Dysregulated neuromodulation in the anterior cingulate cortex in chronic pain

Chronic pain is a significant global socioeconomic burden with limited long-term treatment options. The intractable nature of chronic pain stems from two primary factors: the multifaceted nature of pain itself and an insufficient understanding of the diverse physiological mechanisms that underlie its initiation and maintenance, in both the peripheral and central nervous systems. The development of novel non-opioidergic analgesic approaches is contingent on our ability to normalize the dysregulated nociceptive pathways involved in pathological pain processing. The anterior cingulate cortex (ACC) stands out due to its involvement in top-down modulation of pain perception, its abnormal activity in chronic pain conditions, and its contribution to cognitive functions frequently impaired in chronic pain states. Here, we review the roles of the monoamines dopamine (DA), norepinephrine (NE), serotonin (5-HT), and other neuromodulators in controlling the activity of the ACC and how chronic pain alters their signaling in ACC circuits to promote pathological hyperexcitability. Additionally, we discuss the potential of targeting these monoaminergic pathways as a therapeutic strategy for treating the cognitive and affective symptoms associated with chronic pain.