抄録
Nicotine is a neuronal stimulant and produces various pharmacological effects through nicotinic acetylcholine receptors (nAChRs) activation in the central nervous system; i.e., antinociception, hypothalamo-pituitary-adrenal axis activation and physical dependence liability. It is well-known that nicotine effects were, at least in part, elicited through the activation of endogenous opioid system. On the other hand, the development of tolerance to and dependence on opioid were suppressed by inflammatory pain. The aim of this experiment is to clarify the effects of inflammatory pain on the development of tolerance to and dependence on nicotine in ICR male mice. The antinociceptive effect was evaluated by tail pinch test, and the blood level of serum corticosterone (SCS) was quantified by fluorescence method. A single injection of nicotine or morphine elicits antinociception and SCS elevation. Nicotine-induced antinociception was prevented by ether nAChR antagonist (mecamylamine; MEC) or opioid receptor antagonist (naloxone; NLX), and also by repeated administration of each agents. On the other hand, the nicotine-induced SCS elevation was suppressed by MEC or repeated nicotine, but neither NLX nor repeated morphine. Thus, we predicted that endogenous opioid system might involve in nicotine-induced antinociception but not SCS elevation. Next, we examined whether physical dependence on nicotine was developed by the stimulation of endogenous opioid system. We evaluated SCS increase as an indicator of nicotine withdrawal, because SCS increase is a quantitative indicator for the intensity of morphine withdrawal. NLX elicited SCS increase in mice receiving repeated nicotine in a dose-dependent manner. When opioid antagonist, naltrexone, was administered together with repeated nicotine, NLX-induced SCS increase was significantly suppressed, indicating that endogenous opioid system might participate in the development of physical dependence on nicotine. The intraplantar injection of formalin-induced inflammatory pain suppressed the development of tolerance to the antinociceptive effect of nicotine, but not to nicotine-induced SCS elevation. Furthermore, nicotine withdrawal evaluated by NLX-precipitated SCS increase was suppressed by the intraplantar injection of formalin. These results suggest that inflammatory pain suppresses the endogenous opioid system-mediated antinociceptive tolerance to and physical dependence on nicotine.
