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.

References

Aira, Z., Barrenetxea, T., Buesa, I., Gómez-Esteban, J. C., & Azkue, J. J. (2014). Synaptic upregulation and superadditive interaction of dopamine D2- and ?-opioid receptors after peripheral nerve injury. Pain, 155(12), 2526–2533.
Almeida-Santos, A. F., Ferreira, R. C. M., Duarte, I. D., Aguiar, D. C., Romero, T. R. L., & Moreira, F. A. (2015). The antipsychotic aripiprazole induces antinociceptive effects: Possible role of peripheral dopamine D2 and serotonin 5-HT1A receptors. European Journal of Pharmacology, 765, 300–306.
Chou, T. C. (2006). Theoretical Basis, Experimental Design, and Computerized Simulation of Synergism and Antagonism in Drug Combination Studies. Pharmacological Reviews, 58(3), 621–681.
Cook, C. D., Barrett, A. C., Syvanthong, C., & Picker, M. J. (2000). The dopamine D3/2 agonist 7-OH-DPAT attenuates the development of morphine tolerance but not physical dependence in rats. Psychopharmacology, 152(1), 93–104.
Corder, G., Castro, D. C., Bruchas, M. R., & Scherrer, G. (2018). Endogenous and Exogenous Opioids in Pain. Annual Review of Neuroscience, 41, 453–473.
Dai, W. L., Liu, X. T., Bao, Y. N., Yan, B., Jiang, N., Yu, B. Y., & Liu, J. H. (2018). Selective blockade of spinal D2DR by levo-corydalmine attenuates morphine tolerance via suppressing PI3K/Akt-MAPK signaling in a MOR-dependent manner. Experimental & Molecular Medicine 2018 50:11, 50(11), 1–12.
Dai, W. L., Xiong, F., Yan, B., Cao, Z. Y., Liu, W. T., Liu, J. H., & Yu, B. Y. (2016). Blockade of neuronal dopamine D2 receptor attenuates morphine tolerance in mice spinal cord. Scientific Reports 2016 6:1, 6(1), 1–13.
Dubois, A., Savasta, M., Curet, O., & Scatton, B. (1986). Autoradiographic distribution of the D1 agonist [3H]SKF 38393, in the rat brain and spinal cord. Comparison with the distribution of D2 dopamine receptors. Neuroscience, 19(1), 125–137.
Fei, L., Abrardi, L., & Mediati, R. D. (2012). Unexpected effect of aripiprazole on nociceptive pain. Therapeutic Advances in Psychopharmacology, 2(5), 211.
Ferreira, R. C. M., de Almeida, D. L., Duarte, I. D. G., Aguiar, D. C., Moreira, F. A., & Romero, T. R. L. (2022). The antipsychotic aripiprazole induces peripheral antinociceptive effects through PI3K?/NO/cGMP/KATP pathway activation. European Journal of Pain (London, England), 26(4), 825–834.
Finnerup, N. B., Attal, N., Haroutounian, S., McNicol, E., Baron, R., Dworkin, R. H., Gilron, I., Haanpää, M., Hansson, P., Jensen, T. S., Kamerman, P. R., Lund, K., Moore, A., Raja, S. N., Rice, A. S. C., Rowbotham, M., Sena, E., Siddall, P., Smith, B. H., & Wallace, M. (2015). Pharmacotherapy for neuropathic pain in adults: systematic review, meta-analysis and updated NeuPSIG recommendations. The Lancet. Neurology, 14(2), 162.
Kasahara, S., Kunii, Y., Mashiko, H., Otani, K., Konno, S. ichi, & Niwa, S. ichi. (2011). Four Cases of Chronic Pain That Improved Dramatically Following Low-Dose Aripiprazole Administration. The Primary Care Companion to CNS Disorders, 13(2).
Khalilzadeh, M., Hassanzadeh, F., Aghamiri, H., Dehpour, A. R., & Shafaroodi, H. (2020). Aripiprazole prevents from development of vincristine-induced neuropathic nociception by limiting neural NOS overexpression and NF-kB hyperactivation. Cancer Chemotherapy and Pharmacology 2020 86:3, 86(3), 393–404.
Kinga, S., Anna, F., & Robert, S. (2019). Interventional and preventive effects of aripiprazole and ceftriaxone used alone or in combination on oxaliplatin-induced tactile and cold allodynia in mice. Biomedicine & Pharmacotherapy = Biomedecine & Pharmacotherapie, 111, 882–890.
López?Muñoz, F. J. (1994). Surface of synergistic interaction between dipyrone and morphine in the PIFIR model. Drug Development Research, 33(1).
Mamo, D., Graff, A., Mizrahi, R., Shammi, C. M., Romeyer, F., & Kapur, S. (2007). Differential effects of aripiprazole on D(2), 5-HT(2), and 5-HT(1A) receptor occupancy in patients with schizophrenia: a triple tracer PET study. The American Journal of Psychiatry, 164(9), 1411–1417.
Mercado-Reyes, J., Almanza, A., Segura-Chama, P., Pellicer, F., & Mercado, F. (2019). D2-like receptor agonist synergizes the ?-opioid agonist spinal antinociception in nociceptive, inflammatory and neuropathic models of pain in the rat. European Journal of Pharmacology, 853, 56–64.
Nelson, T. S., Santos, D. F. S., Prasoon, P., Gralinski, M., Allen, H. N., & Taylor, B. K. (2023). Endogenous ?-opioid-Neuropeptide Y Y1 receptor synergy silences chronic postoperative pain in mice. PNAS Nexus, 2(8).
Norouzi, M., Mousavi, Z., & Shafaroodi, H. (2017). Aripiprazole prolongs morphine antinociception effect and disrupts acute morphine tolerance. Biomedical and Pharmacology Journal, 10(3), 1149–1157.
Ossipov, M. H., Lopez, Y., Bian, D., Nichols, M. L., & Porreca, F. (1997). Synergistic antinociceptive interactions of morphine and clonidine in rats with nerve-ligation injury. Anesthesiology, 86(1), 196–204.
Raffa, R. B., Friderichs, E., Reimann, W., Shank, R. P., Codd, E. E., & Vaught, J. L. (1992). Opioid and nonopioid components independently contribute to the mechanism of action of tramadol, an “atypical” opioid analgesic. Journal of Pharmacology and Experimental Therapeutics, 260(1).
Takenoshita, M., Motomura, H., & Toyofuku, A. (2017). Low-Dose Aripiprazole Augmentation in Amitriptyline-Resistant Burning Mouth Syndrome: Results from Two Cases. Pain Medicine: The Official Journal of the American Academy of Pain Medicine, 18(4), 814.
Umezaki, Y., Takenoshita, M., & Toyofuku, A. (2016). Low-dose aripiprazole for refractory burning mouth syndrome. Neuropsychiatric Disease and Treatment, 12, 1229–1231.
Xie, G. X., Jones, K., Peroutka, S. J., & Palmer, P. P. (1998). Detection of mRNAs and alternatively spliced transcripts of dopamine receptors in rat peripheral sensory and sympathetic ganglia. Brain Research, 785(1), 129–135.
Zarrindast, M. R., Dinkoub, Z., Homayoun, H., Bakhtiarian, A., & Khavandgar, S. (2002). Dopamine receptor mechanism(s) and morphine tolerance in mice. Journal of Psychopharmacology (Oxford, England), 16(3), 261–266.
Zhang, L., Zhang, J. T., Hang, L., & Liu, T. (2020). Mu Opioid Receptor Heterodimers Emerge as Novel Therapeutic Targets: Recent Progress and Future Perspective. Frontiers in Pharmacology, 11.
Zhu, H., Clemens, S., Sawchuk, M., & Hochman, S. (2007). Expression and distribution of all dopamine receptor subtypes (D1-D5) in the mouse lumbar spinal cord: A real-time polymerase chain reaction and non-autoradiographic in situ hybridization study. Neuroscience, 149(4).
Zimmermann, M. (1983). Ethical guidelines for investigations of experimental pain in conscious animals. Pain, 16(2), 109–110.

Presenting Author

Juan Pablo Bejarano-Ponce

Poster Authors

Juan Bejarano Ponce

MSc

Centro de Investigación y de Estudios Avanzados del IPN

Lead Author

José de Jesús Aceves-Buendía PhD

Lead Author

Francisco Javier López-Muñoz PhD

CINVESTAV

Lead Author

Topics

  • Models: Chronic Pain - Neuropathic