The neurokinins are a class of peptide signaling molecules that mediate a range of central and peripheral functions including pain processing, gastrointestinal function, stress responses, and anxiety. Recent data have linked these neuropeptides with drug-related behaviors. Specifically, substance P (SP) and neurokinin B (NKB), have been shown to influence responses to alcohol, cocaine, and/or opiate drugs. SP and NKB preferentially bind to the neurokinin-1 receptor (NK1R) and neurokinin-3 receptor (NK3R), respectively, but do have some affinity for all classes of neurokinin receptor at high concentrations. NK1R activity has been shown to influence reward and reinforcement for opiate drugs, stimulatory and neurochemical responses to cocaine, and escalated and stress-induced alcohol seeking. In reinstatement models of relapselike behavior, NK1R antagonism attenuates stress-induced reinstatement for all classes of drugs tested to date. The NK3R also influences alcohol intake and behavioral/neurochemical responses to cocaine, but less research has been performed in regard to this particular receptor in preclinical models of addiction. Clinically, agents targeting these receptors have shown some promise, but have produced mixed results. Here, the preclinical findings for the NK1R and NK3R are reviewed, and discussion is provided to interpret clinical findings. Additionally, important factors to consider in regards to future clinical work are suggested.

Introduction

There are three primary neurokinin peptides, Substance P (SP), Neurokinin A (NKA) and Neurokinin B (NKB). The neurokinin class of peptides is part of the tachykinin family and the associated nomenclature is influenced by this classification (see below). SP and NKA are produced by the preprotachykinin-a (PPTA) propeptide and NKB is produced by preprotachykinin-b (PPTB) propeptide. Other tachykinin peptides including Neuropeptide K and Neuropeptide γ are formed by alternative splicing of the PPTA mRNA, but will not be discussed in this review[1]. Neurokinin systems play a diverse role in physiological processes including regulation of pain processing, cardiovascular function, intestinal motility, and complex behaviors such as stress responses and drug seeking. Genetic association studies have implicated a role of neurokinin receptors in alcohol abuse, attention deficit hyperactivity disorder, and bipolar disorder[2-4]. Also, medications targeting these receptors have been tested for the treatment of depression, substance abuse, and menopausal hot flashes[5-11]. One FDA-approved medication, the neurokinin-1 receptor antagonist aprepitant, is currently in use to treat chemotherapy-induced nausea.