Tachykinins and Neuropsychiatric Disorders

Abstract

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.

Substance P Neurokinin 1 Receptor Activation within the Dorsal Raphe Nucleus Controls Serotonin Release in the Mouse Frontal Cortex

“…These results concur with recent microdialysis experiments performed in awake mice (Zocchi et al, 2003;Guiard et al, 2004), suggesting a lack of tonic regulation of 5-HT transmission by SP. It is noteworthy that NK1 receptor antagonists have been reported to be efficient anxiolytic and antidepressant agents in several animal models (Chahl, 2006). Because SP and 5-HT coexist in a substantial part of the neuronal DRN population in human and rodent brains (Chan-Palay et al, 1978;Sergeyev et al, 1999), it is possible that 5-HT neurons may regulate the release of SP in stressful conditions (Ebner et al, 2004).…”

“…In these conditions, the potential antidepressant effects of NK1 receptor antagonists (Chahl, 2006) could be related to their capacity to block or prevent the reported …”

“…In several species, including rodents and humans, SP distribution overlaps with that of its high-affinity NK1 receptor (Ribeiro-da-Silva and Hokfelt, 2000). Recent clinical and preclinical studies have pointed out the potential therapeutic action of SP (neurokinin 1) receptor antagonists in major depressive disorders (Kramer et al, 1998;Chahl, 2006). Data obtained from NK1 receptor knockout mice have suggested that the antidepressant-like action of NK1 receptor inactivation may result, at least in part, from an increase in central 5-HT neurotransmission through functional desensitization [F (3,33) ϭ 6.1; p Ͻ 0.01].…”

The Pharmacology of l-DOPA-Induced Dyskinesia in Parkinson’s Disease

“…The tachykinins are a family of neuropeptides encompassing neurokinin A, neurokinin B, and substance P (Maggio, 1988;Chahl, 2006). As discussed earlier and as illustrated in Fig.…”

The Neuropeptide VGF Produces Antidepressant-Like Behavioral Effects and Enhances Proliferation in the Hippocampus

“…Finally, we observed increased expression of neuropeptides including VGF, Substance P (SP), and Neuropeptide Y (NPY ). NPY and SP but not VGF have been implicated in psychiatric disorders (Redrobe et al, 2002b;Heilig, 2004;Chahl, 2006;Karl and Herzog, 2007). The regulation of gene expression was dose depen-dent such that the response plateaued at 1 M 5-HT.…”