Mifflin Katherine A, Benson Curtis, Thorburn Kevin C, Baker Glen B, Kerr Bradley J
Neuroscience and Mental Health Institute, University of Alberta, Edmonton, Alberta, Canada.
Department of Pharmacology, University of Alberta, Edmonton, Alberta, Canada.
J Pain. 2016 Apr;17(4):483-98. doi: 10.1016/j.jpain.2015.12.013. Epub 2015 Dec 31.
Changes in serotonin (5-hydroxytryptamine; 5-HT), noradrenaline (NA), and γ-aminobutyric acid (GABA) levels in the spinal cord are known to occur in response to nociceptive stimuli, yet little research has examined possible underlying sex differences in these changes and how they might affect nociception. We have used pharmacological approaches in a well established model of tonic nociception, the formalin test, to explore the effects of altering neurotransmitter levels on nociceptive responses in male and female C57BL/6 mice. The monoamine oxidase (MAO) inhibitor phenelzine (PLZ), its metabolite phenylethylidenehydrazine (PEH), and a derivative compound of PLZ, N(2)-acetylphenelzine (N(2)-AcPLZ), were used to increase endogenous levels of: GABA, 5-HT, and NA (PLZ); GABA alone (PEH); or 5-HT and NA only (N(2)-AcPLZ). Although both sexes had a reduction in second phase nociceptive behaviors with PEH pretreatment, the analgesic effect of PLZ was only observed in male mice. High performance liquid chromatography analysis revealed male mice had greater spinal cord increases in 5-HT and NA levels compared with female mice. Female mice, in contrast, had greater increases in GABA levels with pretreatments. With N(2)-AcPLZ pretreatment, only male mice had a reduction in second phase nociceptive behaviors despite similar increases in 5-HT and NA levels in both sexes. These findings suggest that male mice may utilize serotonergic and noradrenergic pathways more efficiently for the attenuation of nociceptive behavior and female mice are more dependent on alternate mechanisms. To our knowledge, these findings are the first on the antinociceptive properties of altering 5-HT, NA, and GABA levels with the MAO inhibitor PLZ and its derivatives in a model of tonic pain processing. They also reveal significant underlying sex differences associated with these treatments.
The present study found that nociception in male and female mice may be regulated by different neurotransmitter systems. These results indicate that different pharmacological approaches may be needed to treat pain in both sexes.
已知脊髓中血清素（5-羟色胺；5-HT）、去甲肾上腺素（NA）和γ-氨基丁酸（GABA）水平会因伤害性刺激而发生变化，但很少有研究探讨这些变化中可能存在的潜在性别差异以及它们如何影响痛觉感受。我们在一个成熟的紧张性痛觉模型——福尔马林试验中使用药理学方法，以探究改变神经递质水平对雄性和雌性C57BL/6小鼠痛觉反应的影响。单胺氧化酶（MAO）抑制剂苯乙肼（PLZ）、其代谢产物苯乙叉肼（PEH）以及PLZ的一种衍生物N(2)-乙酰苯乙肼（N(2)-AcPLZ）被用于提高内源性水平的：GABA、5-HT和NA（PLZ）；仅GABA（PEH）；或仅5-HT和NA（N(2)-AcPLZ）。尽管两性经PEH预处理后第二阶段痛觉行为均减少，但PLZ的镇痛作用仅在雄性小鼠中观察到。高效液相色谱分析显示，与雌性小鼠相比，雄性小鼠脊髓中5-HT和NA水平升高幅度更大。相比之下，雌性小鼠经预处理后GABA水平升高幅度更大。经N(2)-AcPLZ预处理后，尽管两性5-HT和NA水平升高相似，但只有雄性小鼠第二阶段痛觉行为减少。这些发现表明，雄性小鼠可能更有效地利用5-羟色胺能和去甲肾上腺素能途径来减轻痛觉行为，而雌性小鼠则更依赖于其他机制。据我们所知，这些发现是首次关于在紧张性疼痛处理模型中用MAO抑制剂PLZ及其衍生物改变5-HT、NA和GABA水平的镇痛特性的研究。它们还揭示了与这些治疗相关的显著潜在性别差异。
本研究发现雄性和雌性小鼠的痛觉感受可能由不同的神经递质系统调节。这些结果表明，可能需要不同的药理学方法来治疗两性的疼痛。
