A Novel Clinical-stage Small Molecule Targeting the ‘Dark Side’ of Opioid Addiction

Abstract

<b>Abstract ID 26262</b> <b>Poster Board 168</b> The ‘dark side’ of addiction refers to the temporary relief drug-taking provides from the persistent negative emotional state that emerges as a person develops a substance use disorder . In the context of opioid use disorder, negative affect and craving during acute and protracted withdrawal present major barriers to recovery. There is only one non-opioid treatment for acute opioid withdrawal, associated with limited efficacy and serious side effects, and no treatment for protracted withdrawal. KNX100 is a novel, clinical stage small molecule being developed for the treatment of opioid use disorder. KNX100 has an undisclosed pharmacological mechanism of action but has been shown to act in the nucleus accumbens shell to reduce neuronal hyperexcitability and signalling in the pDYN/DYN/KOR receptor pathway during opioid withdrawal in mice, demonstrating highly disease-relevant neural and molecular actions. Moreover, KNX100 reduced the negative affective symptoms of acute naloxone-precipitated oxycodone withdrawal and inhibited the acquisition of withdrawal-induced conditioned-place aversion in mice. Here, the effects of KNX100 on irritability during spontaneous oxycodone withdrawal and cue-induced reinstatement of oxycodone-seeking during abstinence were examined in rats. Prior to oxycodone self-administration, rats were tested for their baseline irritability (aggressive and defensive behaviours on the bottle brush test) and were assessed for baseline somatic symptoms (wet dog shakes). Rats were then trained to self-administer oxycodone for 15h/day for 44-48 days through a surgically implanted intravenous catheter. Each infusion was accompanied by a light+tone. To elicit spontaneous withdrawal, rats underwent 24-hour without a self-administration session. Spontaneous withdrawal symptoms (irritability and somatic symptoms) were assessed during two counterbalanced withdrawal sessions, once treated with vehicle and once with KNX100. For assessment of cue-induced reinstatement, rats underwent a 15-day protracted abstinence period and were tested for reinstatement on day 2 and 15, with rats receiving KNX100 or vehicle prior to reinstatement testing on day 15. KNX100 treatment significantly reduced withdrawal-induced irritability-like behaviour, but not wet dog shakes, in male and female rats. KNX100 markedly inhibited cue-induced reinstatement of drug seeking 15 days into abstinence. These data further indicate KNX100 may alleviate the negative psychological state that emerges during withdrawal and persists into abstinence that contributes to drug craving and relapse and suggest KNX100 may be a viable therapeutic for alleviating the negative affective aspects of acute withdrawal and promoting abstinence. This work was funded by Kinoxis Therapeutics Pty Ltd under a Master Research Services Agreement with the University of Sydney.