Neuronal and microglial mechanisms for neuropathic pain in the spinal dorsal horn and anterior cingulate cortex

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”. (Figure presented.).