Pain produced by bone cancer is often severe and difficult to treat. Here we examined effects of Resolvin D1 (RvD1) or E1 (RvE1), antinociceptive products of ω-3 polyunsaturated fatty acids, on cancer-induced mechanical allodynia and heat hyperalgesia. Experiments were performed using a mouse model of bone cancer produced by implantation of osteolytic ficrosarcoma into and around the calcaneus bone. Mechanical allodynia and heat hyperalgesia in the tumor-bearing paw were assessed by measuring withdrawal responses to a von Frey monofilament and to radiant heat applied on the plantar hind paw. RvD1, RvE1, and cannabinoid receptor antagonists were injected intrathecally. Spinal content of endocannabinoids was evaluated using UPLC-MS/MS analysis. RvD1 and RvE1 had similar antinociceptive potencies. ED_50s for RvD1 and RvE1 in reducing mechanical allodynia were 0.2 pg (0.53 fmol) and 0.6 pg (1.71 fmol), respectively, and were 0.3 pg (0.8 fmol) and 0.2 pg (0.57 fmol) for reducing heat hyperalgesia. Comparisons of dose-response relationships showed equal efficacy for reducing mechanical allodynia, however, efficacy for reducing heat hyperalgesia was greater for of RvD1. Using UPLC-MS/MS we determined that RvD1, but not RvE1, increased levels of the endocannabinoids Anandamide and 2-Arachidonoylglycerol in the spinal cord. Importantly, Resolvins did not alter acute nociception or motor function in naïve mice.

Our data indicate, that RvD1 and RvE1 produce potent antiallodynia and antihyperalgesia in a model of bone cancer pain. RvD1 also triggers spinal upregulation of endocannabinoids that produce additional antinociception predominantly through CB2 receptors.

骨癌产生的疼痛通常很严重且难以治疗。在这里，我们检查了 Resolvin D1 (RvD1) 或 E1 (RvE1)（ω-3 多不饱和脂肪酸的抗伤害感受产品）对癌症引起的机械异常性疼痛和热痛觉过敏的影响。实验使用通过将溶骨性纤维肉瘤植入跟骨及其周围而产生的骨癌小鼠模型进行。通过测量对 von Frey 单丝和施加在足底后爪上的辐射热的退缩反应来评估带有肿瘤的爪子的机械异常性疼痛和热痛觉过敏。鞘内注射 RvD1、RvE1 和大麻素受体拮抗剂。使用 UPLC-MS/MS 分析评估脊髓中内源性大麻素的含量。 RvD1 和 RvE1 具有相似的抗伤害作用。 RvD1 和 RvE1 在减少机械异常性疼痛方面的 ED ₅₀分别为 0.2 pg (0.53 fmol) 和 0.6 pg (1.71 fmol)，在减少热痛觉过敏方面分别为 0.3 pg (0.8 fmol) 和 0.2 pg (0.57 fmol)。剂量-反应关系的比较显示，RvD1对于减少机械异常性疼痛具有相同的功效，但是对于减少热痛觉过敏的功效更大。使用 UPLC-MS/MS，我们确定 RvD1（而非 RvE1）增加了脊髓中内源性大麻素 Anandamide 和 2-Arachidonoylglycerol 的水平。重要的是，Resolvins 不会改变幼鼠的急性伤害感受或运动功能。

我们的数据表明，RvD1 和 RvE1 在骨癌疼痛模型中产生有效的抗痛觉和抗痛觉过敏。 RvD1 还会触发脊髓内源性大麻素的上调，主要通过 CB2 受体产生额外的镇痛作用。