Singleton Samuel, Hales Tim G
The Institute of Academic Anaesthesia, Division of Systems Medicine, School of Medicine, Ninewells Hospital, University of Dundee, Dundee, UK.
J Physiol. 2023 Apr;601(8):1483-1500. doi: 10.1113/JP284003. Epub 2023 Mar 23.
Morphine diminishes pain, but its long-term use is compromised by tolerance and hyperalgesia. Studies implicate δ receptors, β-arrestin2 and Src kinase in tolerance. We examined whether these proteins are also involved in morphine-induced hypersensitivity (MIH). A common pathway for tolerance and hypersensitivity may provide a single target to guide improved analgesic approaches. We examined mechanical sensitivity using automated von Frey in wild-type (WT) and transgenic male and female C57Bl/6 mice before and after hind paw inflammation by complete Freund's adjuvant (CFA). CFA-evoked hypersensitivity ceased on day 7 in WT but persisted for the 15-day testing period in μ . Recovery was delayed until day 13 in δ . We explored the expression of opioid genes in the spinal cord using quantitative RT-PCR. Restoration to basal sensitivity in WT occurred with increased δ expression. By contrast, κ expression was reduced, while μ remained unchanged. Daily morphine reduced hypersensitivity in WT on day 3 compared to controls; however, hypersensitivity recurred on day 9 and beyond. By contrast, WT had no recurrence of hypersensitivity in the absence of daily morphine. We used β-arrestin2 , δ and Src inhibition by dasatinib in WT to establish whether these approaches, which diminish tolerance, also attenuate MIH. While none of these approaches affected CFA-evoked inflammation or acute hypersensitivity, all caused sustained morphine anti-hypersensitivity, abolishing MIH. Like morphine tolerance, MIH in this model requires δ receptors, β-arrestin2 and Src activity. Our findings suggest that MIH is caused by a tolerance-induced reduction in endogenous opioid signalling. KEY POINTS: Morphine is effective for treating severe acute pain, but tolerance and hypersensitivity often develop during its use in treating chronic pain. It is unclear whether these detrimental effects share similar mechanisms; if so, it might be possible to develop a single approach to minimise both phenomena. Mice deficient in μ receptors, δ receptors or β-arrestin2 and wild type mice treated with the Src inhibitor dasatinib exhibit negligible morphine tolerance. We show that these same approaches also prevent the development of morphine-induced hypersensitivity during persistent inflammation. This knowledge identifies strategies, such as the use of Src inhibitors, which may mitigate tolerance and morphine induced hyperalgesia.
吗啡可减轻疼痛，但其长期使用会因耐受性和痛觉过敏而受到影响。研究表明δ受体、β-抑制蛋白2和Src激酶与耐受性有关。我们研究了这些蛋白质是否也参与吗啡诱导的超敏反应（MIH）。耐受性和超敏反应的共同途径可能提供一个单一靶点，以指导改进镇痛方法。我们在野生型（WT）和转基因雄性及雌性C57Bl/6小鼠中，通过完全弗氏佐剂（CFA）诱导后爪炎症前后，使用自动von Frey检测机械敏感性。CFA诱发的超敏反应在WT小鼠中于第7天停止，但在μ受体缺失小鼠中在15天的测试期内持续存在。δ受体缺失小鼠的恢复延迟至第13天。我们使用定量RT-PCR研究脊髓中阿片类基因的表达。WT小鼠恢复至基础敏感性伴随着δ表达增加。相比之下，κ表达降低，而μ表达保持不变。与对照组相比，每日注射吗啡可使WT小鼠在第3天减轻超敏反应；然而，超敏反应在第9天及之后再次出现。相比之下，在不每日注射吗啡的情况下，WT小鼠不会出现超敏反应复发。我们在WT小鼠中使用达沙替尼抑制β-抑制蛋白2、δ受体和Src，以确定这些减轻耐受性的方法是否也能减轻MIH。虽然这些方法均未影响CFA诱发的炎症或急性超敏反应，但所有方法均导致吗啡抗超敏反应持续存在，消除了MIH。与吗啡耐受性一样，该模型中的MIH需要δ受体、β-抑制蛋白2和Src活性。我们的研究结果表明，MIH是由耐受性诱导的内源性阿片类信号传导减少所致。要点：吗啡对治疗严重急性疼痛有效，但在其用于治疗慢性疼痛期间，耐受性和超敏反应经常出现。尚不清楚这些有害作用是否具有相似机制；如果是这样，或许有可能开发一种单一方法来尽量减少这两种现象。缺乏μ受体、δ受体或β-抑制蛋白2的小鼠以及用Src抑制剂达沙替尼治疗的野生型小鼠表现出可忽略不计的吗啡耐受性。我们表明，这些相同方法也可防止在持续性炎症期间吗啡诱导的超敏反应的发生。这一知识确定了一些策略，如使用Src抑制剂，可能减轻耐受性和吗啡诱导的痛觉过敏。
