Regional-specific GABAergic imbalance in cisplatin-induced neuropathy and antiallodynic effects of intraplantar baclofen in rats

Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating complication of cisplatin chemotherapy, often manifesting as mechanical allodynia, which frequently resists conventional treatments. This study explored the behavioral and molecular alterations induced by cisplatin, with a focus on regional dysfunction of the gamma-aminobutyric acid (GABA) system, and evaluated the therapeutic potential of intraplantar baclofen (a GABAB receptor agonist) in alleviating CIPN. Rats were administered cisplatin (2 mg/kg, i.p., once weekly for 4 weeks), and behavioral assessments revealed significant mechanical allodynia, with no significant effects on cold or heat sensitivity. Molecular analyses (high-performance liquid chromatography (HPLC), reverse transcription polymerase chain reaction (RT-PCR), and Western blot) demonstrated a region-specific GABAergic imbalance: increased GABA levels and glutamate decarboxylase (GAD) mRNA in the dorsal root ganglia (DRG), alongside decreased GABA levels and downregulated GABAB receptor expression in the hind paw skin. Intraplantar baclofen pretreatment delayed the onset of mechanical allodynia, while post-treatment produced a dose-dependent reversal of symptoms, with no effect on hind paw temperature. These findings suggest that peripheral GABAB receptors are a promising target for topical therapy of CIPN, potentially mediated by regional modulation of the GABAergic system.