Departamento de Fisiología y Farmacología, Facultad de Medicina, Universidad de Cantabria, 39011 Santander, Spain, Instituto de Formación e Investigación Marqués de Valdecilla, 39011 Santander, Spain, Instituto de Biomedicina y Biotecnología de Cantabria IBBTEC, 39011 Santander, Spain, Centro de Investigación Biomédica en Red de Salud Mental, Instituto de Salud Carlos III, Spain, Departamento de Anestesiología y Reanimación, Hospital Universitario Valdecilla, Santander, Spain, Pharmaleads SAS, 75013 Paris, France, and Université Paris-Descartes, 75006 Paris, France.
J Neurosci. 2014 Apr 9;34(15):5385-95. doi: 10.1523/JNEUROSCI.4405-13.2014.
Transforming growth factor-β1 (TGF-β1) protects against neuroinflammatory events underlying neuropathic pain. TGF-β signaling enhancement is a phenotypic characteristic of mice lacking the TGF-β pseudoreceptor BAMBI (BMP and activin membrane-bound inhibitor), which leads to an increased synaptic release of opioid peptides and to a naloxone-reversible hypoalgesic/antiallodynic phenotype. Herein, we investigated the following: (1) the effects of BAMBI deficiency on opioid receptor expression, functional efficacy, and analgesic responses to endogenous and exogenous opioids; and (2) the involvement of the opioid system in the antiallodynic effect of TGF-β1. BAMBI-KO mice were subjected to neuropathic pain by sciatic nerve crash injury (SNI). Gene (PCR) and protein (Western blot) expressions of μ- and δ-opioid receptors were determined in the spinal cord. The inhibitory effects of agonists on the adenylyl cyclase pathway were investigated. Two weeks after SNI, wild-type mice developed mechanical allodynia and the functionality of μ-opioid receptors was reduced. By this time, BAMBI-KO mice were protected against allodynia and exhibited increased expression and function of opioid receptors. Four weeks after SNI, when mice of both genotypes had developed neuropathic pain, the analgesic responses induced by morphine and RB101 (an inhibitor of enkephalin-degrading enzymes, which increases the synaptic levels of enkephalins) were enhanced in BAMBI-KO mice. Similar results were obtained in the formalin-induced chemical-inflammatory pain model. Subcutaneous TGF-β1 infusion prevented pain development after SNI. The antiallodynic effect of TGF-β1 was naloxone-sensitive. In conclusion, modulation of the endogenous opioid system by TGF-β signaling improves the analgesic effectiveness of exogenous and endogenous opioids under pathological pain conditions.
转化生长因子-β1（TGF-β1）可预防神经性疼痛的神经炎症事件。TGF-β信号增强是缺乏 TGF-β伪受体 BAMBI（骨形态发生蛋白和激活素膜结合抑制剂）的小鼠的表型特征，导致阿片肽的突触释放增加，并导致纳洛酮可逆转的镇痛/抗痛觉过敏表型。在此，我们研究了以下内容：（1）BAMBI 缺乏对阿片受体表达、功能效力以及对内源性和外源性阿片类药物的镇痛反应的影响；（2）阿片系统在 TGF-β1的抗痛觉过敏作用中的参与。通过坐骨神经冲击损伤（SNI）使 BAMBI-KO 小鼠产生神经性疼痛。在脊髓中确定 μ-和 δ-阿片受体的基因（PCR）和蛋白（Western blot）表达。研究了激动剂对腺苷酸环化酶途径的抑制作用。SNI 后 2 周，野生型小鼠出现机械性痛觉过敏，μ-阿片受体的功能降低。此时，BAMBI-KO 小鼠免受痛觉过敏的影响，并表现出阿片受体表达和功能的增加。SNI 后 4 周，当两种基因型的小鼠均出现神经性疼痛时，BAMBI-KO 小鼠中吗啡和 RB101（一种抑制脑啡肽降解酶的抑制剂，可增加脑啡肽的突触水平）引起的镇痛反应增强。在福尔马林诱导的化学炎症性疼痛模型中也获得了类似的结果。皮下 TGF-β1 输注可预防 SNI 后的疼痛发展。TGF-β1 的抗痛觉过敏作用对纳洛酮敏感。总之，TGF-β 信号对内源性阿片系统的调节可改善病理性疼痛条件下外源性和内源性阿片类药物的镇痛效果。
