Antinociception caused by cannabinoids may have a partial peripheral origin in addition to its central site of action. In fact, we have observed that anandamide selectively and reversibly inhibits GABAA receptors of putative nociceptive neurons of mouse trigeminal sensory ganglia via CB1 receptor activation to inhibit adenylyl cyclase and decrease cAMP with downstream posttranslational alterations. Since cannabinoids are often used chronically, we studied changes in cAMP levels and GABA-mediated currents of trigeminal neurons following 24 h application of anandamide (0.5 μM) or the synthetic cannabinoid WIN 55,212-2 (5 μM). With this protocol GABA responses were similar to control despite persistent fall in cAMP levels. Inhibition by WIN 55,212-2 of GABA effects recovered after 30 min washout and was not associated with changes in CB1 receptor expression, indicating lack of CB1 receptor inactivation and transient loss of negative coupling between CB1 receptors and GABAA receptors. The phosphodiesterase inhibitor rolipram (100 μM; 24 h) enhanced cAMP levels and GABA-mediated currents, suggesting GABAA receptors were sensitive to persistent upregulation via cAMP. While the adenylyl cyclase activator forskolin (1-20 μM) facilitated cAMP levels and GABA currents following 30 min application, this action was lost after 24 h in line with the drug limited lifespan. The PKA inhibitor PKI 14-22 (10 μM) increased cAMP without changing GABA currents. These data indicate that modulation of GABAA receptors by intracellular cAMP could be lost following persistent application of cannabinoids. Thus, these observations provide an insight into the waning antinociceptive effects of these compounds.

中文翻译：

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长期使用大麻素会导致cAMP的变化与小鼠三叉神经感觉神经元的GABAA受体的调节之间解离。

由大麻素引起的抗伤害感受除了其中心作用部位外，可能还具有部分外周起源。实际上，我们已经观察到，anandamide通过CB1受体激活来选择性和可逆地抑制小鼠三叉神经感觉神经节的假定伤害感受性神经元的GABA A受体，从而抑制腺苷酸环化酶并降低cAMP以及下游翻译后改变。由于大麻素经常被长期使用，因此我们研究了在应用anandamide（0.5μM）或合成大麻素WIN 55,212-2（5μM）24小时后，cAMP水平和GABA介导的三叉神经元电流的变化。尽管cAMP水平持续下降，但该方案的GABA反应仍与对照相似。WIN 55的抑制作用 冲洗后30分钟，GABA效果的212-2恢复，并且与CB1受体表达的变化无关，这表明CB1受体失活以及CB1受体和GABAA受体之间的负性偶联暂时丧失。磷酸二酯酶抑制剂咯利普兰（100μM; 24 h）增强cAMP水平和GABA介导的电流，表明GABAA受体对通过cAMP持续上调敏感。虽然腺苷酸环化酶激活剂福司高林（1-20μM）在施用30分钟后促进了cAMP水平和GABA电流，但这种作用在24小时后消失，这与药物的有限寿命相一致。PKA抑制剂PKI 14-22（10μM）在不改变GABA电流的情况下增加了cAMP。这些数据表明，在持续应用大麻素后，细胞内cAMP对GABAA受体的调节作用可能会丢失。因此，