Program in Neuroscience, Indiana University, Bloomington, Indiana; Psychological and Brain Sciences, Indiana University, Bloomington, Indiana.
Psychological and Brain Sciences, Indiana University, Bloomington, Indiana.
Biol Psychiatry. 2018 Nov 15;84(10):722-733. doi: 10.1016/j.biopsych.2017.06.032. Epub 2017 Jul 8.
Activation of cannabinoid CB receptors suppresses pathological pain but also produces unwanted central side effects. We hypothesized that a positive allosteric modulator of CB signaling would suppress inflammatory and neuropathic pain without producing cannabimimetic effects or physical dependence. We also asked whether a CB positive allosteric modulator would synergize with inhibitors of endocannabinoid deactivation and/or an orthosteric cannabinoid agonist.
GAT211, a novel CB positive allosteric modulator, was evaluated for antinociceptive efficacy and tolerance in models of neuropathic and/or inflammatory pain. Cardinal signs of direct CB-receptor activation were evaluated together with the propensity to induce reward or aversion and physical dependence. Comparisons were made with inhibitors of endocannabinoid deactivation (JZL184, URB597) or an orthosteric cannabinoid agonist (WIN55,212-2). All studies used 4 to 11 subjects per group.
GAT211 suppressed allodynia induced by complete Freund's adjuvant and the chemotherapeutic agent paclitaxel in wild-type but not CB knockout mice. GAT211 did not impede paclitaxel-induced tumor cell line toxicity. GAT211 did not produce cardinal signs of direct CB-receptor activation in the presence or absence of pathological pain. GAT211 produced synergistic antiallodynic effects with fatty acid amide hydrolase and monoacylglycerol lipase inhibitors in paclitaxel-treated mice. Therapeutic efficacy was preserved over 19 days of chronic dosing with GAT211, but it was not preserved with the monoacylglycerol lipase inhibitor JZL184. The CB antagonist rimonabant precipitated withdrawal in mice treated chronically with WIN55,212-2 but not in mice treated with GAT211. GAT211 did not induce conditioned place preference or aversion.
Positive allosteric modulation of CB-receptor signaling shows promise as a safe and effective analgesic strategy that lacks tolerance, dependence, and abuse liability.
大麻素 CB 受体的激活可抑制病理性疼痛，但也会产生中枢不良反应。我们假设，CB 信号的正变构调节剂将抑制炎症性和神经性疼痛，而不会产生大麻样作用或身体依赖性。我们还询问了 CB 正变构调节剂是否会与内源性大麻素失活抑制剂和/或正构大麻素激动剂协同作用。
评估新型 CB 正变构调节剂 GAT211 在神经病理性和/或炎症性疼痛模型中的镇痛效果和耐受性。评估了直接 CB 受体激活的主要迹象，以及引起奖赏或厌恶以及身体依赖性的倾向。将其与内源性大麻素失活抑制剂（JZL184、URB597）或正构大麻素激动剂（WIN55,212-2）进行了比较。所有研究均使用每组 4 至 11 只动物。
GAT211 抑制了完全弗氏佐剂和化疗药物紫杉醇在野生型但不是 CB 敲除小鼠中引起的痛觉过敏。GAT211 不会阻碍紫杉醇引起的肿瘤细胞系毒性。在存在或不存在病理性疼痛的情况下，GAT211 均不会产生直接 CB 受体激活的主要迹象。GAT211 与脂肪酸酰胺水解酶和单酰基甘油脂肪酶抑制剂在紫杉醇处理的小鼠中产生协同抗痛觉过敏作用。GAT211 的治疗效果在 19 天的慢性给药中得到保留，但在单酰基甘油脂肪酶抑制剂 JZL184 中则没有保留。CB 拮抗剂利莫那班在接受慢性 WIN55,212-2 治疗的小鼠中引发戒断，但在接受 GAT211 治疗的小鼠中则没有。GAT211 不会引起条件性位置偏好或厌恶。
CB 受体信号的正变构调节作为一种安全有效的镇痛策略具有很大的前景，它没有耐受性、依赖性和滥用倾向。
