Dapsone and N-Acetylcysteine Exert a Synergistic Antinociceptive Effect Associated with Oxidative Stress After Traumatic Spinal Cord Injury: An Isobolographic Study.

Background/

Objectives

Neuropathic pain (NP) after traumatic spinal cord injury (SCI) is highly prevalent, markedly impairs quality of life, and remains difficult to treat because available therapies show limited efficacy and may cause relevant adverse effects. Because oxidative stress and glutamate-mediated excitotoxicity contribute to central sensitization after SCI, this study evaluated the antinociceptive and antioxidant effects of dapsone (DDS), N-acetylcysteine (NAC), and their combination in rats with SCI. An isobolographic analysis was also performed to determine the pharmacodynamic interaction between the two drugs.

Methods

Female Wistar rats with SCI that developed stimulus-dependent hypersensitivity from day 15 after injury were treated once daily for 7 days with DDS (1.5-12.5 mg/kg, i.p.), NAC (9.3-75 mg/kg, i.p.), or 1:1 fixed-ratio combinations. Mechanical allodynia and hyperalgesia were assessed with Von Frey filaments, whereas lipid peroxidation (LP) and reduced glutathione (GSH) were quantified in injured spinal cord tissue.

Results

DDS and NAC produced dose-dependent antinociceptive effects, with DDS being more potent than NAC in both endpoints. The individual ED50 values were 4.92 and 33.47 mg/kg for allodynia, and 4.06 and 27.74 mg/kg for hyperalgesia, for DDS and NAC, respectively. The DDS/NAC combination showed synergistic interactions in allodynia (ED50 = 7.45 mg/kg vs. Zadd = 19.19 mg/kg; γ = 0.388) and hyperalgesia (ED50 = 4.21 mg/kg vs. Zadd = 15.90 mg/kg; γ = 0.265), with stronger synergism in hyperalgesia. Combined treatment also improved LP and GSH levels.

Conclusions

These findings indicate that DDS and NAC exert complementary actions and that their combination produces a synergistic antinociceptive effect associated with diminished oxidative stress after SCI.