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

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

Alleviating effect of lycorine on CFA‑induced arthritic pain via inhibition of spinal inflammation and oxidative stress

“…Mice were acclimatized to the environment for 5 days prior to the experiments, and randomly divided into three groups: Control, CFA, and CFA + lycorine (n=10 per group). A mouse model of CFA was established by intra-articular injection with 10 µl CFA into the left hind knee joint on days 0 and 7; the control group was injected with the same volume of saline (36). Behavioral tests were performed on days 0, 7, and 14.…”

Dopaminergic Agents in Rheumatoid Arthritis

“…In vitro, the stimulation of D2-like DR had anti-inflammatory effects on lymphocytes from CIA mice (Lu et al 2015). Besides the effects on inflammation, D2DR seem to be involved also in nociception in mice (Robledo-Gonzalez et al 2017). In rats, the role of D2-like DR is controversial.…”