Brainstem serotonin amplifies nociceptive transmission in a mouse model of Parkinson's disease.

Grivet, Zoé; Aby, Franck; Verboven, Aude; Bouali-Benazzouz, Rabia; Sueur, Benjamin; Maingret, François; Naudet, Frédéric; Dhellemmes, Thibault; De Deurwaerdere, Philippe; Benazzouz, Abdelhamid; Fossat, Pascal

Parkinson's disease arises from the degeneration of dopaminergic neurons in the substantia nigra pars compacta, leading to motor symptoms such as akinesia, rigidity, and tremor at rest. The non-motor component of Parkinson's disease includes increased neuropathic pain, the prevalence of which is 4 to 5 times higher than the general rate. By studying a mouse model of Parkinson's disease induced by 6-hydroxydopamine, we assessed the impact of dopamine depletion on pain modulation. Mice exhibited mechanical hypersensitivity associated with hyperexcitability of neurons in the dorsal horn of the spinal cord (DHSC). Serotonin (5-HT) levels increased in the spinal cord, correlating with reduced tyrosine hydroxylase (TH) immunoreactivity in the nucleus raphe magnus (NRM) and increased excitability of 5-HT neurons. Selective optogenetic inhibition of 5-HT neurons attenuated mechanical hypersensitivity and reduced DHSC hyperexcitability. In addition, the blockade of 5-HT2A and 5-HT3 receptors reduced mechanical hypersensitivity. These results reveal, for the first time, that PD-like dopamine depletion triggers spinal-mediated mechanical hypersensitivity, associated with serotonergic hyperactivity in the NRM, opening up new therapeutic avenues for Parkinson's disease-associated pain targeting the serotonergic systems.

PARKINSON'S disease; MEDICAL sciences; DOPAMINERGIC neurons; TYROSINE hydroxylase; SPINAL cord

NPJ Parkinson's Disease, 2025, Vol 11, Issue 1, p1

2373-8057

Academic Journal

10.1038/s41531-024-00857-1