TOPICAL MIROGABALIN AND PREGABALIN ALLEVIATE NEUROPATHIC PAIN VIA PERIPHERAL MECHANISMS BY SUPPRESSING SPINAL NEURONAL HYPERACTIVITY

Gabapentinoids are first-line treatments for neuropathic pain that bind to the α₂δ subunit of voltage-gated calcium channels to suppress excitatory neurotransmission. However, the analgesic efficacy of gabapentinoids following local peripheral application remains poorly understood. Here, we investigated the antinociceptive effects of mirogabalin and pregabalin applied topically to the hind paw in male ICR mice using partial sciatic nerve ligation (PSNL)-induced neuropathic pain and complete Freund’s adjuvant (CFA)-induced inflammation pain models. In the PSNL model, topical mirogabalin (50-100 µg) produced a robust, dose-dependent reduction in thermal hyperalgesia and mechanical allodynia. The analgesic effect emerged within 15 minutes, peaked at 4 hours, and persisted for up to 6 hours. Crucially, contralateral application was ineffective, indicating a local peripheral mechanism of action. Pregabalin produced antinociceptive effects comparable to those of mirogabalin in the neuropathic model. In contrast, in the CFA model, mirogabalin induced only modest analgesia, whereas pregabalin failed to significantly alter pain thresholds. Given the pronounced behavioral effects observed in PSNL mice, immunohistochemical analyses were conducted in this model. PSNL surgery markedly increased FosB expression and α2δ-1 immunoreactivity bilaterally in the spinal dorsal horn. Topical gabapentinoid treatment significantly reduced the density of FosB-positive neurons, indicating suppression of spinal neuronal hyperactivity, while α2δ-1 expression levels remained unchanged. These findings demonstrated that peripherally applied gabapentinoids effectively alleviate neuropathic pain by attenuating sustained excitatory input to the spinal dorsal horn, supporting a promising and potentially safer peripherally mediated therapeutic strategy for neuropathic pain.