Tachykinins and neuropsychiatric disorders

The classical tachykinins, substance P, neurokinin A and neurokinin B are predominantly found in the nervous system where they act as neurotransmitters and neuromodulators. Their respective preferred receptors are NK1,NK2, and NK3 receptors. The presence of substance P in nociceptive primary afferent neurons, electrophysiological studies showing that it activated neurons in the dorsal horn of the spinal cord, and behavioral studies in animals, supported the concept that substance P was an important transmitter in the nociceptive pathway. It was therefore surprising that non-peptide NK1 receptor antagonists were ineffective as analgesics in clinical pain conditions. Nevertheless, the discovery that NK1 receptor antagonists had antidepressant activity led to renewed interest in these antagonists. It is disappointing that clinical trials of MK869 (aprepitant) for depression were suspended. The future of NK1 receptor antagonists as antidepressant drugs will depend on the outcome of clinical trials with other NK1 receptor antagonists. NK1 receptor antagonists were also found to be effective antiemetics, and aprepitant has recently become available for the treatment of chemotherapy induced emesis. Although less is known of the potential of NK2 and NK3 receptor antagonists, recent trials of NK3 receptor antagonists have shown efficacy in schizophrenia. The discovery of a new family of tachykinins, the hemokinins and endokinins which acts on NK1 receptors and has potent effects on immune cells, has implications for the clinical use of NK1 receptor antagonists. Thus specific therapeutic strategies may be required to enable NK1 receptor antagonists to be introduced for treatment of neuropsychiatric disorders.