First in vivo evidence for a functional interaction between chemokine and cannabinoid systems in the brain
First in vivo evidence for a functional interaction between chemokine and cannabinoid systems in the brain
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DOI：
10.1124/jpet.107.135053
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发表时间：
2008-05-01
影响因子：
3.5
通讯作者：
Adler, Martin W.
中科院分区：
文献类型：
--
作者：
Benamar, Khalid;Geller, Ellen B.;Adler, Martin W.
越来越多的证据支持这样一种观点，即除了在免疫系统中的既定作用外，趋化因子可能在正常和病理性脑功能中发挥作用，并且趋化因子网络可以与其他神经调质相互作用。测试趋化因子基质细胞衍生生长因子（SDF）-1 α/CXCL 12（CXC趋化因子家族的一个成员）对大麻素受体激动剂氨基烷基吲哚4，5-二氢-2-甲基-4-甲基-N-（2-甲基-N-（N-甲基-N-（4-吗啉基甲基）-1-（1-萘基-羰基）-6H-吡咯并-[ 3，2，1 ij]喹啉-6-酮[（+）-WIN 55，212 -2，以下简称WIN 55，212 -2]在导水管周围灰质（PAG）水平，对疼痛信号的处理至关重要的大脑区域，以及许多镇痛化合物的主要作用部位。将WIN 55，212 -2（0.1-0.4 μ g/μ l）给予PAG，以剂量依赖性方式产生抗伤害感受作用。将选择性大麻素（CB）1拮抗剂N-（哌啶-1-基）-5-（4-氯苯基）-1-（2，4-二氯苯基）-4-甲基-1H-吡唑-3-甲酰胺盐酸盐（SR 141716 A; 1-10 μ g）给予PAG可阻断WIN 55，212 -2诱导的镇痛作用。相反，选择性CB 2拮抗剂N-[（1 S）-内-1，3，3-三甲基双环庚-2-基]-5-（4-氯-3-甲基苯基）-1-（4-甲基苄基）-吡唑-3-甲酰胺（SR 144528; 10 μ g）未改变WIN 55，212 -2诱导的抗伤害感受。用SDF-1 alpha/CXCL 12（100 ng）预处理导致WIN 55，212 -2的抗伤害反应减少。SDF-1 α/CXCL 12对WIN 55，212 -2诱导的抗伤害感受的抑制作用被八盐酸盐水合物（AMD 3100）（10-50 ng）逆转，八盐酸盐水合物是SDF-1 α/CXCL 12的拮抗剂，作用于其受体CXCR 4。这项研究报告了大脑中趋化因子和大麻素系统之间功能性相互作用的第一个体内证据，表明PAG中SDF-1 α/CXCL 12受体（CXCR 4）的激活干扰了WIN 55212-2的镇痛作用。
Growing evidence supports the idea that in addition to their well established role in the immune system, chemokines might play a role in both normal and pathological brain function, and the chemokine network could interact with other neuromodulators. The chemokine stromal cell-derived growth factor (SDF)-1 alpha/CXCL12, a member of the CXC chemokine family, was tested for its possible effect on the analgesic responses of the cannabinoid receptor agonist aminoalkylindole 4,5-dihydro-2-methyl-4-( 4-morpholinylmethyl)-1-(1-naphthalenyl-carbonyl)-6H-pyrrolo-[ 3,2,1ij]quinolin-6-one [(+)-WIN 55,212-2, hereafter WIN 55,212-2] at the level of the periaqueductal gray (PAG), a brain region critical to the processing of pain signals, and a primary site of action of many analgesic compounds. The administration of WIN 55,212-2 (0.1-0.4 mu g/mu l) into the PAG resulted in antinociception in a dose-dependent manner. The selective cannabinoid (CB) 1 antagonist N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide hydrochloride (SR 141716A; 1-10 mu g) given into the PAG blocked the WIN 55,212-2-induced antinociception. In contrast, the selective CB2 antagonist N-[(1S)-endo-1,3,3-trimethyl bicyclo heptan-2-yl]-5-(4-chloro-3-methylphenyl)-1-( 4-methylbenzyl)-pyrazole-3-carboxamide (SR144528; 10 mu g) did not alter the WIN 55,212-2-induced antinociception. Pretreatment with SDF-1 alpha/CXCL12 (100 ng) caused a reduction in antinociceptive responses of WIN 55,212-2. The inhibitory effect of SDF-1 alpha/CXCL12 on WIN 55,212-2-induced antinociception was reversed by octahydrochloride hydrate (AMD 3100) (10-50 ng), an antagonist of the SDF-1 alpha/CXCL12, acting at its receptor, CXCR4. This study reports the first in vivo evidence of a functional interaction between chemokine and cannabinoid systems in the brain, showing that the activation of SDF-1 alpha/CXCL12 receptors (CXCR4) in the PAG interferes with the analgesic effects of WIN 55212-2.