Pharmacological and neurobehavioral evaluation of the bifunctional opioid peptide Gluten exorphin B5.

Depression is a prevalent neuropsychiatric disorder that remains inadequately managed by current pharmacotherapies due to delayed onset of action, treatment resistance, and adverse effects. A growing body of evidence implicates the endogenous opioid system in mood regulation, highlighting opioid peptides as potential targets for novel antidepressant strategies. Exogenous opioid peptides (exorphins) derived from dietary proteins have attracted interest for their neuropsychopharmacological properties. In this study, the pharmacological and neurobehavioral profile of the bifunctional opioid peptide gluten exorphin B5 (GE-B5; YGGWL), derived from wheat gluten, was investigated. Opioid receptor activity was evaluated using isolated tissue bioassays, namely the mouse vas deferens (MVD) and guinea pig ileum (GPI), to assess δ- and μ-opioid receptor agonism, respectively. GE-B5 exhibited pronounced μ-opioid agonist activity in the GPI assay (IC50 = 4.96 mM) and moderate δ-opioid agonist activity in the MVD assay (IC50 = 3.50 mM), with inhibitory effects on acetylcholine-induced contractions that were reversible by naloxone. The in vivo neurobehavioral effects of GE-B5 were further assessed following intravenous administration using established behavioural paradigms, including the elevated plus maze, open field test, tail suspension test, and forced swim test. GE-B5 produced behavioural responses indicative of anxiolytic- and antidepressant-like effects across these models. Collectively, these findings suggest that gluten exorphin B5 exhibits μ-opioid receptor-mediated pharmacological activity accompanied by measurable neurobehavioral effects.