Polo Sara, Díaz Andrés Felipe, Gallardo Núria, Leánez Sergi, Balboni Gianfranco, Pol Olga
Grup de Neurofarmacologia Molecular, Institut d'Investigació Biomèdica Sant Pau, Barcelona, Spain.
Grup de Neurofarmacologia Molecular, Institut de Neurociències, Universitat Autònoma de Barcelona, Barcelona, Spain.
Front Pharmacol. 2019 Mar 26;10:283. doi: 10.3389/fphar.2019.00283. eCollection 2019.
We investigated whether administration of the δ-opioid receptor (DOR) agonist H-Dmt-Tic-NH-CH(CH2-COOH)-Bid (UFP-512), which also activates nuclear factor erythroid 2-related factor 2 (Nrf2), alleviated chronic inflammatory and/or neuropathic pain and inhibited the depressive-like behaviors associated with persistent neuropathic pain. The possible mechanisms implicated were also assessed. We evaluated the following effects in male C57BL/6J mice with inflammatory pain induced by or neuropathic pain caused by the chronic constriction of sciatic nerve: (1) the antinociceptive effects of UFP-512; (2) the effects of UFP-512 on the expression of Nrf2, heme oxygenase 1 (HO-1), NAD(P)H quinone oxidoreductase 1, phosphoinositide 3-kinase (PI3K), protein kinase B (Akt), inducible nitric oxide synthase, DOR, and mitogen-activated protein kinases (MAPK) in the spinal cord of animals with inflammatory or neuropathic pain; (3) the antinociceptive effects of the coadministration of UFP-512 with the Nrf2 activator sulforaphane (SFN); and (4) the antidepressant effects of UFP-512 in animals with depressive-like behaviors associated with neuropathic pain. Our results demonstrated that the intraperitoneal administration of UFP-512 inhibited chronic inflammatory and neuropathic pain and reduced the depressive-like behaviors associated with persistent neuropathic pain. The antiallodynic effects of UFP-512 were significantly augmented when it was coadministered with SFN in both types of chronic pain. The administration of UFP-512 increased/reestablished the spinal cord protein levels of Nrf2 and HO-1 in mice with inflammatory or neuropathic pain. However, while during inflammatory pain UFP-512 inhibited spinal c-Jun N-terminal kinase (JNK) and extracellular signal regulated kinase 1/2 (ERK1/2) phosphorylation induced by peripheral inflammation. This DOR agonist blocked the spinal activated PI3K/Akt signaling pathway under chronic neuropathic pain conditions, but it did not alter the enhanced protein levels of p-JNK or p-ERK1/2 induced by sciatic nerve injury. These results revealed the antinociceptive and antidepressant effects of UFP-512 in animals with chronic pain and the different mechanism of action of this DOR agonist in the presence of inflammatory or neuropathic pain. Our data also suggest the administration of UFP-512 as an alternative for the treatment of chronic pain and the depressive-like behaviors associated with neuropathic pain.
我们研究了δ-阿片受体（DOR）激动剂H-Dmt-Tic-NH-CH(CH2-COOH)-Bid（UFP-512）（其也可激活核因子红细胞2相关因子2（Nrf2））是否能减轻慢性炎症性和/或神经性疼痛，并抑制与持续性神经性疼痛相关的抑郁样行为。我们还评估了其中可能涉及的机制。我们在雄性C57BL/6J小鼠中评估了以下效应：由[具体炎症诱导方式未给出]诱导的炎症性疼痛或坐骨神经慢性缩窄引起的神经性疼痛：（1）UFP-512的抗伤害感受作用；（2）UFP-512对炎症性或神经性疼痛动物脊髓中Nrf2、血红素加氧酶1（HO-1）、NAD(P)H醌氧化还原酶1、磷酸肌醇3激酶（PI3K）、蛋白激酶B（Akt）、诱导型一氧化氮合酶、DOR和丝裂原活化蛋白激酶（MAPK）表达的影响；（3）UFP-512与Nrf2激活剂萝卜硫素（SFN）联合给药的抗伤害感受作用；（4）UFP-512对伴有神经性疼痛相关抑郁样行为动物的抗抑郁作用。我们的结果表明，腹腔注射UFP-512可抑制慢性炎症性和神经性疼痛，并减少与持续性神经性疼痛相关的抑郁样行为。在两种类型的慢性疼痛中，当UFP-512与SFN联合给药时，其抗痛觉过敏作用显著增强。UFP-512给药可增加/恢复炎症性或神经性疼痛小鼠脊髓中Nrf2和HO-1的蛋白水平。然而，在炎症性疼痛期间，UFP-512抑制外周炎症诱导的脊髓c-Jun氨基末端激酶（JNK）和细胞外信号调节激酶1/2（ERK1/2）磷酸化。在慢性神经性疼痛条件下，这种DOR激动剂阻断脊髓激活的PI3K/Akt信号通路，但它并未改变坐骨神经损伤诱导的p-JNK或p-ERK1/2蛋白水平升高。这些结果揭示了UFP-512在慢性疼痛动物中的抗伤害感受和抗抑郁作用，以及这种DOR激动剂在存在炎症性或神经性疼痛时不同的作用机制。我们的数据还表明，UFP-512可作为治疗慢性疼痛和与神经性疼痛相关的抑郁样行为的一种替代药物。
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