Antiemetic and motor-depressive actions of CP55,940: cannabinoid CB1 receptor characterization, distribution, and G-protein activation.
Antiemetic and motor-depressive actions of CP55,940: cannabinoid CB1 receptor characterization, distribution, and G-protein activation.
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DOI：
10.1016/s0014-2999(02)02815-7
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发表时间：
2003-01
影响因子：
5
通讯作者：
N. Darmani;L. Sim‐Selley;B. Martin;Jano J. Janoyan;Jennifer L. Crim;B. K. Parekh;C. Breivogel
中科院分区：
文献类型：
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作者：
N. Darmani;L. Sim‐Selley;B. Martin;Jano J. Janoyan;Jennifer L. Crim;B. K. Parekh;C. Breivogel
二苯并吡喃(WIN9-四氢大麻酚)和氨基烷基吲哚[R(+)-[2，3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrolol[1，2，3-de]-1，4-benzoxazin-yl]-(1-naphthalenyl)甲烷甲磺酸盐(Δ55,212-2)]大麻类化合物通过大麻素CB1受体抑制顺铂引起的呕吐。本研究研究了“非经典”大麻素CP55,940[1α，2β-(R)-5α]-(−)-5-(1，1-dimethyl)-2-[5-hydroxy-2-(3-hydroxypropyl)[环己基苯酚]对顺铂引起的呕吐的止吐潜力，并评估了大麻素CB1受体在最小的地鼠(Cryptotis Parva)脑中的存在和功能。CP55,940(0.025~0.3 mg/kg)可降低顺铂引起的呕吐次数(ID_(50)=0.025 mg/kg)和呕吐率(ID_(50)=0.09 mg/kg)。CP55,940在该剂量下也能抑制地鼠的运动行为(ID50=0.06-0.21 mg/kg)。CP55,940的止吐和运动抑制作用可被SR141716A[N-piperidino-5-(4-chlorophenyl)-1-(2，4-dichlorophenyl)-4-methylpyrazole-3-carboxamide]，拮抗，表明这两种作用都是由大麻素CB1受体介导的。用[~3H]-SR141716A和[35S]-GTPγ与S结合的放射自显影研究表明，大麻素CB1受体的分布和激活模式与啮齿类动物的脑相似，并在控制呕吐的脑部位(如孤束核)有显著水平。不同结构的大麻素配体对大麻素CB1受体在树鼠脑中的亲和力排序与啮齿动物脑相似：HU-210=CP55,940=SR141716A≥WIN55,212-2≥delta-9-tetrahydrocannabinol>；methanandamide=HU-211=cannabidiol=2-arachidonoylglycerol.这种亲和力顺序与刺激γS的大麻素EC50效价顺序相似且高度相关，但WIN55、212-2和Delta9-四氢大麻酚的效价顺序被颠倒。受试大麻素的亲和力和效价顺序与它们对顺铂引起的呕吐(CP55,940>；WIN55,212-2=delta-9-tetrahydrocannabinol)以及由2-花生四烯基甘油或SR141716A(CP55,940>；WIN55,212-2>；delta-9-tetrahydrocannabinol).引起的呕吐的ID50效价顺序显著相关
Dibenzopyran (Δ9-tetrahydrocannabinol) and aminoalkylindole [R(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrolol[1,2,3-de]-1,4-benzoxazin-yl]-(1-naphthalenyl) methanone mesylate; (WIN55,212-2)] cannabinoids suppress vomiting produced by cisplatin via cannabinoid CB1receptors. This study investigates the antiemetic potential of the “nonclassical” cannabinoid CP55,940 [1α,2β-(R)-5α]-(−)-5-(1,1-dimethyl)-2-[5-hydroxy-2-(3-hydroxypropyl) cyclohexyl-phenol] against cisplatin-induced vomiting and assesses the presence and functionality of cannabinoid CB1receptors in the least shrew (Cryptotis parva) brain. CP55,940 (0.025–0.3 mg/kg) reduced both the frequency of cisplatin-induced emesis (ID50=0.025 mg/kg) and the percentage of shrews vomiting (ID50=0.09 mg/kg). CP55,940 also suppressed shrew motor behaviors (ID50=0.06– 0.21 mg/kg) at such doses. The antiemetic and motor-suppressant actions of CP55,940 were countered by SR141716A [N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide], indicating both effects are cannabinoid CB1receptor-mediated. Autoradiographic studies with [3H]-SR141716A and [35S]-GTPγS binding revealed that the distribution of the cannabinoid CB1receptor and its activation pattern are similar to rodent brain and significant levels are present in brain loci (e.g., nucleus tractus solitarius (NTS)) that control emesis. The affinity rank order of structurally diverse cannabinoid ligands for cannabinoid CB1receptor in shrew brain is similar to rodent brain: HU-210=CP55,940=SR141716A≥WIN55,212-2≥delta-9-tetrahydrocannabinol>methanandamide=HU-211=cannabidiol=2-arachidonoylglycerol. This affinity order is also similar and is highly correlated to the cannabinoid EC50potency rank order for GTPγS stimulation except WIN55,212-2 and delta-9-tetrahydrocannabinol potency order were reversed. The affinity and the potency rank order of tested cannabinoids were significantly correlated with their antiemetic ID50potency order against cisplatin-induced vomiting (CP55,940>WIN55,212-2=delta-9-tetrahydrocannabinol) as well as emesis produced by 2-arachidonoylglycerol or SR141716A (CP55,940>WIN55,212-2>delta-9-tetrahydrocannabinol).