Li Ming-Hua, Suchland Katherine L, Ingram Susan L
Department of Neurological Surgery, Oregon Health & Science University, Portland, Oregon 97239
Department of Neurological Surgery, Oregon Health & Science University, Portland, Oregon 97239.
J Neurosci. 2017 Jan 18;37(3):626-636. doi: 10.1523/JNEUROSCI.1310-16.2016.
The rostral ventromedial medulla (RVM) is a relay in the descending pain modulatory system and an important site of endocannabinoid modulation of pain. Endocannabinoids inhibit GABA release in the RVM, but it is not known whether this effect persists in chronic pain states. In the present studies, persistent inflammation induced by complete Freund's adjuvant (CFA) increased GABAergic miniature IPSCs (mIPSCs). Endocannabinoid activation of cannabinoid (CB1) receptors known to inhibit presynaptic GABA release was significantly reduced in the RVM of CFA-treated rats compared with naive rats. The reduction in CFA-treated rats correlated with decreased CB1 receptor protein expression and function in the RVM. Paradoxically, the nonselective CB1/CB2 receptor agonist WIN55212 inhibited GABAergic mIPSCs in both naive and CFA-treated rats. However, WIN55212 inhibition was reversed by the CB1 receptor antagonist rimonabant in naive rats but not in CFA-treated rats. WIN55212-mediated inhibition in CFA-treated rats was blocked by the CB2 receptor-selective antagonist SR144528, indicating that CB2 receptor function in the RVM is increased during persistent inflammation. Consistent with these results, CB2 receptor agonists AM1241 and GW405833 inhibited GABAergic mIPSC frequency only in CFA-treated rats, and the inhibition was reversed with SR144528. When administered alone, SR144528 and another CB2 receptor-selective antagonist AM630 increased mIPSC frequency in the RVM of CFA-treated rats, indicating that CB2 receptors are tonically activated by endocannabinoids. Our data provide evidence that CB2 receptor function emerges in the RVM in persistent inflammation and that selective CB2 receptor agonists may be useful for treatment of persistent inflammatory pain.
These studies demonstrate that endocannabinoid signaling to CB1 and CB2 receptors in adult rostral ventromedial medulla is altered in persistent inflammation. The emergence of CB2 receptor function in the rostral ventromedial medulla provides additional rationale for the development of CB2 receptor-selective agonists as useful therapeutics for chronic inflammatory pain.
延髓头端腹内侧区（RVM）是下行性疼痛调制系统中的一个中继站，也是内源性大麻素调节疼痛的重要部位。内源性大麻素抑制RVM中的GABA释放，但尚不清楚这种作用在慢性疼痛状态下是否持续存在。在本研究中，完全弗氏佐剂（CFA）诱导的持续性炎症增加了GABA能微小抑制性突触后电流（mIPSCs）。与未处理的大鼠相比，已知抑制突触前GABA释放的大麻素（CB1）受体的内源性大麻素激活在CFA处理的大鼠的RVM中显著降低。CFA处理的大鼠中的这种降低与RVM中CB1受体蛋白表达和功能的降低相关。矛盾的是，非选择性CB1/CB2受体激动剂WIN55212在未处理和CFA处理的大鼠中均抑制GABA能mIPSCs。然而，CB1受体拮抗剂利莫那班在未处理的大鼠中可逆转WIN55212的抑制作用，但在CFA处理的大鼠中则不能。WIN55212在CFA处理的大鼠中介导的抑制作用被CB2受体选择性拮抗剂SR144528阻断，表明在持续性炎症期间RVM中CB2受体功能增强。与这些结果一致，CB2受体激动剂AM1241和GW405833仅在CFA处理的大鼠中抑制GABA能mIPSC频率，且该抑制作用可被SR144528逆转。单独给药时，SR144528和另一种CB2受体选择性拮抗剂AM630增加了CFA处理的大鼠RVM中的mIPSC频率，表明CB2受体被内源性大麻素持续激活。我们的数据提供了证据，表明在持续性炎症中RVM中出现了CB2受体功能，且选择性CB2受体激动剂可能对治疗持续性炎性疼痛有用。
这些研究表明，在持续性炎症中，成年延髓头端腹内侧区中内源性大麻素向CB1和CB2受体的信号传导发生了改变。延髓头端腹内侧区中CB2受体功能的出现为开发CB2受体选择性激动剂作为慢性炎性疼痛的有效治疗药物提供了额外的理论依据。
