Beyond motor control: the subthalamic nucleus as a central hub for pain in Parkinson's disease

Neurosci Biobehav Rev. 2026 Apr 17:106691. doi: 10.1016/j.neubiorev.2026.106691. Online ahead of print.

ABSTRACT

The subthalamic nucleus (STN), considered a primarily motor structure within the basal ganglia, is recognized as a key contributor to a wider set of behaviors. Among these, nociceptive processing has gained particular attention, especially given the high prevalence and early emergence of pain in Parkinson's disease (PD). This review brings together anatomical, physiological and translational evidence to examine how the STN integrates motor and nociceptive information. The STN receives ascending afferents from brainstem nociceptive pathways and its activity tracks the intensity and salience of noxious stimuli, recruiting cortical and limbic networks that shape both sensory and affective dimensions of pain. In PD, the organization and dynamics of the STN are profoundly disrupted. Abnormal bursting and exaggerated beta oscillations, central to motor symptoms, also appear to promote central sensitization and enhanced pain responses. Studies from animal models consistently support the notion that parkinsonian states perturbate nociceptive signaling within the STN. Deep brain stimulation (DBS) of the STN, a well-established therapy for motor symptoms, further demonstrates the involvement of the nucleus in the pathophysiology of pain. Evidence from clinical and preclinical studies indicates that STN-DBS attenuates nociceptive hypersensitivity and modulates pain processing at spinal level, suggesting an intrinsic analgesic action rather than a secondary effect of motor improvement. Finally, recent optogenetic and chemogenetic approaches clarified how therapeutic interventions act on STN circuits, showing that symptom relief is linked to the suppression of pathological firing patterns. Together, these findings position the STN as a central node linking motor and pain networks in PD.

PMID:42002247 | DOI:10.1016/j.neubiorev.2026.106691