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. This study evaluated the antinociceptive effects of the GABA-derived short peptides pyroglutamylGABA, pyroglutamylGABA ethyl ester, and pyroglutamyl diGABA in combination with pregabalin in a rat model of neuropathic pain induced by chronic constriction injury. Pain-related behavior was assessed using the hot plate test by recording changes in the latency and frequency of licking, jumping, and locomotor activity. Co-administration of peptide-pregabalin combinations modulated nociceptive responses compared with control animals in a time- and compound-dependent manner. The combination of pyroglutamylGABA with pregabalin was associated with increased licking latency and reduced licking frequency, particularly at early time points after injury. The pyroglutamylGABA ethyl ester-pregabalin combination produced the most pronounced effects on jumping-related parameters. A delay in movements was recorded when a combination of pyroglutamyl diGABA and pregabalin was used, whereas all combinations demonstrated increased locomotor activity, suggesting that the antinociceptive effects were not accompanied by the motor suppression typically associated with pregabalin treatment. To explore the potential mechanisms, molecular docking studies were performed targeting key GABAergic system components, including the GAT1 transporter, GABA-AT enzyme, and GABA-B receptors. The investigated peptides demonstrated favorable binding affinities across these targets, suggesting that potential interactions with multiple targets are involved in GABAergic neurotransmission. These findings indicate that the combinations of GABA-derived peptides with pregabalin could be an effective approach in neuropathic pain management. However, further investigation is required to validate these effects and clarify the underlying mechanisms.