Vaught J L
Janssen Research Foundation, Spring House, PA 19477.
Life Sci. 1988;43(18):1419-31. doi: 10.1016/0024-3205(88)90253-6.
This review focused entirely on the hypothesis that a substance P/neurokinin antagonist should have, and the experimental evidence examining whether they do have, analgesic/antinociceptive properties. Such a hypothesis is reasonable considering the wealth of evidence implicating substance P in the nociceptive process and the demonstration that antibodies to substance P produce or potentiate antinociception. However, despite the availability of several putative antagonists, their pharmacological purity, specificity and selectivity are questionable. Thus, the investigator may not have, as yet, the appropriate tool drug with which to work. Much of the information concerning these points is generated utilizing in vitro (referring to isolated tissue preparations) bioassay tests which may not adequately reflect nor predict their pharmacology in the CNS. Differences in species responsiveness further complicate experimental design and interpretation. Apart from these factors, the choice of test or tests becomes an important consideration. What test, if any, adequately and appropriately reflects the endogenous physiological activity of substance P in nociception and predicts clinically useful activity of an antagonist? Several different models have been described and I have emphasized that conclusions based on a single model should be interpreted with caution. If the ultimate intent of the study is to further define the role of substance P in nociception, then most of the models discussed are adequate. However, if the intent is to demonstrate that a substance P/neurokinin antagonist should have therapeutically useful analgesic activity, it is incumbant on the investigator to demonstrate that, in their model, substance P release is a primary event, the resultant analgesia correlates to the occupancy of the neurokinin receptor by antagonist (ultimately important for all conclusions) and that the model adequately reflects activity of known analgesics in clinical use (validation of the model). In conclusion, given the complexities and contradictions of existing information, the hypothesis that a substance P/neurokinin antagonist should have analgesic/antinociceptive properties remains to be proven.
本综述完全聚焦于这样一种假说，即P物质/神经激肽拮抗剂应具备镇痛/抗伤害感受特性，以及检验它们是否确实具有这些特性的实验证据。鉴于大量证据表明P物质参与伤害感受过程，且证明P物质抗体可产生或增强抗伤害感受作用，这样的假说是合理的。然而，尽管有几种所谓的拮抗剂可供使用，但其药理纯度、特异性和选择性仍存在疑问。因此，研究者可能尚未拥有合适的工具药物来开展研究。关于这些要点的许多信息是通过体外（指分离的组织制剂）生物测定试验获得的，这些试验可能无法充分反映或预测其在中枢神经系统中的药理学特性。物种反应性的差异进一步使实验设计和解释变得复杂。除了这些因素，选择一种或多种试验成为一个重要的考虑因素。何种试验（如果有的话）能充分且恰当地反映P物质在伤害感受中的内源性生理活性，并预测拮抗剂的临床有用活性？已经描述了几种不同的模型，我强调基于单一模型得出的结论应谨慎解读。如果研究的最终目的是进一步明确P物质在伤害感受中的作用，那么所讨论的大多数模型是足够的。然而，如果目的是证明P物质/神经激肽拮抗剂应具有治疗上有用的镇痛活性，那么研究者有责任证明，在其模型中，P物质的释放是一个主要事件，由此产生的镇痛作用与拮抗剂对神经激肽受体的占据相关（这对所有结论最终都很重要），并且该模型能充分反映临床使用中已知镇痛药的活性（模型的验证）。总之，鉴于现有信息的复杂性和矛盾性，P物质/神经激肽拮抗剂应具有镇痛/抗伤害感受特性这一假说仍有待证实。
