Mika J, Jurga A M, Starnowska J, Wasylewski M, Rojewska E, Makuch W, Kwiatkowski K, Malek N, Przewlocka B
Department of Pain Pharmacology, Institute of Pharmacology, Polish Academy of Sciences, Krakow, Poland.
Department of Pain Pharmacology, Institute of Pharmacology, Polish Academy of Sciences, Krakow, Poland.
Neuroscience. 2015 May 21;294:38-50. doi: 10.1016/j.neuroscience.2015.03.003. Epub 2015 Mar 10.
Neuropathic pain is a severe clinical problem, often appearing as a co-symptom of many diseases or manifesting as a result of damage to the nervous system. Many drugs and agents are currently used for the treatment of neuropathic pain, such as tricyclic antidepressants (TCAs). The aims of this paper were to test the effects of two classic TCAs, doxepin and amitriptyline, in naïve animals and in a model of neuropathic pain and to determine the role of cytokine activation in the effects of these drugs. All experiments were carried out with Albino-Swiss mice using behavioral tests (von Frey test and the cold plate test) and biochemical analyses (qRT-PCR and Western blot). In the mice subjected to chronic constriction injury (CCI), doxepin and amitriptyline attenuated the symptoms of neuropathic pain and diminished the CCI-induced increase in the levels of spinal interleukin (IL)-6 and -1β mRNA, but not the protein levels of these cytokines, measured on day 12. Unexpectedly, chronic administration of doxepin or amitriptyline for 12 days produced allodynia and hyperalgesia in naïve mice. The treatment with these drugs did not influence the spinal levels of IL-1β and IL-6 mRNA, however, the protein levels of these pronociceptive factors were increased. The administration of ondansetron (5-HT3 receptor antagonist) significantly weakened the allodynia and hyperalgesia induced by both antidepressants in naïve mice; in contrast, yohimbine (α2-adrenergic receptors antagonist) did not influence these effects. Allodynia and hyperalgesia induced in naïve animals by amitriptyline and doxepin may be associated with an increase in the levels of pronociceptive cytokines resulting from 5-HT3-induced hypersensitivity. Our results provide new and important information about the possible side effects of antidepressants. Further investigation of these mechanisms may help to guide decisions about the use of classic TCAs for therapy.
神经病理性疼痛是一个严重的临床问题，常作为许多疾病的伴随症状出现，或因神经系统损伤而表现出来。目前有许多药物和制剂用于治疗神经病理性疼痛，如三环类抗抑郁药（TCAs）。本文的目的是测试两种经典的三环类抗抑郁药多塞平和阿米替林在未处理动物和神经病理性疼痛模型中的作用，并确定细胞因子激活在这些药物作用中的作用。所有实验均使用白化瑞士小鼠进行，采用行为测试（von Frey测试和冷板测试）和生化分析（qRT-PCR和蛋白质印迹法）。在遭受慢性压迫损伤（CCI）的小鼠中，多塞平和阿米替林减轻了神经病理性疼痛症状，并减少了CCI诱导的脊髓白细胞介素（IL）-6和-1β mRNA水平的升高，但在第12天测量时，这些细胞因子的蛋白质水平并未降低。出乎意料的是，多塞平或阿米替林连续12天的慢性给药在未处理小鼠中产生了痛觉过敏和痛觉超敏。这些药物的治疗并未影响脊髓中IL-1β和IL-6 mRNA的水平，然而，这些促痛因子的蛋白质水平却升高了。昂丹司琼（5-HT3受体拮抗剂）的给药显著减弱了两种抗抑郁药在未处理小鼠中诱导的痛觉过敏和痛觉超敏；相比之下，育亨宾（α2-肾上腺素能受体拮抗剂）并未影响这些作用。阿米替林和多塞平在未处理动物中诱导的痛觉过敏和痛觉超敏可能与5-HT3诱导的超敏反应导致的促痛细胞因子水平升高有关。我们的结果为抗抑郁药可能的副作用提供了新的重要信息。对这些机制的进一步研究可能有助于指导关于使用经典三环类抗抑郁药进行治疗的决策。
