Gómez Raquel, Navarro Miguel, Ferrer Belén, Trigo José M, Bilbao Ainhoa, Del Arco Ignacio, Cippitelli Andrea, Nava Felice, Piomelli Daniele, Rodríguez de Fonseca Fernando
University Institute of Drug Dependencies, Department of Psychobiology, University Complutense of Madrid, Madrid 28223, Spain.
J Neurosci. 2002 Nov 1;22(21):9612-7. doi: 10.1523/JNEUROSCI.22-21-09612.2002.
Recent studies suggest that the endocannabinoid system modulates feeding. Despite the existence of central mechanisms for the regulation of food intake by endocannabinoids, evidence indicates that peripheral mechanisms may also exist. To test this hypothesis, we investigated (1) the effects of feeding on intestinal anandamide accumulation; (2) the effects of central (intracerebroventricular) and peripheral (intraperitoneal) administration of the endocannabinoid agonist anandamide, the synthetic cannabinoid agonist R-(+)-(2,3-dihydro-5-methyl-3-[(4-morpholinyl)methyl]pyrol[1,2,3-de]-1,4-benzoxazin-6-yl)(1-naphthalenyl) methanone monomethanesulfonate (WIN55,212-2), and the CB1-selective antagonist N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide (SR141716A) on food intake in rats; and (3) the effects of sensory deafferentation on the modulation of feeding by cannabinoids. Food deprivation produced a sevenfold increase in anandamide content in the small intestine but not in the brain or stomach. Refeeding normalized intestinal anandamide levels. Peripheral but not central administration of anandamide or WIN55,212-2 promoted hyperphagia in partially satiated rats. Similarly, peripheral but not central administration of SR141716A reduced food intake. Capsaicin deafferentation abolished the peripheral effects of both cannabinoid agonists and antagonists, suggesting that these agents modulate food intake by acting on CB1 receptors located on capsaicin-sensitive sensory terminals. Oleoylethanolamide, a noncannabinoid fatty ethanolamide that acts peripherally, prevented hyperphagia induced by the endogenous cannabinoid anandamide. Pretreatment with SR141716A enhanced the inhibition of feeding induced by intraperitoneal administration of oleoylethanolamide. The results reveal an unexpected role for peripheral CB1 receptors in the regulation of feeding.
近期研究表明，内源性大麻素系统可调节进食。尽管存在内源性大麻素调节食物摄入的中枢机制，但有证据表明外周机制可能也存在。为验证这一假设，我们进行了以下研究：（1）进食对肠道花生四烯酸乙醇胺蓄积的影响；（2）向大鼠中枢（脑室内）和外周（腹腔内）注射内源性大麻素激动剂花生四烯酸乙醇胺、合成大麻素激动剂R-(+)-(2,3-二氢-5-甲基-3-[(4-吗啉基)甲基]吡咯并[1,2,3-de]-1,4-苯并恶嗪-6-基)(1-萘基)甲酮甲磺酸盐（WIN55,212-2）以及CB1选择性拮抗剂N-哌啶基-5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基吡唑-3-甲酰胺（SR141716A）对食物摄入的影响；（3）感觉传入阻滞对大麻素调节进食的影响。禁食使小肠中花生四烯酸乙醇胺含量增加了7倍，但对脑和胃中该物质含量无影响。重新进食后，肠道花生四烯酸乙醇胺水平恢复正常。向部分饱足的大鼠外周而非中枢注射花生四烯酸乙醇胺或WIN55,212-2可促进摄食过多。同样，外周而非中枢注射SR141716A可减少食物摄入量。辣椒素传入阻滞消除了大麻素激动剂和拮抗剂的外周作用，提示这些药物通过作用于辣椒素敏感感觉末梢上的CB1受体来调节食物摄入。油酰乙醇胺是一种在外周起作用的非大麻素类脂肪乙醇酰胺，可预防内源性大麻素花生四烯酸乙醇胺诱导的摄食过多。用SR141716A预处理可增强腹腔注射油酰乙醇胺对进食的抑制作用。这些结果揭示了外周CB1受体在进食调节中出人意料的作用。
