Creative Bio-Peptides, Inc, a preclinical-stage biotechnology company developing novel therapies to balance the innate immune system and promote regeneration of damaged neurons, today announced the publication of findings from a preclinical study showing that treatment with the multi-chemokine receptor antagonist oral peptide RAP-103 substantially reduced heroin self-administration and motivation to consume heroin. RAP-103 also reduced the severity of naloxone-precipitated withdrawal responses in morphine dependence, as well as morphine-induced respiratory depression. In addition, RAP-103 normalized the components of addiction chemistry in the brain that are altered by opioid abuse.
These data were published online ahead of print in the September 2022 issue of the peer-reviewed scientific journal Drug and Alcohol Dependence.
“In collaboration with The Center for Substance Abuse Research at Temple University, the team at Creative Bio-Peptides has uncovered a potential non-opioid treatment to reduce the desire to consume opioids and to limit opioid withdrawal and respiratory depression,” said Michael Ruff, PhD, President and CEO of Creative Bio-Peptides.
The results identify chemokine receptor antagonist RAP-103 as a potential treatment to enhance opioid analgesia and inhibit opioid-derived dependence, withdrawal and respiratory depression. Chemokines are small peptide hormones of the innate immune system that regulate inflammation, pain and substance abuse. In recent years, research has demonstrated that chemokine-opioid crosstalk is a physiological crossroads for influencing therapeutic and adverse effects of opioids. Activated chemokine receptors, especially CCR2, CCR5 and CXCR4, can control the body’s opioid receptors to increase pain states by reducing opioid-induced analgesia via desensitization of OPRM1 receptors. In studies funded by the National Institutes of Health’s (NIH) HEAL Initiative and the National Institute on Drug Abuse, conducted at The Center for Substance Abuse Research at the Lewis Katz School of Medicine at Temple University, the possible therapeutic use of RAP-103, an orally active small molecule that blocks these multiple chemokine receptors active in pain, was evaluated for its effects to reduce opioid administration, motivation to consume opioids, opioid withdrawal symptoms and opioid respiratory depression.
“Chemokine receptor antagonism, with compounds such as RAP-103, has high potential as a pharmacotherapy because blocking specific cell surface receptors with small molecules (called antagonists) is a cornerstone goal of the biopharmaceutical industry,” said Scott Rawls, PhD, the study’s principal investigator, and Professor, Department of Neural Sciences, Center for Substance Abuse Research, Lewis Katz School of Medicine, Temple University.
About the Study
The study was designed to examine the potential medically assisted treatment (MAT) capabilities for opioid use disorder (OUD) with RAP-103, a small orally stable chemokine receptor antagonist peptide that blocks opioid acquisition, maintenance, and withdrawal. In the study, researchers conducted tests of animal self-administration, the gold standard for evaluating abuse liability of drugs. In self-administration experiments, RAP-103 reduced heroin intake and reinforced strength. Daily administration of RAP-103 delayed the onset, and reduced the magnitude, of heroin self-administration. In other experiments, RAP-103 greatly reduced the motivation to maintain opioid use.
Other adverse effects of opioids blocked by RAP-103 included the severity of morphine physical dependence and respiratory depression. The behavioral effects of RAP-103 were associated with changes in mesolimbic brain regions known to play a role in dopamine transmission and substance abuse.
In additional current studies, the objective is to further demonstrate the feasibility of RAP-103 as a MAT agent and to achieve results to support progressing to clinical trials. The goal is to identify the optimized lowest dose at which RAP-103 mitigates opioid self-administration in progressive-ratio experiments. In view of the unique mechanism of RAP-103 action via chemokine receptor antagonism, researchers will identify chemokine and cytokine changes in mesolimbic (ventral tegmental area and nucleus accumbens) brain reward areas to provide a mechanism for how RAP-103 may mitigate the rewarding effects of opioids and other drugs of abuse.