Spinal cord stimulation: An emerging strategy for chronic pain relief after spinal cord injury.

The discovery of dopamine’s role as a neurotransmitter in the late 1950s transformed the understanding of neurological disorders, particularly Parkinson’s disease (PD). Using histofluorescence techniques, Carlsson and colleagues first identified distinct dopaminergic neuronal populations (Carlsson et al., 1957), and soon after, Birkmayer and Hornykiewicz (1961) demonstrated that PD was characterized by striatal dopamine deficiency, with levodopa therapy producing symptomatic relief. A subsequent histological study by Dahlström and Fuxe (1964) confirmed that degeneration of neurons in the substantia nigra pars compacta (SNpc) was a pathological hallmark of PD, correlating closely with the emergence of motor symptoms. These foundational discoveries established the centrality of nigrostriatal dopamine loss in PD pathophysiology, guiding decades of neurochemical, electrophysiological, and pharmacological research (Hornykiewicz, 1998, 2006). Although dopaminergic depletion underlies the hallmark motor features of PD, the disorder is now recognized as a complex, multisystem neurodegenerative condition. Neurodegeneration extends beyond the nigrostriatal pathway, affecting noradrenergic neurons in the locus coeruleus, cholinergic cells in the basal forebrain, and serotonergic and glutamatergic circuits, contributing to non-motor symptoms such as cognitive impairment, sleep disturbances, and mood disorders (Yahr and Duvoisin, 1972; Paredes-Rodriguez et al., 2020). Despite this broader neurodegeneration, the selective vulnerability of SNpc dopaminergic neurons remains a defining and incompletely understood feature of PD (Marsden and Parkes, 1977; de Rijk et al., 2000). Nigrostriatal dopaminergic neurons are exposed to distinct metabolic, physiological, and structural stressors that may render them particularly susceptible to degeneration. Their vast axonal arborization and high synaptic burden necessitate elevated energy consumption, making them disproportionately vulnerable to mitochondrial dysfunction and oxidative stress (O’Callaghan et al., 2021). These neurons also maintain sustained pacemaker activity with calcium influx, which compounds mitochondrial strain and accelerates cellular aging (Bohnen et al., 2022) at the molecular level, converging insults from α-synuclein aggregation, proteostatic collapse, and neuroinflammatory signaling cascade into progressive neuronal damage, distinguishing SNpc neurons from more resilient neighboring populations, such as those in the ventral tegmental area (VTA) (Braak and Del Tredici, 2008; Bohnen et al., 2022).