Synergistic Effect of Cacao Extract and Pregabalin on TNF-α and ERK MAPK Expression in a Rat Model of Neuropathic Pain

Abstract

Neuropathic pain remains a major clinical challenge due to its persistence and poor response to conventional analgesics. This experimental study aimed to evaluate the synergistic potential of cacao extract combined with pregabalin in modulating peripheral and central sensitization markers in a rat model of neuropathic pain induced by chronic constriction injury (CCI). Four groups were studied: control group (K-) received placebo, treatment group 1 (K1) received pregabalin 60mg/kgBW, treatment group 2 (K2) received pregabalin 60mg/kgBW + cacao extract 1mg/gBW, and treatment group 3 (K3) received pregabalin 30mg/kgBW + cacao extract 1mg/gBW. Serum levels of tumor necrosis factor-alpha (TNF-α) and brain expression of extracellular signal-regulated kinase (ERK) were assessed alongside mechanical allodynia using von Frey filament testing. The CCI + Placebo group showed marked elevations in TNF-α and ERK levels, accompanied by severe mechanical allodynia. Pregabalin monotherapy moderately reduced these markers and improved pain thresholds. The combination therapies produced the most substantial reductions in TNF-α and ERK expression and significantly improved von Frey thresholds, indicating attenuation of both peripheral inflammation and central sensitization. These results suggest a synergistic interaction between cacao polyphenols and pregabalin, offering enhanced anti-inflammatory and antinociceptive effects compared to pregabalin alone. The findings provide a basis for further preclinical investigations into the pharmacodynamic and pharmacokinetic profiles of this combination and highlight the potential of cacao extract as a safe, natural adjuvant in neuropathic pain management strategies.