The Locus Coeruleus to Thalamic Reticular Nucleus Pathway in the Comorbidity of Chronic Pain and Attention Deficit-like Behaviors

The comorbidity of chronic pain and attention deficit complicates treatment, as each condition intensifies the other through mechanisms that are not well understood. The locus coeruleus (LC) integrates a variety of somatosensory and emotional inputs and has been implicated in both chronic pain and attention deficit disorders. We hypothesized that the LC and its projections may contribute to the pathophysiology of comorbid chronic pain and attention deficit. We found that in male mice with chronic sciatic nerve constriction injury (CCI), LC neurons were easily activated by mechanical and thermal stimuli. Chemogenetic activation of LC neurons improved hypersensitivity and attention deficit-like behaviors in naive mice, while inhibition of these neurons exacerbated hypersensitivity and attention deficit-like behaviors in CCI mice. Through neuronal tracing, chemogenetics, optogenetics, and electrophysiology, we discovered a monosynaptic dopaminergic pathway from the locus coeruleus to the thalamic reticular nucleus, influencing pain modulation in naive mice. In CCI mice, both projections were enhanced, and activation of these pathways resulted in analgesic and anti-attention deficit-like effects. This study suggests that LC, particularly the LC-thalamic reticular circuit, is crucial in the regulation of comorbid chronic pain and attention deficit.