Kishioka Shiroh, Kiguchi Norikazu, Kobayashi Yuka, Saika Fumihiro, Yamamoto Chizuko
Nihon Arukoru Yakubutsu Igakkai Zasshi. 2014 Oct;49(5):227-37.
Nicotine (NIC) regulates various cellular functions acting on the nicotinic acetylcholine receptor (nAChR). And nAChR consists of ligand-gated cation channels with pentameric structure and composed of α and β subunits. In the central nervous system, α 4 β 2 and α 7 nAChRs are the most abundantly expressed as nAChR subtypes. There are several lines of evidence indicating that systemic administration of NIC elicits the release of endogenous opioids, such as, endorphins, enkephalins and dynorphins, in the brain. NIC exerts numerous acute effects, for example, antinociceptive effects and the activating effects of the hypothalamic-pituitary-adrenal (HPA) axis. In these effects, NIC-induced antinociception, but not HPA axis activation, was inhibited by opioid receptor antagonist, naloxone (NLX), and was also suppressed in morphine tolerated mice, indicating the participation of the endogenous opioid system in NIC-induced antinociception, but not HPA axis activation. Moreover, NIC-induced antinociception was antagonized by both α 4 β 2 and α 7 nAChR antagonists, while NIC-induced HPA axis activation was antagonized by α 4 β 2 nAChR antagonist, but not by α 7 nAChR antagonist. These results suggest that the endogenous opioid system may not be located on the downstream of α 4 β 2 nAChR. On the other hand, NIC has substantial physical dependence liability. NLX elicits NIC withdrawal after repeated NIC administration evaluated by corticosterone increase as a withdrawal sign, and NLX-precipitated NIC withdrawal is inhibited by concomitant administration of other opioid receptor antagonist, naltrexone, indicating the participation of endogenous opioid system in the development of physical dependence on NIC. NLX-precipitated NIC withdrawal was also inhibited by concomitant administration of an α 7 nAChR antagonist, but not an α 4 β 2 nAChR antagonist. Taken together, these findings suggest that the endogenous opioid system may be located on the downstream of α 7 nAChR and participates in the development of physical dependence on NIC.
尼古丁（NIC）通过作用于烟碱型乙酰胆碱受体（nAChR）来调节多种细胞功能。nAChR由具有五聚体结构的配体门控阳离子通道组成，由α和β亚基构成。在中枢神经系统中，α4β2和α7 nAChR作为nAChR亚型表达最为丰富。有几条证据表明，全身给予NIC会引发脑内内源性阿片类物质的释放，如内啡肽、脑啡肽和强啡肽。NIC会产生多种急性效应，例如，抗伤害感受效应以及下丘脑 - 垂体 - 肾上腺（HPA）轴的激活效应。在这些效应中，NIC诱导的抗伤害感受作用，而非HPA轴激活作用，会被阿片受体拮抗剂纳洛酮（NLX）抑制，并且在吗啡耐受小鼠中也受到抑制，这表明内源性阿片系统参与了NIC诱导的抗伤害感受作用，但不参与HPA轴激活作用。此外，α4β2和α7 nAChR拮抗剂均可拮抗NIC诱导的抗伤害感受作用，而α4β2 nAChR拮抗剂可拮抗NIC诱导的HPA轴激活作用，α7 nAChR拮抗剂则不能。这些结果表明，内源性阿片系统可能并不位于α4β2 nAChR的下游。另一方面，NIC具有很强的身体依赖性。重复给予NIC后，NLX会引发NIC戒断反应，通过皮质酮升高作为戒断标志来评估，并且同时给予其他阿片受体拮抗剂纳曲酮可抑制NLX引发的NIC戒断反应，这表明内源性阿片系统参与了对NIC身体依赖性的形成。同时给予α7 nAChR拮抗剂也可抑制NLX引发的NIC戒断反应，但给予α4β2 nAChR拮抗剂则不能。综上所述，这些发现表明内源性阿片系统可能位于α7 nAChR的下游，并参与了对NIC身体依赖性的形成。
Nihon Arukoru Yakubutsu Igakkai Zasshi. 2014-10
J Pharmacol Sci. 2014
Psychopharmacology (Berl). 2018-3-16
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