Radioligand binding assay was used to evaluate characteristics of central mu-opioid receptors after peripheral administration of mu-opioid receptor agonist loperamide and antagonist methylnaloxone. These substances do not cross the blood-brain barrier. Loperamide and methylnaloxone produced opposite effects on the density of mu-opioid receptors in the frontal cortex of rat brain. These data confirm our hypothesis on reciprocal interactions between central and peripheral compartments of the endogenous opioid system.

β-Endorphin content in the extracellular space of rat cingulate cortex was measured using intravital microdialysis followed by ELISA. Intragastric administration of μ-opioid ligands loperamide and methylnaloxone not crossing the blood-brain barrier produced different effects on β-endorphin level: loperamide reduced and methylnaloxone significantly increased the release of β-endorphin into the extracellular space of rat cingulate cortex. Emotional stress caused by immobilization resulted in slight increase in β-endorphin level in the cingulate cortex. Peripheral administration of loperamide (but not methylnaloxone) significantly increased the release of the neuropeptide during stress. These findings support our hypothesis of reciprocal interaction between the central and peripheral compartments of the endogenous opioid system and provide explanations for the anti-stress effects of loperamide.

Changes in the parameters of operant feeding behavior and body weight were studied in rats after intragastric administration of μ-opioid receptor agonist loperamide. Loperamide administration significantly suppressed foraging behavior in rats and reduced their body weight. Our findings suggest that peripheral loperamide administration, according to the hypothesis of reciprocal interactions between the central and peripheral parts of the endogenous opioid system, suppresses activity of central opioid mechanisms of feeding behavior organization. Changes in feeding behavior can appear due to disturbances in the mechanisms of assessment of food reward. We hypothesized that natural activation of μ-opioid receptors of the stomach with food-derived peptides can be associated with "sensory satiation" mechanism limiting excessive food intake.