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Antidepressant properties of substance P antagonists: relationship to monoaminergic mechanisms?

机译：P物质拮抗剂的抗抑郁特性：与单胺能机制的关系？

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Substance P (SP) is a neuropeptide with a known involvement in anxiety and nociception processes, which acts through the activation of neurokinin-1 (NK(1)) receptors. Recently, a NK(1) receptor antagonist has been shown to display antidepressant activity comparable to that of the selective serotonin reuptake inhibitor paroxetine, but with a better side effect profile. Given their lack of affinity for monoamine transmitters, the antidepressant role of NK(1) receptor antagonists has been attributed to a unique mechanism. However, monoaminergic neurons receive an important SP innervation and also posses NK(1) receptors (noradrenergic neurons of the locus coeruleus) or are in close apposition to NK(1)-containing cells (serotonergic neurons of the dorsal raphe nucleus). In addition, NK(1) receptors are expressed in brain regions involved in the regulation of affective behaviours and the neurochemical response to stress. For these reasons, it has also been postulated that the purported antidepressant action of NK(1) receptor antagonists may result from the modulation of such brain monoaminergic systems. Indeed, systemic administration of NK(1) receptor antagonists enhances the firing rate of dopaminergic, noradrenergic and serotonergic neurons. This effect on serotonergic cells is seen consistently only after long-term treatment and has been associated with a functional desensitisation of somatodendritic 5-HT(1A) autoreceptors. Mice lacking NK(1) receptors also show an increased basal firing rate of 5-HT cells in vivo. These observations are suggestive of a predominating inhibitory role of SP upon monoaminergic neurons under physiological conditions and would provide support for the antidepressant activity of NK(1) receptor antagonists, although this may be achieved through an indirect action on other transmitter systems. The possibility that this class of drugs can modulate the function of only certain serotonergic pathways could be the basis of their better side effect profile. However, although preliminary studies showed some therapeutic efficacy for NK(1) receptor antagonists, the first compound developed (MK-869) has been discontinued from Phase III trials because it was not more effective than placebo in the treatment of depression. Further research is needed to ascertain whether the mechanism of action of NK(1) receptor antagonists may be relevant to the antidepressant treatment.
机译：P物质（SP）是一种已知参与焦虑和伤害感受过程的神经肽，其通过激活神经激肽1（NK（1））受体发挥作用。最近，已显示NK（1）受体拮抗剂显示出与选择性5-羟色胺再摄取抑制剂帕罗西汀相当的抗抑郁活性，但具有较好的副作用。由于它们缺乏对单胺递质的亲和力，NK（1）受体拮抗剂的抗抑郁作用已被归因于独特的机制。但是，单胺能神经元接受重要的SP神经支配，并且还具有NK（1）受体（蓝斑原位的去甲肾上腺素能神经元）或与含有NK（1）的细胞（背ra核的5-羟色胺能神经元）紧密相邻。此外，NK（1）受体在参与调节情感行为和对压力的神经化学反应的大脑区域表达。由于这些原因，还假定NK（1）受体拮抗剂的抗抑郁作用可能是由这种脑单胺能系统的调节引起的。的确，NK（1）受体拮抗剂的全身给药可提高多巴胺能，去甲肾上腺素能和血清素能神经元的放电速度。仅在长期治疗后才能始终看到这种对血清素能细胞的作用，并且与躯体树突状5-HT（1A）自体受体的功能脱敏有关。缺少NK（1）受体的小鼠体内还显示了5-HT细胞的基础激发速率增加。这些观察结果表明在生理条件下SP对单胺能神经元具有主要的抑制作用，并且可以为NK（1）受体拮抗剂的抗抑郁活性提供支持，尽管这可以通过对其他递质系统的间接作用来实现。这类药物仅能调节某些血清素能途径功能的可能性可能是其更好的副作用特征的基础。但是，尽管初步研究显示了对NK（1）受体拮抗剂的某些治疗功效，但已开发的第一种化合物（MK-869）已从III期试验中终止，因为它在治疗抑郁症方面不比安慰剂有效。需要进一步研究以确定NK（1）受体拮抗剂的作用机制是否可能与抗抑郁药治疗有关。

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