As the incidence and survival rates of patients with cancer continues to grow, an increasing number of people are living with comorbidities, which often manifests as cancer-induced bone pain (CIBP). The majority of patients with CIBP report poor pain control from currently available analgesics. A conotoxin, Contulakin-G (CGX), has been demonstrated to be an antinociceptive agent in postsurgical and neuropathic pain states via a neurotensin receptor 2 (NTSR2)-mediated pathway. However, the efficacy and side effect profile of CGX have never been assessed in CIBP. Here, we evaluated CGX's antinociceptive potential in a rodent model of CIBP. We hypothesized that CGX engages the NTSR2 pathway, providing pain relief with minimal tolerance and motor side effects. Our results demonstrated that CGX intrathecal injection in mice with CIBP attenuated both spontaneous pain behaviors and evoked mechanical hypersensitivity, regardless of their sex. Furthermore, the antinociceptive effect of CGX was dependent upon expression of NTSR2 and the R-type voltage-gated calcium channel (Cav2.3); gene editing of these targets abolished CGX antinociception without affecting morphine antinociception. Examination of the side effect profile of CGX demonstrated that, unlike morphine, chronic intrathecal infusion maintained antinociception with reduced tolerance in rats with CIBP. Moreover, at antinociceptive doses, CGX had no impact on motor behavior in rodents with CIBP. Finally, RNAScope and immunoblotting analysis revealed expression of NTSR2 in both dorsal and ventral horns, while Cav2.3 was minimally expressed in the ventral horn, possibly explaining the sensory selectivity of CGX. Together, these findings support advancing CGX as a potential therapeutic for cancer pain.

中文翻译：

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芋螺毒素 Contulakin-G 可逆转在癌症引起的骨痛啮齿动物模型中观察到的超敏反应，且不会引起耐受性或运动障碍。


随着癌症患者的发病率和生存率持续增长，越来越多的人患有合并症，通常表现为癌症引起的骨痛（CIBP）。大多数 CIBP 患者报告目前可用的镇痛药控制疼痛效果不佳。芋螺毒素 Contulakin-G (CGX) 已被证明是通过神经降压素受体 2 (NTSR2) 介导的途径在术后和神经性疼痛状态下发挥镇痛作用的药物。然而，CGX 的功效和副作用从未在 CIBP 中进行过评估。在这里，我们评估了 CGX 在 CIBP 啮齿动物模型中的抗伤害潜力。我们假设 CGX 参与 NTSR2 通路，以最小的耐受性和运动副作用提供疼痛缓解。我们的结果表明，无论性别如何，对 CIBP 小鼠进行鞘内注射 CGX 均可减轻自发疼痛行为并诱发机械超敏反应。此外，CGX 的镇痛作用依赖于 NTSR2 和 R 型电压门控钙通道 (Cav2.3) 的表达。这些靶点的基因编辑消除了 CGX 的镇痛作用，但不影响吗啡的镇痛作用。对 CGX 副作用的检查表明，与吗啡不同，慢性鞘内输注可维持 CIBP 大鼠的镇痛作用，但耐受性降低。此外，在抗伤害剂量下，CGX 对患有 CIBP 的啮齿动物的运动行为没有影响。最后，RNAScope 和免疫印迹分析显示 NTSR2 在背角和腹角都有表达，而 Cav2.3 在腹角表达最少，这可能解释了 CGX 的感觉选择性。总之，这些发现支持推进 CGX 作为癌症疼痛的潜在治疗方法。