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 GABA_B 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 GABA_B 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 GABA_B receptors are a promising target for topical therapy of CIPN, potentially mediated by regional modulation of the GABAergic system.