EXPRESS: Combination of GABA-derived short peptides and pregabalin in neuropathic pain: in vivo and in silico evaluation

Neuropathic pain is a significant clinical issue due to the limited efficacy and adverse effects of existing therapies. The present study evaluated the analgesic effects of GABA-derived short peptides-pyroglutamylGABA, pyroglutamylGABA ethyl ester, and pyroglutamyl diGABA-in combination with pregabalin, in neuropathic pain model induced by chronic constriction injury, in rats. Pain-related behavior was assessed using the hot plate test by recording changes in latency and frequency of licking, jumping, as well as locomotor activity. Among the tested combinations, pyroglutamylGABA with pregabalin demonstrated the longest licking latency and the lowest licking frequency. The administration of pyroglutamylGABA ethyl ester with pregabalin revealed the longest jumping latency and the lowest jumping frequency. A delay in movements was recorded when using a combination of pyroglutamyl diGABA with pregabalin, while all combinations were associated with increased locomotor activity, suggesting that the an-algesic effects were not accompanied by motor suppression typically associated with pregabalin treatment. To explore potential mechanisms, molecular docking studies were performed targeting key components of the GABAergic system, including GAT1 trans-porter, GABA-AT enzyme, and GABA-B receptors. The docking results suggest that the investigated peptides may interact with multiple targets involved in GABAergic neuro-transmission. Overall, these findings indicate that combinations of GABA-derived pep-tides and pregabalin may represent a potential strategy for neuropathic pain management. However, further investigation is required to validate these effects and clarify the underlying mechanisms.