Chronic pain is a major medical problem that is resistant to conventional medical intervention. It also causes emotional changes such as anxiety and fear. Furthermore, anxiety or fear often enhances ...the suffering of pain. Based on recent studies, I propose chronic anxiety triggered by injury or chronic pain is mediated through presynaptic long-term potentiation (LTP) in the anterior cingulate cortex (ACC), a key cortical region for pain perception. Conversely, NMDA receptor-dependent postsynaptic LTP plays a more important role in behavioral sensitization in chronic pain. Thus, postsynaptic and presynaptic LTP in ACC neurons are likely the key cellular mechanisms for causing chronic pain and its associated anxiety, respectively. This suggests potential targets for treating chronic pain and related anxiety.
Investigation of the synaptic mechanisms for sensory transmission and modulation provide us with critical information about the transmission of painful sensation as well as the basic mechanisms of ...chronic pain. Recent studies consistently demonstrate that glutamatergic synapses not only play an important role in sensory transmission, including pain and itch transmission, but also contribute to nociceptive sensitization at different levels of the brain. Different subtypes of glutamate receptors play selective roles in synaptic transmission and long-term potentiation (LTP), as well as synaptic modulation. Understanding the contribution of each subtype of glutamate receptors, and related downstream signaling pathways may provide a new opportunity to design better medicine for the treatment of different forms of chronic pain.
This article is part of the Special Issue entitled ‘Ionotropic glutamate receptors’.
•Long-term potentiation contributes to chronic pain.•NMDA receptor contribute to postsynaptic potentiation after injury in the brain.•Kainate receptor contribute to pain-related anxiety by enhancing presynaptic glutamate release in the brain.•Glutamate acts as neurotransmitter for pain and itch.
Highlights • Glutamate is the major excitatory transmitter in the insular cortex. • Insular synapses can undergo long-term potentiation. • Long-term potentiation in the insular cortex contributes to ...chronic pain.
Adult brain structures such as the hippocampus are highly plastic to learning and gaining new experiences. Recent studies reveal that cortical areas that respond to sensory noxious stimuli (stimuli ...that cause pain in humans) are also highly plastic, like the learning-related hippocampus. Long-term potentiation (LTP), a key cellular model for learning and memory, is reported in the anterior cingulate cortex (ACC) and insular cortex (IC), two key cortical areas for pain perception. ACC and IC LTP exist in at least two major forms: presynaptically expressed LTP, and postsynaptically expressed LTP (post-LTP). In this short review, I will review, recent progress made in cortical LTPs, and explore potential roles of other forms of LTPs such as synaptic tagging. Their contribution to chronic pain as well as emotional changes caused by injury will be discussed.
Glutamate is the primary excitatory transmitter of sensory transmission and perception in the central nervous system. Painful or noxious stimuli from the periphery ‘teach’ humans and animals to avoid ...potentially dangerous objects or environments, whereas tissue injury itself causes unnecessary chronic pain that can even last for long periods of time. Conventional pain medicines often fail to control chronic pain. Recent neurobiological studies suggest that synaptic plasticity taking place in sensory pathways, from spinal dorsal horn to cortical areas, contributes to chronic pain. Injuries trigger long-term potentiation of synaptic transmission in the spinal cord dorsal horn and anterior cingulate cortex, and such persistent potentiation does not require continuous neuronal activity from the periphery. At the synaptic level, potentiation of excitatory transmission caused by injuries may be mediated by the enhancement of glutamate release from presynaptic terminals and potentiated postsynaptic responses of AMPA receptors. Preventing, ‘erasing’ or reducing such potentiation may serve as a new mechanism to inhibit chronic pain in patients in the future.
Investigation of the basic mechanisms of chronic pain not only provides insights into how the brain processes and modulates sensory information but also provides the basis for designing novel ...treatments for currently intractable clinical conditions. Human brain imaging studies have revealed new roles of cortical neuronal networks in chronic pain, including its unpleasant quality, and mouse studies have provided molecular and synaptic mechanisms underlying relevant cortical plasticity. This review paper will critically examine the current literature and propose a cortical network model for chronic pain.
