Rotigotine Attenuates Mechanical Hypersensitivity in 6-OHDA-Lesioned Rats: Associations with D2/D3 Receptors and Spinal Glial NF-κB/p65 Signaling

Abstract Pain is a debilitating non-motor symptom of Parkinson’s disease (PD). This study investigated whether rotigotine attenuated pain hypersensitivity (allodynia and hyperalgesia) in hemiparkinsonian rats and explored D1/D2/D3 receptor involvement, NF-κB/p-p65 signaling modulation in glial cells, and spinal TNF-α and IL-1β expression. The PD model was induced by unilateral 6-OHDA injection into the substantia nigra pars compacta (SNpc). Pain sensitivity was assessed using von Frey filaments. Immunohistochemistry and immunofluorescence were used to analyze tyrosine hydroxylase levels in the SNpc and striatum, GFAP, Iba-1, and NF-κB/p-p65 expression in the dorsal horn of the L5 spinal cord, and ELISA was used to determine TNF-α and IL-1β levels in the lumbar spinal cord. Both acute (8 h) and subacute (5-day) intranasal rotigotine (0.1, 0.5, 0.75, and 1 mg/kg) showed antiallodynic and antihyperalgesic effects. These effects were prevented by selective D2 (L-741,626; 14.6 nmol) and D3 (nafadotride; 3 nmol) receptor antagonists, but not by the D1 receptor antagonist SCH-23,390 (30 nmol). Subacute rotigotine was associated with reduced 6-OHDA-induced glial activation, decreased NF-κB/p-p65 expression, and attenuated spinal TNF-α and IL-1β levels. Molecular docking suggests a potential interaction between rotigotine and the p65 subunit of NF-κB, with favorable binding energy. In conclusion, rotigotine moderated PD-related pain, potentially through D2/D3 receptor activation and modulation of neuroinflammation. This suggested antinociceptive effect may be linked to suppressing glial activation and inhibiting spinal astrocytes’ NF-κB/p-p65 signaling, potentially reducing subsequent proinflammatory cytokine release. These findings suggest that rotigotine may represent a promising therapeutic option for managing sensory hypersensitivity in PD.