Why are substance P(NK1)-receptor antagonists ineffective in pain treatment?

Abstract

The undecapeptide substance P is expressed by primary afferent neurons where it is considered to be a cotransmitter of other peptides and glutamate. Since it is predominantly found in sensory neurons with unmyelinated fibres (C-fibres), substance P has long been thought to be a "pain transmitter". Following stimulation of nociceptive afferents, substance P is released in the spinal cord and substance P-mediated transmission is primarily brought about by tachykinin NK1 receptors. To inhibit this process, a considerable number of non-peptide, highly potent, highly selective and brain penetrant NK1 receptor antagonists have been developed during the past decade. Experimental studies have proved that NK1 receptor antagonists are indeed able to blunt pain in sensitized states and thus to reverse hyperalgesia, whereas acute pain is left fairly unchanged. The hyperalgesic role of substance P has been corroborated by the sensory deficits seen in substance P and NK1 receptor knockout mice. However, the concept that NK1 receptor antagonists would represent a novel class of analgesic drugs, as suggested by the preclinical studies, has not been borne out by the clinical trials that have been reported thus far. This article offers an overview of those hyperalgesic conditions in which NK1 receptor antagonists may be of therapeutic value and discusses possible reasons for the discrepancies between preclinical and clinical trials with NK1 receptor antagonists.