Pain research is currently undergoing dramatic changes. In the area of basic pain research, new discoveries have been made towards the understanding of pain transmission, modulation and plasticity. ...However, many of these basic discoveries have not yet led to the development of new drugs for the treatment of chronic pain. One major reason for this disconnection is the lack of translational research and drug discovery based directly on the novel pain mechanism. In this review, I focus on activity-dependent potentiation in pain-related cortical areas and recent translational research on adenylyl cyclase subtype 1 (AC1) as a novel target for treating chronic pain. In particular, I discuss the AC1 inhibitor, NB001, which produces powerful analgesic effects in animal models of chronic pain by inhibiting chronic pain-related cortical potentiation.
Alzheimer's disease (AD) is the most common form of neurodegenerative disease. The vast majority cases of AD are sporadic, without clear cause, and a combination of environmental and genetic factors ...has been implicated. The hypothesis that homocysteine (Hcy) is a risk factor for AD was initially prompted by the observation that patients with histologically confirmed AD had higher plasma levels of Hcy, termed hyperhomocysteinemia (HHcy), than age-matched controls. Most evidence accumulated so far implicates HHcy as a risk factor for AD onset, but there are also conflicting results. In this review we summarize reports on the relationship between HHcy and AD from epidemiological investigations, including observational studies and randomized controlled clinical trials. We also examine recent in vivo and in vitro studies of potential mechanisms whereby HHcy could influence AD development. Finally, we discuss possible reasons for the existing conflicting data and provide suggestions for future studies.
The study of glutamatergic synapses mainly focuses on the memory-related hippocampus. Recent studies in the cortical areas such as the anterior cingulate cortex (ACC) show that excitatory synapses ...can undergo long-term plastic changes in adult animals. Long-term potentiation (LTP) of cortical synapses may play important roles in chronic pain and anxiety. In addition to NMDA and AMPA receptors, kainate (KA) receptors have been found to play roles in synaptic transmission, regulation and presynaptic forms of LTP. In this brief review, I will summarize the new progress made on KA receptors, and propose that ACC synapses may provide a good synaptic model for understanding cortical mechanism for behavioral anxiety, and its related emotional disorders.
Neuropathic pain is a debilitating chronic pain condition occurring after damage in the nervous system and is refractory to the currently available treatments. Major challenges include elucidating ...its mechanisms and developing new medications to treat it. Nerve injury‐induced pain hypersensitivity involves aberrant excitability in spinal dorsal horn (SDH) neurons as a consequence of dysfunction of inhibitory interneurons and of hyperactivity of glial cells, especially microglia, the immune cells of the central nervous system. Evidence of this is found using animal models to investigate the molecular and cellular mechanisms of neuropathic pain. The pathologically altered somatosensory signals in the SDH then convey to the brain regions, including the anterior cingulate cortex (ACC). In these regions, nerve injury produces pre‐ and postsynaptic long‐term plasticity, which contributes to negative emotions and anxiety associated with chronic pain conditions. Furthermore, recent evidence also indicates that the descending projection pathways from the ACC directly and indirectly to the SDH (the top‐down corticospinal network) regulate nociceptive sensory transmission in the SDH. Thus, understanding a possible connection between the SDH and ACC, including a neuron–microglia interaction, may provide us with insights into the mechanisms used to amplify pain signals related to neuropathic pain and clues to aid the development of new therapeutic agents for the management of chronic pain.
This article is part of the special article series “Pain”.
Neuropathic pain is a debilitating chronic pain condition occurring after nerve damage. Nerve injury‐induced neuronal hyperexcitability in the spinal dorsal horn (SDH) involves signals from microglia. In the anterior cingulate cortex (ACC), nerve injury produces pre‐ and postsynaptic long‐term plasticity, which contributes to negative emotions and anxiety. As there are direct and indirect connections between these two regions, we think that understanding the link between the SDH and ACC may provide us with insights into the mechanisms for amplifying pain signals under chronic pain conditions.
This article is part of the special article series “Pain”.
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