Coronel María F, Villar Marcelo J, Brumovsky Pablo R, González Susana L
Laboratorio de Nocicepción y Dolor Neuropático, Instituto de Biología y Medicina Experimental - CONICET, Vuelta de Obligado 2490, C1428ADN, Buenos Aires, Argentina.
Instituto de Investigaciones en Medicina Traslacional, Universidad Austral - CONICET, Av. Juan Domingo Perón 1500, B1629AHJ, Pilar, Argentina.
Peptides. 2017 Feb;88:189-195. doi: 10.1016/j.peptides.2017.01.001. Epub 2017 Jan 3.
Patients with spinal cord injury (SCI) develop chronic pain that severely compromises their quality of life. We have previously reported that progesterone (PG), a neuroprotective steroid, could offer a promising therapeutic strategy for neuropathic pain. In the present study, we explored temporal changes in the expression of the neuropeptides galanin and tyrosine (NPY) and their receptors (GalR1 and GalR2; Y1R and Y2R, respectively) in the injured spinal cord and evaluated the impact of PG administration on both neuropeptide systems and neuropathic behavior. Male rats were subjected to spinal cord hemisection at T13 level, received daily subcutaneous injections of PG or vehicle, and were evaluated for signs of mechanical and thermal allodynia. Real time PCR was used to determine relative mRNA levels of neuropeptides and receptors, both in the acute (1day) and chronic (28days) phases after injury. A significant increase in Y1R and Y2R expression, as well as a significant downregulation in GalR2 mRNA levels, was observed 1day after SCI. Interestingly, PG early treatment prevented Y1R upregulation and resulted in lower NPY, Y2R and GalR1 mRNA levels. In the chronic phase, injured rats showed well-established mechanical and cold allodynia and significant increases in galanin, NPY, GalR1 and Y1R mRNAs, while maintaining reduced GalR2 expression. Animals receiving PG treatment showed basal expression levels of galanin, NPY, GalR1 and Y1R, and reduced Y2R mRNA levels. Also, and in line with previously published observations, PG-treated animals did not develop mechanical allodynia and showed reduced sensitivity to cold stimulation. Altogether, we show that SCI leads to considerable changes in the spinal expression of galanin, NPY and their associated receptors, and that early and sustained PG administration prevents them. Moreover, our data suggest the participation of galaninergic and NPYergic systems in the plastic changes associated with SCI-induced neuropathic pain, and further supports the therapeutic potential of PG- or neuropeptide-based therapies to prevent and/or treat chronic pain after central injuries.
脊髓损伤（SCI）患者会出现慢性疼痛，这严重损害了他们的生活质量。我们之前报道过，孕酮（PG）作为一种具有神经保护作用的类固醇，可能为神经性疼痛提供一种有前景的治疗策略。在本研究中，我们探究了受损脊髓中神经肽甘丙肽和神经肽Y（NPY）及其受体（分别为GalR1和GalR2；Y1R和Y2R）表达的时间变化，并评估了PG给药对这两种神经肽系统和神经病理性行为的影响。雄性大鼠在T13水平进行脊髓半横断，每天接受皮下注射PG或赋形剂，并评估其机械性和热性痛觉过敏的体征。实时定量PCR用于确定损伤后急性期（1天）和慢性期（28天）神经肽和受体的相对mRNA水平。SCI后1天观察到Y1R和Y2R表达显著增加，以及GalR2 mRNA水平显著下调。有趣的是，PG早期治疗可防止Y1R上调，并导致NPY、Y2R和GalR1 mRNA水平降低。在慢性期，受损大鼠表现出明确的机械性和冷痛觉过敏，甘丙肽、NPY、GalR1和Y1R mRNA显著增加，同时GalR2表达持续降低。接受PG治疗的动物甘丙肽、NPY、GalR1和Y1R的表达水平处于基础水平，Y2R mRNA水平降低。此外，与之前发表的观察结果一致，接受PG治疗的动物未出现机械性痛觉过敏，对冷刺激的敏感性降低。总之，我们表明SCI导致脊髓中甘丙肽、NPY及其相关受体的表达发生显著变化，早期和持续给予PG可预防这些变化。此外，我们的数据表明甘丙肽能和NPY能系统参与了与SCI诱导的神经病理性疼痛相关的可塑性变化，并进一步支持了基于PG或神经肽的疗法在预防和/或治疗中枢损伤后慢性疼痛方面的治疗潜力。
