Novel application of pharmaceutical AMD3100 to reduce risk in opioid use disorder: investigations of a causal relationship between CXCR4 expression and addiction vulnerability

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Project Summary/Abstract In 2020, 2.7 million Americans met the criterion for opioid use disorder but only 11.2% of those affected were treated with medication-assisted treatment (MAT), despite it being the gold-standard in treatment for opioid use disorder. Even for those who are prescribed MAT, adherence rates are poor and relapse rates are high along with increased risk of diversion and misuse of medication. There is a clear and pressing need to explore alternative therapeutics to expand options and improve outcomes for opioid use disorder. A promising avenue to exploit is the relationship between part of the neuroimmune system called the chemokine system, and the opioid system. Chemokines are inflammatory molecules primarily known for their role in orchestrating an appropriate immune response to inflamed tissue but also engage in crosstalk with the opioid system. Not surprisingly, the chemokine system and opioid system interact as inflammation and pain responses are often co-occurring, such as with physical trauma. Evidence suggests that activation of chemokine receptors can desensitize mu-opioid receptors and reduce opioid-induced antinociception. These findings are critical since the sensitization of opioid receptors is related to behavioral effects such as opioid tolerance and opioid induced hyperalgesia or increased pain after extended opioid use. Drugs that inhibit the binding of chemokines to their receptors, chemokine receptor antagonists (CRAs), are presently available for clinical use in HIV and the mobilization of hematopoietic stem cells in cancer treatment. Early evidence suggests that CRAs, while alone do not produce any pain-relieving qualities, have the ability to enhance the analgesic effects of opioids and make lower doses of opioids more effective. While the effects on pain perception alone are exciting, the impact of CRAs on motivation to consume opioids has not been studied. Of particular interest is AMD3100, a CRA that binds to CXCR4, blocking its natural ligand CXCL12 which both are present along canonical reward circuitry in the brain including the nucleus accumbens (NAc) and ventral tegmental area (VTA). Recent data from our lab shows CXCR4 protein expression in the VTA is increased following chronic morphine exposure. The experiments presented below investigate the ability for AMD3100 to reduce heroin self-administration in males and females (Aim 1) and heroin seeking/relapse behaviors (Aim 3) while examining the role of CXCR4 expression in dopaminergic neurons within VTA (either enhanced or reduced expression) to modify heroin taking (Aim 2).