The central mechanisms of chronic pain remain elusive.
On January 3, 2024, Changhe Wang from Xi'an Jiaotong University, Feng Wei from the University of Maryland, Zuying Chai from Hopkins University, and Xinjiang Kang from Southwest Medical University jointly published a paper entitled "An ACC-VTA-ACC Positive-feedback loop mediates the persistence of neuropathic pain and emotional" in Nature Neuroscience** consequences", which identified a reciprocal neuronal circuit between the anterior cingulate cortex (ACC) and the ventral tegmental area (VTA) in mice that mediates the reciprocal exacerbation between hyperalgesia and allanalgesia and their emotional consequences, leading to chronic neuropathic pain.
ACC glutamatergic neurons (ACCglu) indirectly inhibit dopaminergic neurons (VTADA) by activating local GABAergic interneurons (VTAGABA), and this effect is enhanced after nerve injury. VTADA neurons project to ACC in turn and synapse with the initial ACCglu neuron to transmit feedback information from mood changes. Thus, the accglu-vtagaba-vtada-accglu positive feedback loop mediates the progression and maintenance of persistent pain and comorbid anxiety-depressive-like behaviors. In a mouse model of neuropathic pain, disruption of this feedback loop attenuates hyperalgesia and anxiety-depressive-like behaviors, both acute and chronic.
Chronic pain is one of the most prevalent health problems in humans, affecting more than 30% of the world's population. Although multiple analgesics are effective in acute pain, chronic pain is an important clinical problem, and the core mechanism of chronic pain persistence is unclear. Various maladaptive changes in the plasticity of the peripheral nervous system (e.g., sensitization of peripheral nociceptors) and central nervous system (including central sensitization) may contribute to chronic pain. The persistence of these plasticity changes requires repeated renewal through a process similar to reconsolidation, which relies on sustained sensory input from injured tissue or nerves. How chronic pain persists and worsens long after the injured tissue has healed remains a mystery. Depression and anxiety, which in turn exacerbate the severity of the pain condition and impede effective analgesia**. Tricyclic antidepressants can reduce the sensory and emotional symptoms of neuropathic pain through an unknown mechanism. Although several brain regions, such as ACC, medial prefrontal cortex (MPFC), dorsal middle nucleus (DRN), nucleus accumbens (NAC), and amygdala (CEA), are all associated with affective disorder comorbidities in chronic pain, whether or not they may serve as central hubs for cross-linking pain processing and affective patterns, and if so, by which pathways, it is unclear. Although multiple pathways, including DRN-CEA-lateral nucleus, thalamic-ACC, locus coeruleus (LC)-ACC, striated bed nucleus-lateral hypothalamus, and ventral tegmental area (VTA)-MPFC, have been reported to be involved in comorbid mood changes during chronic pain development, how these conditions exacerbate pain remains unknown.
The working model of the ACC-VTA-ACC positive feedback loop in chronic neuropathic pain (Figure courtesy of Nature Neuroscience) in the limbic dopamine (DA) pathway innervates brain regions involved in emotional and motivational functions. Low activity of VTADA neurons has been reported in both preclinical pain models and patients with chronic pain, and drug-targeted effects of the DA pathway affect responsiveness to opioid and non-opioid analgesics during chronic pain**. However, it remains unknown whether and how DA transmission is critical to the crosstalk between pain sensation and emotion, as well as the progression of persistent pain. The study identified a positive feedback neuronal circuit between ACC (nociceptive centers) and VTA (emotional response centers) that mediates crosstalk between sensation and emotion by using circuit optogenetics and chemogenetics combined with electrophysiological recordings, electrochemical recordings, two-photon Ca2+ imaging in awake mice, and fiber optophotometric recordings in free-moving mice. They reinforce each other and the progression and maintenance of neuropathic pain. Notably, in a mouse model of neuropathic pain, disruption of this positive feedback loop has an acute and long-lasting beneficial effect on hyperalgesia and comorbid anxiety-depressive-like behavior. Original link: