Université de Montpellier, Montpellier, France.
Inserm U-1298, Institut des Neurosciences de Montpellier, Montpellier, France.
Nat Commun. 2024 Nov 7;15(1):9633. doi: 10.1038/s41467-024-54054-y.
Navigating the duality of opioids' potent analgesia and side effects, including tolerance and hyperalgesia, is a significant challenge in chronic pain management, often prompting hazardous dose escalation to maintain analgesic effects. The peripheral mu-opioid receptor (MOR) is known to mediate these contradictory effects. Here, we show that the fms-like tyrosine kinase receptor 3 (FLT3) in peripheral somatosensory neurons drives morphine tolerance and hyperalgesia in a male rodent model. We found that chronic morphine treatment increases FLT3 and MOR co-expression, and that inhibiting FLT3 represses MOR-induced hyperactivation of the cyclic adenosine monophosphate (cAMP) signaling pathway, mitigating maladaptive excitatory processes engaged after chronic morphine treatment. Furthermore, in postsurgical or inflammatory models of chronic pain, co-administering morphine with a FLT3-specific inhibitor not only prevents or suppresses tolerance and hyperalgesia but also potentiates the analgesic efficacy of morphine, without aggravating other morphine-induced adverse effects. Our findings suggest that pairing morphine with FLT3 inhibitors could become a promising avenue for chronic pain management to safely harness the power of opioids, without the risk of dose escalation. By enhancing morphine analgesic potency through FLT3 inhibition, this approach could minimize opioid dosage, thereby curtailing the risk of addiction and other opioid-related side effects.
在外周感觉神经元中，原纤维细胞生长因子受体 3（FLT3）驱动吗啡耐受和痛觉过敏。我们发现，慢性吗啡处理增加了 FLT3 和 MOR 的共表达，并且抑制 FLT3 抑制了 MOR 诱导的环磷酸腺苷（cAMP）信号通路的过度激活，减轻了慢性吗啡处理后参与的适应性兴奋性过程。此外，在手术后或慢性疼痛的炎症模型中，与吗啡联合使用 FLT3 特异性抑制剂不仅可以预防或抑制耐受和痛觉过敏，而且还增强了吗啡的镇痛作用，而不会加重其他吗啡引起的不良反应。我们的研究结果表明，将吗啡与 FLT3 抑制剂联合使用可能成为安全利用阿片类药物治疗慢性疼痛的一种有前途的方法，而不会增加剂量增加的风险。通过抑制 FLT3 增强吗啡的镇痛效力，这种方法可以最小化阿片类药物的剂量，从而降低成瘾和其他与阿片类药物相关的副作用的风险。
