Background & Aims
Pharmacological combination is a tool that offers several advantages compared to monotherapy. One of the most important is synergy, in which the components work together to generate a potentiated response. The co-activation of two Gi protein-coupled to receptors, such as µ-opioid receptors and D2 receptors, could generate synergy through a convergent mechanism in the same neuron. Previous research demonstrated that D2 agonists can be used as adjuvants in the antinociceptive effect of µ-receptor agonists. Additionally, both activation and blockade of the D2 receptor were shown to attenuate the development of opioid-induced tolerance. A new pharmacological treatment for neuropathic pain (NP) combining aripiprazole (ARI) with tramadol (TRA) is proposed. The main objective of this study was to evaluate the possible synergistic interactions of ARI plus TRA combinations, both in anti-hyperalgesic effects and in reducing the development of PT, under NP conditions in the CCI model.
Methods
The CCI model was replicated in male Wistar rats. The von Frey filament assay calibrated to 15 g was used to determine the anti-hyperalgesic effect. The antinociceptive effects of SHAM, CCI control, ARI (10 mg/kg, i.p.), TRA (17.8 and 31.6 mg/kg, i.p.), and ARI (10 mg/kg, i.p.) plus TRA (17.8 or 31.6 mg/kg, i.p.) were evaluated in two administration schemes: single (SimAdm) and repeated (RepAdm). The SimAdm evaluation was conducted on day 1 and involved a single administration of one of the treatments. Subsequently, from days 2 to 5, a RepAdm scheme was applied to detect PT development. Finally, on day 6, the behavioral evaluation was again performed to determine the antinociceptive effects of the treatments on RepAdm.
Synergistic interactions were determined by comparative analysis of the overall antinociceptive effects (AUC) of the treatments. The development of tolerance was determined by comparing the overall effects such as AUC generated in both administration schemes.
Results
ARI, TRA and the combinations of ARI plus TRA exhibited anti-hyperalgesic effects in both administration schemes. The RepAdm scheme did not induce ARI PT. However, our RepAdm protocol led to the development of TRA PT, the effects decreased compared to SimAdm. The addition of the antipsychotic in the combinations managed to reduce the development of PT by up to 66.1% compared to individual treatment with TRA.
Finally, the anti-hyperalgesic effect of the combination of ARI at 10.0 mg/kg plus TRA at 17.8 mg/kg in RepAdm was higher than the sum of the effects of the individual treatments (supra-additive interaction) and higher than TRA at 31.6 mg/kg in RepAdm. Individual treatment with the opioid (17.8 mg/kg) led to the development of PT; conversely, this combination reduced it. The use of this association in the correct proportions potentiated the anti-hyperalgesic effect by 22.6%, managed to decrease the opioid dose by 1.77 times, and still provided a better effect than TRA alone.
Conclusions
The combination of ARI plus TRA generates synergistic interactions in the antinociceptive effects and in the reduction of the development of pharmacological tolerance. A new association with potential for clinical utility in the treatment of hyperalgesia caused by NP is proposed.
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Presenting Author
Juan Pablo Bejarano-Ponce
Poster Authors
Topics
- Models: Chronic Pain - Neuropathic