Department of Pharmacology and Systems Therapeutics, Box 1603, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029, USA.
Pharmacol Rev. 2011 Sep;63(3):461-70. doi: 10.1124/pr.110.003491. Epub 2011 Jul 13.
Alterations in the endogenous cannabinoid system have been described in almost every category of disease. These changes can alternatively be protective or maladaptive, such as producing antinociception in neuropathic pain or fibrogenesis in liver disease, making the system an attractive therapeutic target. However, the challenge remains to selectively target the site of disease while sparing other areas, particularly mood and cognitive centers of the brain. Identifying regional changes in cannabinoid receptor-1 and -2 (CB(1)R and CB(2)R) expression is particularly important when considering endocannabinoid system-based therapies, because regional increases in cannabinoid receptor expression have been shown to increase potency and efficacy of exogenous agonists at sites of disease. Although there have been extensive descriptive studies of cannabinoid receptor expression changes in disease, the underlying mechanisms are only just beginning to unfold. Understanding these mechanisms is important and potentially relevant to therapeutics. In diseases for which cannabinoid receptors are protective, knowledge of the mechanisms of receptor up-regulation could be used to design therapies to regionally increase receptor expression and thus increase efficacy of an agonist. Alternatively, inhibition of harmful cannabinoid up-regulation could be an attractive alternative to global antagonism of the system. Here we review current findings on the mechanisms of cannabinoid receptor regulation in disease and discuss their therapeutic implications.
几乎在每一种疾病类别中都描述了内源性大麻素系统的改变。这些变化可以是保护性的，也可以是适应性不良的，例如在神经病理性疼痛中产生抗伤害感受作用，或者在肝病中产生纤维化，这使得该系统成为一个有吸引力的治疗靶点。然而，仍然存在的挑战是选择性地针对疾病部位，同时避免其他区域，特别是大脑的情绪和认知中心受到影响。在考虑基于内源性大麻素系统的治疗时，特别重要的是要识别大麻素受体 1 和 2（CB1R 和 CB2R）表达的区域性变化，因为已经表明，在疾病部位大麻素受体表达的区域性增加会增加外源性激动剂的效力和功效。尽管已经有大量关于疾病中大麻素受体表达变化的描述性研究，但这些机制才刚刚开始显现。了解这些机制很重要，并且可能与治疗有关。在大麻素受体具有保护作用的疾病中，了解受体上调的机制可以用于设计区域性增加受体表达的治疗方法，从而提高激动剂的疗效。或者，抑制有害的大麻素上调可能是对抗该系统的全身拮抗作用的一种有吸引力的替代方法。在这里，我们综述了疾病中大麻素受体调节的机制的最新发现，并讨论了它们的治疗意义。
