The locus coeruleus (LC) is located in the rostral pons and is characterized by its rich concentration of noradrenergic neurons. It provides the most of noradrenergic innervation for the whole brain, playing a critical role in a wide range of cognitive and physiological functions. The LC plays also an important role in pain control. Recent neuropathological data has shown that LC degeneration may facilitate the occurrence of neurodegenerative diseases such as Alzheimer’s disease or chronic neuropathic pain (Martins et al., Anesthesiology 123(3):642–-53, 2015; Galgani and Giorgi, Curr Neurol Neurosci Rep, 23(12):925–-936, 2023). Diabetes mellitus is one of the most common serious metabolic disorders in humans. Manifestations of diabetic cerebral disorders have been demonstrated at a neurochemical, electrophysiological, structural, and behavioral level. Animal models of diabetes exhibit alterations in neurotransmission, such as reduced evoked GABA release, increased excitatory glutamate signaling, and reduced dopamine signaling (Broderick and Jacoby, Diabetes, 37(7):956–-60, 1988; Perez-Taboada et al., Mov Disord 35(9):1636–-1648, 2020). These alterations may explain the increased risk for the development of affective disorders observed in these patients. This review describes the complex role of the LC and the noradrenergic system within the context of diabetic neuropathic neurodegeneration. Our data show that electrical or chemical stimulation techniques of the LC can reduce diabetic neuropathic pain. Therefore, therapies targeting the LC could be beneficial in attenuating or preventing the development of persistent pain and related comorbidities.