbrain and Enhanced Long-Term Potentiation in Perforant Path

“…WT, ␣4YFP, and ␣4 KO (Ross et al, 2000) mice showed similar baseline reaction times to sensing pain on the hot plate. Similar to the previous studies (Marubio et al, 1999;Damaj et al, 2007), we found that ␣4 KO mice (Ross et al, 2000) are relatively resistant to nicotine-induced antinociception, whereas ␣4YFP Hom, Het, and WT mice showed similar pharmacological sensitivity to nicotine-induced antinociception (supplemental Fig. S3, available at www.jneurosci.org as supplemental material).…”

“…Previous work showed that ␣4* nAChRs mediate nicotineinduced antinociception on the hot plate (Marubio et al, 1999;Damaj et al, 2007). WT, ␣4YFP, and ␣4 KO (Ross et al, 2000) mice showed similar baseline reaction times to sensing pain on the hot plate.…”

Genetic variability in nicotinic acetylcholine receptors and nicotine addiction: Converging evidence from human and animal research

“…These data suggest that C57BL/6 mice have increased sensitivity to the rewarding properties of nicotine relative to other strains. Inbred mouse strains such as A/J and 129/SvEv mice were more sensitive to the antinociceptive effects of acute nicotine than C57BL/6J and DBA/2Ibg mice [29]. However, C57BL/6J mice showed increased sensitivity to pain during nicotine-precipitated withdrawal, but precipitated withdrawal had no effect on pain perception in 129/SvEv mice [28].…”

“…The mutation is lethal to homozygous mice but not to heterozygous mice that possess a neomycin resistance cassette [86]. Subsequent research has demonstrated that Leu9'Ser heterozygous mice are more sensitive to the antinociceptive effects of nicotine than WT mice [29]. Although in vivo research using Leu9'Ser mice is limited to heterozygotes, Tapper and colleagues [167] have shown that Leu9'Ala homozygous mice are viable and will exhibit a ~50-fold increase in sensitivity to nicotine, develop nicotine CPP at a ~50-fold lower dose of nicotine than in WT mice, and develop tolerance to nicotine-induced changes in body temperature at a ~50-fold lower dose of nicotine.…”

Insights into the Neurobiology of the Nicotinic Cholinergic System and Nicotine Addiction from Mice Expressing Nicotinic Receptors Harboring Gain-of-Function Mutations

“…This approach may be a useful way to inducibly destroy midbrain DA neurons similar to the DA neuron loss seen in Parkinson's disease (Schwarz et al, 2006). ␣4 L9ЈS mice also highlight the importance of ␣4* nAChRs in analgesic pathways and mechanisms, because ␣4 L9ЈS heterozygotes were 6-fold more sensitive to the antinociceptive effect of nicotine in the hotplate assay (Damaj et al, 2007). …”