Attenuation of nicotine-induced antinociception, rewarding effects, and dependence in mu-opioid receptor knock-out mice

Abstract

The involvement of mu-opioid receptors in different behavioral responses elicited by nicotine was explored by using mu-opioid receptor knock-out mice. The acute antinociceptive responses induced by nicotine in the tail-immersion and hot-plate tests were reduced in the mutant mice, whereas no difference between genotypes was observed in the locomotor responses. The rewarding effects induced by nicotine were then investigated using the conditioning place-preference paradigm. Nicotine produced rewarding responses in wild-type mice but failed to produce place preference in knock-out mice, indicating the inability of this drug to induce rewarding effects in the absence of mu-opioid receptors. Finally, the somatic expression of the nicotine withdrawal syndrome, precipitated in dependent mice by the injection of mecamylamine, was evaluated. Nicotine withdrawal was significantly attenuated in knock-out mutants when compared with wild-type mice. In summary, the present results show that mu-opioid receptors are involved in the rewarding responses induced by nicotine and participate in its antinociceptive responses and the expression of nicotine physical dependence.

Fig. 1.

Effects of acute nicotine on locomotion in μ-opioid receptor knock-out and wild-type mice. Horizontal (A) and vertical (B) locomotion were measured 5 min after nicotine administration (0, 1, and 3 mg/kg, s.c.). Data are expressed as mean ± SEM of photocell counts during a 10 min period in wild-type (white bars) and knock-out (black bars) mice (n = 10 mice for each group). ^★ p < 0.05; ^★★ p < 0.01 when comparing with saline group of the same genotype (Dunnett test).

Fig. 2.

Antinociceptive effects of acute nicotine in μ-opioid receptor knock-out and wild-type mice. Antinociceptive responses in the hot-plate (A) and tail-immersion (B) tests were measured 15 and 16 min, respectively, after nicotine administration (0, 1, and 3 mg/kg, s.c.). Data are expressed as mean ± SEM of percentage of maximum possible effect in wild-type (white bars) and knock-out (black bars) mice (n = 10 mice for each group). ^★★ p < 0.01 when comparing with saline group of the same genotype.^⋆ p < 0.05;^⋆⋆ p < 0.01 when comparing between genotypes (Dunnett test).

Fig. 3.

Rewarding effects of nicotine in μ-opioid receptor knock-out and wild-type mice. Data are expressed as mean ± SEM of score values in wild-type (white bars) and knock-out (black bars) mice (n = 10–15 mice for each group). Nicotine was administered subcutaneously at doses of 0.5 (A), 0.7 (B), and 1 mg/kg (C) immediately before each conditioning session.^★★ p < 0.01 when comparing with saline group of the same genotype (one-way ANOVA).

Fig. 4.

Mecamylamine-precipitated nicotine withdrawal in μ-opioid receptor knock-out and wild-type mice. Abstinence was precipitated by acute mecamylamine administration (1 mg/kg, s.c.) after 6 d of nicotine perfusion (10 mg · kg⁻¹ · d⁻¹) by using subcutaneous minipumps. A global withdrawal score was calculated for each animal by giving each individual sign a relative weight. Data are expressed as mean ± SEM in wild-type (white bars) and knock-out (black bars) mice (n = 20–25 mice for each group).^★★ p < 0.01 when comparing with saline group of the same genotype.^⋆⋆ p < 0.01 when comparing between genotypes (one-way ANOVA).