Substance P antagonists and analgesia: a review of the hypothesis.

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.