Chronic pain is long-lasting pain that often persists during chronic diseases or after recovery from disease or injury. It often causes serious side effects, such as insomnia, anxiety, or depression which negatively impacts the patient’s overall quality of life. Serotonin (5-HT) in the central nervous system (CNS) has been recognized as an important neurotransmitter and neuromodulator which regulates various physiological functions, such as pain sensation, cognition, and emotions–especially anxiety and depression. Its widespread and diverse receptors underlie the functional complexity of 5-HT in the CNS. Recent studies found that both chronic pain and anxiety are associated with synaptic plasticity in the anterior cingulate cortex (ACC), the insular cortex (IC), and the spinal cord. 5-HT exerts multiple modulations of synaptic transmission and plasticity in the ACC and the spinal cord, including activation, inhibition, and biphasic actions. In this review, we will discuss the multiple actions of the 5-HT system in both chronic pain and injury-related anxiety, and the synaptic mechanisms behind them. It is likely that the specific 5-HT receptors would be new promising therapeutic targets for the effective treatment of chronic pain and injury-related anxiety in the future.
Anterior cingulate cortex (ACC) is critical for pain perception; while the retrosplenial cortex (RSC) plays an important role in navigation and memory. It is known that RSC projects to ACC, less is known about the function of this projection. Here we used integrative approaches to show that there is direct excitatory glutamatergic projections from the RSC to the ACC, and postsynaptic excitatory responses are mediated by AMPA receptors. Activation of RSC-ACC by optogenetics significantly facilitated behavioral responses to nociceptive stimuli (mechanical and thermal) in freely moving mice. By contrast, spinal nociceptive tail-flick and anxiety-like activities were not affected. Our results suggest that RSC to ACC projection preferentially affects nociceptive process in supraspinal cortical region. Our results have identified a new facilitatory cortico-cortical circuit for sensory nociceptive process, and this pathway serves to link memory ‘engram’ to pain perception in humans and animals.
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