Synergistic antiallodynic and antihyperalgesic interaction between L-DOPA and celecoxib in parkinsonian rats is mediated by NO–cGMP–ATP-sensitive K+ channel

Pain is a usual and troublesome non-motor symptom of Parkinson's disease, with a prevalence of 29–82%. Therefore, it's vital to find pharmacological treatments for managing PD-associated pain symptoms, to improve patients' quality of life. For this reason, we tested the possible synergy between L-DOPA and celecoxib in decreasing allodynia and hyperalgesia induced by unilateral lesioning with 6-OHDA into the SNpc in rats. We also tested whether the antiallodynic and antihyperalgesic effect induced by combination of L-DOPA and celecoxib is mediated by the NO–cGMP–ATP-sensitive K+ channel pathway. Tactile allodynia and mechanical hyperalgesia were evaluated using von Frey filament. Isobolographic analyses were employed to define the nature of the drug interaction using a fixed dose ratio (0.5: 0.5). We found that acute and sub-acute (10-day) treatment with a single dose of L-DOPA (3–25 mg/kg, i. p.) or celecoxib (2.5–20 mg/kg, i. p.) induced a dose-dependent antiallodynic and antihyperalgesic effect in parkinsonian rats. Isobolographic analysis revealed that the ED50 values obtained by L-DOPA + celecoxib combination was significantly less than calculated additive values, indicating that co-administration of L-DOPA with celecoxib produces synergistic interactions in its antiallodynic and antihyperalgesic effect in animals with nigrostriatal lesions. Moreover, the antiallodynic and antihyperalgesic effects induced by L-DOPA + celecoxib combination were blocked by intrathecal pre-treatment with L-NAME, ODQ, and glibenclamide. Taken together, the data suggest that L-DOPA + celecoxib combination produces an antiallodynic and antihyperalgesic synergistic interaction at the systemic level, and these effects are mediated, at the central level, through activation of the NO–cGMP–ATP-sensitive K+ channel pathway.