Mathes W F, Kanarek R B
The GRASP Digestive Disease Center and the Molecular Pharmacology Research Center, New England Medical Center, Boston, MA 02111, USA.
Physiol Behav. 2001;74(1-2):245-51. doi: 10.1016/s0031-9384(01)00577-7.
Recent work has shown that chronic exercise is associated with a reduction in the pain-relieving actions of opioid drugs in experimental animals. To determine whether this reduction represents an interaction between exogenously administered opioids and the endogenous opioid system, or is the result of altered drug pharmacokinetics, the antinociceptive actions of morphine and its metabolite, morphine-6-glucuronide (M6G), were compared in active and inactive female Long-Evans rats. Active animals were housed in running wheels and inactive animals in standard laboratory cages for 3 weeks preceding determinations of antinociception using the tail-flick test. At the end of the 3-week period, active rats were running the equivalent of 9-11 km a day. Antinociceptive responses, determined following subcutaneous injections of either morphine (0.625-20 mg/kg) or M6G (0.3-10.0 mg/kg), were significantly reduced in active rats relative to inactive rats. This reduction was manifested by both a lower magnitude of antinociception, and a shorter duration of antinociception after drug administration in active compared to inactive rats. This reduction was not associated with alterations in the estrous cycle or with differences in body weight between the active and inactive animals. The present results support the hypothesis that cross-tolerance develops between endogenous opioid peptides released in response to exercise and exogenously administered opioid drugs.
最近的研究表明，长期运动与实验动物中阿片类药物的止痛作用减弱有关。为了确定这种减弱是外源性给予的阿片类药物与内源性阿片系统之间相互作用的结果，还是药物药代动力学改变的结果，我们比较了吗啡及其代谢产物吗啡-6-葡萄糖醛酸苷（M6G）在活跃和不活跃的雌性Long-Evans大鼠中的抗伤害感受作用。在使用甩尾试验测定抗伤害感受之前，将活跃的动物饲养在跑轮中，不活跃的动物饲养在标准实验室笼子中3周。在3周结束时，活跃的大鼠每天跑的距离相当于9-11公里。皮下注射吗啡（0.625-20mg/kg）或M6G（0.3-10.0mg/kg）后测定的抗伤害感受反应，与不活跃的大鼠相比，活跃的大鼠明显降低。这种降低表现为抗伤害感受的程度较低，并且与不活跃的大鼠相比，活跃的大鼠给药后抗伤害感受的持续时间较短。这种降低与发情周期的改变或活跃和不活跃动物之间的体重差异无关。目前的结果支持这样的假设，即运动时释放的内源性阿片肽与外源性给予的阿片类药物之间会产生交叉耐受性。
