The role of the mesocortical dopaminergic pathway in the processing of chronic pain signals
Date
2020-04-27
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Abstract
Chronic pain is a debilitating condition which is prevalent in terminal diseases and aged populations. Pain medications are frequently ineffective for chronic use due to resistance to treatment. This is because the pathophysiology, especially cerebral mechanisms of chronic pain is not fully understood. The processing of chronic pain signals is mainly through the cortical areas, the limbic system, and the nucleus accumbens in the brain, which outputs affect downstream targets exerting top-down control. These brain areas mediate emotional and salience-related processing of pain signals, forming the ‘pain matrix’. The ‘pain matrix’ refers to the brain regions mediating different functions such as valance, salience, emotion, and memory that are able to interact with each other to allow pain perception to emerge. The ‘pain matrix’ also process reward information. Signals from pain and reward converge in the ‘pain matrix’and dopamine modulates the emotional and salience aspects of both. The medial prefrontal cortex (mPFC) is a cortical region that controls many executive functions such as attention, working memory, and learning. The mPFC is involved in pain perception, and undergoes plasticity during development of chronic pain. The PFC receives dopaminergic inputs from the ventral tegmental area (VTA), forming the mecoscortical pathway. The mesocortical circuit modulates neuronal plasticity in the mPFC. This modulation has been shown to affect working memory and aversion; however, whether and how the VTA-mPFC dopaminergic inputs are involved in chronic pain remains incompletely understood. This PhD dissertation examines the hypothesis that VTA dopaminergic neurons undergo plasticity during chronic pain states, and projections from these neurons to the mPFC modulate chronic pain-associated behaviours. Dopaminergic subpopulations of both the lateral and medial VTA were defined by action potential firing patterns. However, plasticity induced by neuropathic chronic pain only resides in specific dopaminergic subpopulations. In addition, dopaminergic subpopulations of lateral and medial VTA are differentially altered after induction of neuropathic pain. Using optogenetic approaches to selectively target dopaminergic inputs to the mPFC, we found that phasic activation of VTA-mPFC dopaminergic inputs reduced mechanical hypersensitivity during neuropathic pain states. Photostimulation of dopamine input to the mPFC also induced a preference for photostimulation-paired context only in mice with neuropathic pain. Fiber photometry imaging of calcium signals demonstrated that dopamine enhances the activity of mPFC neurons projecting to the ventrolateral periaquductal gray, a crucial downstream target for top-down regulation of pain states. Altogether, this study indicates an important modulatory role of mesocortical dopamine in cerebral chronic pain signaling.
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Keywords
Chronic pain, Dopamine, The ventral tegmental area, The prefrontal cortex, Plasticity, Optogenetics
Citation
Huang, S. (2020). The role of the mesocortical dopaminergic pathway in the processing of chronic pain signals (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca.