Repeated administration of mazindol reduces spontaneous pain-related behaviors without modifying bone density and microarchitecture in a mouse model of complete Freund’s adjuvant-induced knee arthritis

Abstract

Background

The role of dopaminergic system in the development of rheumatoid arthritis-related pain, a major symptom in this disease, has not been explored. Therefore, the anti-nociceptive effect of mazindol, a dopamine uptake inhibitor, was evaluated in a model of complete Freund’s adjuvant (CFA)-induced arthritis. Furthermore, as studies have shown that the dopaminergic system regulates bone metabolism, the effect of mazindol on bone mass and microarchitecture was determined.

Methods

Adult ICR male mice received intra-articular injections of either CFA or saline into the right knee joint every week. Spontaneous pain-like behaviors (flinching and guarding) and locomotor activity were assessed at day 26 post-first CFA, following which, a single intraperitoneally (i.p.) administered dose of mazindol was given (1, 3 and 10 mg/kg). Then, the antinociceptive effect of a repeated administration of 3 mg/kg mazindol (daily, i.p.; day 15–day 26) was evaluated. Additionally, at day 26, the participation of D1-like, D2-like or opioid receptors in the antinociceptive effect of mazindol was evaluated. The effect of mazindol on bone density and microarchitecture was evaluated by micro-computed tomography.

Results

Acute administration of mazindol decreased the spontaneous pain-like behaviors in a dose-dependent manner without reducing the knee edema. However, mazindol at 10 mg/kg significantly increased the locomotor activity; therefore, 3 mg/kg mazindol was used for further studies. Repeated administration of 3 mg/kg mazindol significantly decreased the pain-like behaviors without modifying locomotor activity. The antinociceptive effect of mazindol was blocked by administration of a D2-like receptor antagonist (haloperidol), but not by administration of D1-like receptor antagonist (SCH 23390) or an opioid receptor antagonist (naloxone). Repeated administration of mazindol did not significantly modify the density and microarchitecture of periarticular bone of the arthritic and nonarthritic knee joints.

Conclusion

Results suggest that mazindol via D2-like receptors has an antinociceptive role in mice with CFA-induced knee arthritis without modifying the bone health negatively.

Keywords:

• dopamine
• analgesia
• arthritic pain
• micro-computed tomography

Acknowledgments

The authors kindly thank Aleyda Arianne Loredo-Perez and Carlos Enrique Montalvo-Blancothe for the technical support. The authors wish to thank Sarah Woller who assisted in the proof-reading of the manuscript. This work was partially supported by CONACyT (CB-2014/240829 and INFR-2016/270549), Universidad Autónoma de Tamaulipas (PFI2016-34) and LERG CONACyT fellowship (No. 581277).

Author contributions

LERG, RIAG and JMJA designed the study, executed the experiments, analyzed the data as well as wrote the manu-script. AMM and VMVM performed micro-CT analysis. RIAG, RPS, and JGRG assisted in the statistical analysis and interpretation of data, as well as revised the manuscript. MAR and CFDVL revised the manuscript. All authors contributed toward data analysis, drafting and critically revising the paper and agree to be accountable for all aspects of the work.

Disclosure

MAR and CFDVL work for Productos Medix, S.A de C.V., which is a pharmaceutical company that sells mazindol as an anorectic in Mexico. However, Productos Medix, S.A de C.V. were not involved in the recollection and analysis of data. The authors report no conflicts of interest in this work.