The Effect of Rotigotine Extended-Release Microspheres Alone or With Celecoxib on the Inflammatory Pain.

Keke Li,Fenghua Fu,Yijia Zhang,Enming Tian,Zikai Liu,Tian Wang

doi:10.3389/fphar.2020.594387

Abstract

Clinical trials of rotigotine extended-release microspheres (RTGT-MS), which provides a sustained release of rotigotine for near 2 weeks in vivo, have been conducted in the treatment of Parkinson’s disease (PD). This study was to investigate the analgesic effect of RTGT-MS, and to know whether RTGT-MS have synergistic interaction with non-steroidal anti-inflammatory drug, celecoxib. The inflammatory pain model of rats was prepared by carrageenan-induced paw edema. The thermal and mechanical stimuli were applied and the hindpaw withdrawal latency (HWL) response was evaluated. Treatment with RTGT-MS increased the HWL in a dose-dependent manner. The ED50 of RTGT-MS was 24.68 ± 1.02 mg/kg. Isobolographic analysis shows that the combination of RTGT-MS and celecoxib resulted in a synergistic antinociceptive effect. Further results demonstrated that antinociceptive effect of RTGT-MS was accompanied with that PKA, cAMP, COX-2, and PGE2 levels were decreased. Chlorpromazine, a dopamine receptor blocker, not only weakened the analgesic effect of RTGT-MS, but also increased the levels of cAMP, PKA, COX-2, and PGE2. These findings provide a rationale for the combination of RTGT-MS and celecoxib in the treatment of PD, which may reduce the dose of celecoxib, thereby lowering the incidence of adverse effects and improving the pain management in PD patients.

Highlights

Parkinson’s disease (PD) is a long-term, progressive neurodegenerative disease with typical clinical symptoms of static tremor, muscle rigidity, motor delay, and abnormal gait
The results show that the hindpaw withdrawal latency (HWL) of both hindpaws in response to thermal and mechanical stimulations were significantly reduced in the model group compared with those in the control group (p < 0.001)
Effects of Rotigotine Extended-Release Microspheres on the Cyclooxygenase-2 and Prostaglandin E2 Levels. It shows that the COX-2 and prostaglandin E2 (PGE2) levels were increased in the model group compared with those in the control group (p < 0.001)

Summary

Introduction

Parkinson’s disease (PD) is a long-term, progressive neurodegenerative disease with typical clinical symptoms of static tremor, muscle rigidity, motor delay, and abnormal gait. Over six million patients with PD have been reported worldwide, and the prevalence of PD over the age of 65 is 1–2% (GBDPDS Collaborators, 2018). PD is generally recognized as a complex disorder with clinical features encompassing motor, non-motor and neuro-psychiatric symptoms. Previous study shows that at least one non-motor symptom (NMS) has been observed in 99% of PD patients (Chaudhuri et al, 2006). It is well known that pain is a commonly reported non-motor symptom of PD, being prevalent in a large proportion of patients the neurophysiology of pain in PD is not well understood. PD patients exhibited the incidence of pain ranges from 40% to 85% and the pain may significantly impair the quality of life of PD patients (Antonini et al, 2018; Broen et al, 2012)

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