Current Understanding of the Neural Circuitry in the Comorbidity of Chronic Pain and Anxiety

Abstract

Chronic pain patients often develop mental disorders, and anxiety disorders are common. We hypothesize that the comorbid anxiety results from an imbalance between the reward and antireward system due to persistent pain, which leads to the dysfunction of the pain and anxiety regulatory system. In this review, we will focus on changes in neuroplasticity, especially in neural circuits, during chronic pain and anxiety as observed in animal studies. Several neural circuits within specific regions of the brain, including the nucleus accumbens, lateral habenular, parabrachial nucleus, medial septum, anterior cingulate cortex, amygdala, hippocampus, medial prefrontal cortex, and bed nucleus of the stria terminalis, will be discussed based on novel findings after chemogenetic or optogenetic manipulation. We believe that these animal studies provide novel insights into human conditions and can guide clinical practice.

Figure 1

Possible explanation of the comorbidity of chronic pain and anxiety. Persistent pain inhibits the brain's reward and motivational center—the nucleus accumbens (NAc)—and diminishes the motivational/incentive salience of natural reinforcers (reward deficiency). In response to this state, the antireward system center—the lateral habenular (LHb)—is overexcited, releasing stress-related chemicals—including corticotropin-releasing factor (CRF), norepinephrine (NE), and dynorphin—leading to excessive dopaminergic trafficking (reduced dopamine receptors, diminished dopamine synthesis, and increased dopamine transporters) that results in the dysfunction of the pain and anxiety regulatory system (pain chronification). The pain and anxiety syndromes in chronic pain patients are thus the result of the dysfunction of the regulatory system.

Figure 2

Potential neural circuits underlying the comorbidity of chronic pain and anxiety. ACC: anterior cingulate cortex; BLA: basolateral amygdala; BNST: bed nucleus of the stria terminalis; CeA: central amygdala; DRN: dorsal raphe nucleus; HPC: hippocampus; LH: lateral hypothalamus; LHb: lateral habenula; LS: lateral septum; mPFC: medial prefrontal cortex; MS: medial septum; NAc: nucleus accumbens; PAG: periaqueductal gray; PB: parabrachial nucleus; RVM: rostromedial ventral medulla; TH: thalamus; VTA: ventral tegmental area. ?, not confirmed for chronic pain-related anxiety.