Background <p>Neuropathic pain remains a significant clinical problem that necessitates the development of more effective treatment options. Compared with commonly used clinical drugs, such as gabapentin and pregabalin, mirogabalin is a novel gabapentinoid that exhibits greater affinity and selectivity for the α2δ-1/-2 subunits of voltage-gated calcium channels, properties associated with strong nociceptive modulation. The aim of this study was to determine whether and how mirogabalin influences neuropathy symptoms and the antinociceptive effects of antidepressants (amitriptyline and duloxetine).</p> Methods <p>Studies were conducted in mice after chronic constriction injury of the sciatic nerve. On Day 7, a single intraperitoneal administration of mirogabalin (5–60 mg/kg), amitriptyline (1–10 mg/kg), or duloxetine (10–30 mg/kg) at various doses was performed. Additionally, mirogabalin (10 mg/kg) was chronically injected twice daily, while amitriptyline (5 mg/kg) or duloxetine (10 mg/kg) was administered once daily. Hypersensitivity was assessed using the von Frey and the cold plate tests.</p> Results <p>Using a mouse model of neuropathy, a single injection of mirogabalin, amitriptyline, or duloxetine reduced tactile and thermal hypersensitivity to a similar degree, with the most durable effect observed with mirogabalin, persisting up to 6 hours. Repeated twice-daily intraperitoneal administration of mirogabalin combined with once-daily intraperitoneal dosing of amitriptyline or duloxetine resulted in a potentiated anti-nociceptive response in the used model.</p> Conclusions <p>These results may serve as a basis for further evaluation of the potential use of mirogabalin in the clinical treatment of neuropathic pain. Furthermore, they suggest that using mirogabalin together with amitriptyline or duloxetine may provide significant therapeutic benefits, enabling the use of lower doses of these medications, which may reduce the risk of adverse events.</p> Graphical Abstract <p></p>