Galeote Lola, Kieffer Brigitte L, Maldonado Rafael, Berrendero Fernando
Laboratori de Neurofarmacologia, Facultat de Ciències de la Salut i de la Vida, Universitat Pompeu Fabra, Barcelona, Spain.
J Neurochem. 2006 Apr;97(2):416-23. doi: 10.1111/j.1471-4159.2006.03751.x. Epub 2006 Mar 15.
Several studies have shown the participation of the endogenous opioid system on the antinociceptive effects and addictive properties of nicotine. The aim of the present study was to explore the involvement of the mu-opioid receptors in the development of tolerance to nicotine antinociception. Chronic treatment of C57BL/6 mice with nicotine (5 mg/kg s.c., three times daily during 12 days) resulted in tolerance to its antinociceptive responses in the tail-immersion test. We investigated the possible existence of adaptive changes in the expression and/or functional activity of mu-opioid receptors in these tolerant mice by using autoradiography of [(3)H]D-Ala(2)-MePhe(4)-Gly-ol(5) enkephalin ([(3)H]DAMGO) binding and DAMGO-stimulated guanosine [(35)S]5'-(gamma-thio)-triphosphate ([(35)S]GTPgammaS) binding. The density of mu-opioid receptors in the spinal cord was not modified in nicotine-tolerant mice, whereas a decrease was found in the caudate-putamen, as well as in the core and the shell of the nucleus accumbens. However, the functional activity of these receptors was significantly increased in the spinal cord as a consequence of nicotine treatment. To further investigate the role of mu-opioid receptors in the tolerance to nicotine-induced antinociception, we evaluated this response in C57BL/6 mu-opioid receptor knockout mice. Chronic nicotine treatment produced tolerance in both wild-type and knockout animals, but tolerance developed faster in mice lacking mu-opioid receptors. These results indicate that mu-opioid receptors play an important role in the development of tolerance to nicotine antinociceptive effects.
多项研究表明内源性阿片系统参与了尼古丁的抗伤害感受作用和成瘾特性。本研究的目的是探讨μ-阿片受体在尼古丁抗伤害感受耐受性形成中的作用。用尼古丁（5毫克/千克，皮下注射，每天3次，共12天）对C57BL/6小鼠进行慢性处理，导致其在尾部浸入试验中对尼古丁的抗伤害感受反应产生耐受性。我们通过使用[(3)H]D-Ala(2)-MePhe(4)-Gly-ol(5)脑啡肽([(3)H]DAMGO)结合的放射自显影和DAMGO刺激的鸟苷[(35)S]5'-(γ-硫代)-三磷酸([(35)S]GTPγS)结合，研究了这些耐受小鼠中μ-阿片受体表达和/或功能活性的适应性变化的可能存在情况。尼古丁耐受小鼠脊髓中μ-阿片受体的密度未发生改变，而在尾状核-壳核以及伏隔核的核心和壳部发现有所降低。然而，由于尼古丁处理，这些受体在脊髓中的功能活性显著增加。为了进一步研究μ-阿片受体在尼古丁诱导的抗伤害感受耐受性中的作用，我们在C57BL/6μ-阿片受体基因敲除小鼠中评估了这种反应。慢性尼古丁处理在野生型和基因敲除动物中均产生了耐受性，但在缺乏μ-阿片受体的小鼠中耐受性发展得更快。这些结果表明，μ-阿片受体在尼古丁抗伤害感受作用耐受性的形成中起重要作用。
