Effects of the NK1 antagonist, aprepitant, on response to oral and intranasal oxycodone in prescription opioid abusers

Substance P, a peptide of the tachykinin family (Herpfer and Lieb, 2005) is distributed throughout the central and peripheral nervous systems; it was associated early on with pain physiology due to its localization in small, unmyelinated sensory fibers in spinal cord and its high density concentration in the dorsal roots (von Euler and Gaddum, 1931). The NK1 receptor, which preferentially binds Substance P, is a Gq-coupled member of the 7-transmembrane, G-protein-coupled receptor superfamily. NK1 receptor densities in the human nervous system are highest in spinal cord, striatum and brain regions involved in affect and reward, including the nucleus accumbens, amygdala, hippocampus and septum. The NK1 receptor is also highly expressed in lower brain nuclei, including the raphe, locus ceruleus, periaquaductal gray, midbrain nuclei (e.g., substantia nigra and pars reticulata) and distributed throughout various cortical regions (Hargreaves, 2002; Mai et al., 1986; Nomura, Shiosaka and Tohyama, 1987). The NK1 receptor system has been implicated in numerous behaviors, including nociception (Trang, Quirion and Jhamandas, 2005), vomiting reflexes (Rubenstein et al., 2006), affective dysfunction (including anxiety and depression) (Ebner and Singewald, 2006; Herpfer and Lieb, 2005; Santarelli et al., 2002) and pain perception (Birklein and Schmelz, 2008; Hill, 2002; King et al., 2005; Trang et al., 2005). Numerous studies have now examined the interaction between NK1 receptor antagonism and opioid-related responses, including physical dependence, tolerance, analgesia and reward-related behavior. With regard to the role of substance P in the development and expression of physiological opioid dependence, one early study examined naloxone-precipitated withdrawal in rats rendered opioid dependent following a daily morphine-dosing regimen. Intracerebroventricular administration of a selective NK1 receptor antagonist, RP67580, decreased opioid withdrawal signs in response to naloxone administration (Maldonado, Girdlestone and Roques, 1993). Subsequent studies examined opioid dependence and withdrawal in the genetically modified NK1 knock-out mouse (NK1−/−) in which the NK1 receptor is absent. NK1−/− mice rendered dependent on morphine and then spontaneously withdrawn exhibited some opioid withdrawal signs but failed to show the prototypic withdrawal response (i.e., jumping) in contrast to the wildtypes (Murtra et al., 2000). Moreover, the NK1−/− mice treated chronically with morphine failed to develop a conditioned place aversion in response to naloxone administration. The NK1 knock-out mice are similar to the wildtype with respect to level of motor activity, exploratory behavior in the open field, acute nociceptive responses to both the tail flick and hot plate tests (De Felipe et al., 1998) and exhibit comparable distribution and functionality of the mu opioid receptor system (De Felipe et al., 1998). However, unlike the wildtypes, NK−/− mice do not exhibit acute morphine-induced increased locomotor activity nor sensitization after chronic morphine exposure to the locomotor effects of morphine (Murtra et al., 2000; Ripley et al., 2002). Murtra and colleagues (2000) demonstrated that NK1 knock-out mice failed to develop a conditioned place preference (CPP) in response to the administration of morphine, but did develop CPPs for cocaine and food, suggesting that the deletion of the receptor selectively reduced the rewarding effects of opioid agonist administration (Murtra et al., 2000). Conversely, an early study demonstrated that direct microinjection of Substance P and its C-terminal fragments that retain affinity for the NK1 receptor supported the development of a CPP (Hasenohrl, Gerhardt and Huston, 1992), and this was blocked by pretreatment with naloxone (Hasenohrl, Gerhardt and Huston, 1991), suggesting that the rewarding effects of NK1 activation were mediated, in part, through opioid systems. Gadd and colleagues (2003) demonstrated that chemo-ablation (through the use of the selective neurotoxin, SP-saporin) of neurons expressing NK1 receptors in the amygdala reduced the locomotor-stimulating effects of acute morphine and attenuated morphine CPP, while the responses to cocaine on these same measures remained intact (Gadd et al., 2003). Finally, using an operant lever press self-administration model, the NK1 knock-out mice acquired food self-administration more readily compared to the wildtypes (i.e., higher response rate, higher number of reinforcers earned), but the knock-out mice self-administered significantly fewer morphine infusions compared to the wildtypes, while cocaine self-administration was comparable (Ripley et al., 2002). These studies suggest that deletion or pharmacological blockade of the NK1 receptor may selectively diminish the response to opioids on an array of outcomes. Potential clinical implications arising from these preclinical findings include the possibility that NK1 antagonists could be used to reduce the development of tolerance and/or physical dependence in patients taking opioids chronically (e.g., for pain) and/or that treatment with NK1 antagonists could diminish the reinforcing or abuse liability related effects of opioids. While more than 300 patents have been filed for chemical entities with NK1 receptor activity (Huang and Korlipara, 2010) and numerous candidate NK1 antagonists have been in development for target indications of anxiety and depression and, more recently, treatment of alcohol dependence (George et al., 2008), there is only one NK1 antagonist currently approved and marketed in the U.S. for oral use. Aprepitant, previously known as MK-869, is marketed by Merck as Emend® and has been widely used as an anti-emetic, principally for the treatment of chemotherapy-induced nausea and vomiting in cancer patients (Dando and Perry, 2004). Aprepitant has good oral bioavailability estimated at about 60–65% after single dose administration (Majumdar et al., 2006). It exhibits first-order kinetics (Nakade et al., 2008), reaches peak maximum concentrations approximately 4 hr after oral dosing and has an estimated half-life in plasma of approximately 9–13 hr (Majumdar et al., 2006). Thus, it is suitable for producing a sustained effect if given acutely and has sufficient duration of action to lend itself to chronic administration. The purpose of the present study was to examine the effects of aprepitant on the subjective and physiologic response to a prototypic mu opioid agonist in individuals with histories of prescription opioid abuse as a first proof-of-concept test that NK1 antagonists may diminish the effects of opioids related to their abuse potential. Oxycodone, a now common drug of abuse, was chosen as the prototypic opioid and was tested after both oral and intranasal administration because these are both common routes of misuse associated but with different pharmacodynamic characteristics.