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Substance use disorder, and particularly cocaine use disorder, is a complex disease that affects societal, economic, and psychological factors. Endogenous β-endorphin released after prolonged cocaine withdrawal has been reported to activate the accumbal delta-opioid receptor (DOR), leading to attenuated cocaine seeking. However, using DOR β-endorphin activation to treat cocaine use disorder is impractical since β-endorphin does not cross the blood-brain barrier. Also, only activation of the sub-group DOR1 efficiently attenuates craving, as activation of DOR2 yields an opposite effect. Here, we isolated a specific peptide, PEP1, from a phage display peptide library with similar biological properties to β–endorphin, demonstrating specificity for DOR1 and functioning as full receptor agonists. Our pharmacodynamic results showed fast trafficking incorporation of DOR into the cell membrane, interpreted as superior rehabilitation of the receptor and its bioavailability compared to commercial agonists. We administered PEP1, either intrabrain or intranasal, to rats trained to self-administer cocaine. PEP1 induced a significant decrease in cocaine-craving behavior and reinstatement in three different animal models of addiction. Also, PEP1 did not exhibit rewarding properties and did not interfere with the natural reward system. ICP-OES analysis revealed that at least one hour post-administration, PEP1 was retained in the brain rather than in peripheral organs. These findings render PEP1 a potential novel regulator of cocaine craving, especially for being non-addictive. Hence, PEP1 should be further examined as a possible new therapy for substance use disorder.

Obesity is a major public health concern that is associated with negative health outcomes. Exercise and dietary restriction are commonly recommended to prevent or combat obesity. This study investigates how voluntary exercise mitigates abnormal gene expression in the hypothalamic arcuate nucleus (ARC) of diet-induced obese (DIO) rats. Using a transcriptomic approach, novel genes in the ARC affected by voluntary wheel running were assessed alongside physiology, pharmacology, and bioinformatics analysis to evaluate the role of miR-211 in reversing obesity. Exercise curbed weight gain and fat mass, and restored ARC gene expression. High-fat diet (HFD) consumption can dysregulate satiety/hunger mechanisms in the ARC. Transcriptional clusters revealed that running altered gene expression patterns, including inflammation and cellular structure genes. To uncover regulatory mechanisms governing gene expression in DIO attenuation, we explored miR-211, which is implicated in systemic inflammation. Exercise ameliorated DIO overexpression of miR-211, demonstrating its pivotal role in regulating inflammation in the ARC. Further, in vivo central administration of miR-211-mimic affected the expression of immunity and cell cycle-related genes. By cross-referencing exercise-affected and miR-211-regulated genes, potential candidates for obesity reduction through exercise were identified. This research suggests that exercise may rescue obesity through gene expression changes mediated partially through miR-211.

Recent research points to mesenchymal stem cells’ potential for treating neurological disorders, especially drug addiction. We examined the longitudinal effect of placenta-derived mesenchymal stromal-like cells (PLX-PAD) in a rat model for cocaine addiction. Sprague–Dawley male rats were trained to self-administer cocaine or saline daily until stable maintenance. Before the extinction phase, PLX-PAD cells were administered by intracerebroventricular or intranasal routes. Neurogenesis was evaluated, as was behavioral monitoring for craving. We labeled the PLX-PAD cells with gold nanoparticles and followed their longitudinal migration in the brain parallel to their infiltration of essential peripheral organs both by micro-CT and by inductively coupled plasma-optical emission spectrometry. Cell locations in the brain were confirmed by immunohistochemistry. We found that PLX-PAD cells attenuated cocaine-seeking behavior through their capacity to migrate to specific mesolimbic regions, homed on the parenchyma in the dentate gyrus of the hippocampus, and restored neurogenesis. We believe that intranasal cell therapy is a safe and effective approach to treating addiction and may offer a novel and efficient approach to rehabilitation.