Differential roles of dopamine D1 and D2 receptors in pain modulation: a review

Dopamine D1 and D2 receptors (D1R, D2R) are widely distributed in the central nervous system and play important yet distinct roles in pain regulation. Although their involvement in reward, motivation, and emotional processing is well established, a systematic understanding of their region-specific and subtype-specific functions in pain remains incomplete. This review integrates research from the past decade on four core pain-related brain regions: the prefrontal cortex (PFC), nucleus accumbens (NAc), anterior cingulate cortex (ACC), and amygdala. Existing evidence shows that D1R and D2R exhibit significant regional heterogeneity and functional complexity. In the PFC, D1R has been implicated in pain signal integration and salience encoding in some studies, while D2R shows a context-dependent regulatory role; however, the literature remains heterogeneous, and causal evidence is limited. In the NAc, D1R may mediate the intersection of endogenous and exogenous analgesic signals and may participate in pain-reward balance; D2R has been shown to modulate inflammatory pain and neuropathic pain, opioid synergy, and stress analgesia. In the ACC, D1R appears to provide tonic suppression under physiological conditions, but its function may diminish in chronic pain, potentially contributing to hyperalgesia maintenance. Conversely, activation of D2R has been reported to suppress pain symptoms and to restore inhibitory control in some studies. In the amygdala, D1R exhibits region- and cell-type specific effects, while D2R within the central amygdala may serve as an important mediator of the VTA-CeA reward-analgesia pathway. More importantly, the interaction between D1R and D2R presents patterns of functional synergy, functional antagonism, and state-dependent reorganization, which together precisely regulate the sensory and emotional dimensions of pain. Treatment targeting the dopamine receptor system is a promising pain management strategy. However, many challenges remain in achieving precise treatment targeting specific regions and cell types. Additional clinical studies are needed in the future to evaluate the efficacy of this approach in patients with chronic pain and mood disorders.