The anti-alodin and anti-hyperalgesic effect induced by rotigotine is mediated by the activation of dopamine D2/D3 receptors in hemiparkinsonian rats

Abstract

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by motor symptoms such as bradykinesia, rigidity, and tremors. PD is caused by the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc), resulting in a dopamine deficiency. In addition, patients with PD experience various non-motor symptoms, including depression, sleep disturbances, fatigue, and pain. Pain is one of the most common non-motor symptoms of PD, negatively impacting patients' quality of life. This study aims to investigate the potential antiallodynic and antihyperalgesic effects induced by rotigotine and determine whether these effects are mediated through the activation of dopaminergic D1, D2, and D3 receptors and the subsequent reduction in the production of proinflammatory cytokines (IL-1β, IL-6, and TNFα) in 6-OHDA-infected rats. The antiallodynic and antihyperalgesic effects of rotigotine (0.5 mg/kg, int.) were evaluated with acute (8 hours) and subacute (5 days) administration. Intranasal administration of rotigotine reversed acute and subacute allodynia and hyperalgesia in male rats with 6-OHDA lesions. Furthermore, co-administration of nafadotride (3 nmol, int.), a selective D3 receptor antagonist, with rotigotine blocked the antiallodynic and antihyperalgesic effects induced by rotigotine.

Similarly, co-administration of L-741,626 (14.6 nmol, int.), a selective D2 receptor antagonist, with rotigotine decreased the antinociceptive effect of rotigotine. Finally, co-administration of a D1 receptor antagonist, SCH 23390 (3 nmol, i.n.), plus rotigotine, did not decrease the antinociceptive effects induced by rotigotine. The different dopamine antagonists alone had no effect on allodynia or hyperalgesia in rats with 6-OHDA lesions. These results indicate the involvement of D3/D2 dopamine receptors, but not D1 receptors, in pain modulation. Furthermore, a decrease in the production of proinflammatory cytokines was observed in rats treated with rotigotine. In conclusion, the antinociceptive effects of rotigotine occur through the D2/D3 dopaminergic receptors, but not the D1 receptor, and the final signaling pathway is activated by the D2/D3 dopaminergic receptors, probably inducing NFKB activation, since rotigotine inhibits the production of pro-inflammatory cytokines in 6-OHDA-injured rats, which are related to the development and maintenance of pain.