Neuroinflammation and Central Sensitization in Chronic and Widespread Pain

Abstract

Chronic pain is maintained in part by central sensitization, a phenomenon of synaptic plasticity, and increased neuronal responsiveness in central pain pathways after painful insults. Accumulating evidence suggests that central sensitization is also driven by neuroinflammation in the peripheral and central nervous system. A characteristic feature of neuroinflammation is the activation of glial cells, such as microglia and astrocytes, in the spinal cord and brain, leading to the release of proinflammatory cytokines and chemokines. Recent studies suggest that central cytokines and chemokines are powerful neuromodulators and play a sufficient role in inducing hyperalgesia and allodynia after central nervous system administration. Sustained increase of cytokines and chemokines in the central nervous system also promotes chronic widespread pain that affects multiple body sites. Thus, neuroinflammation drives widespread chronic pain via central sensitization. We also discuss sex-dependent glial/immune signaling in chronic pain and new therapeutic approaches that control neuroinflammation for the resolution of chronic pain.

Neuregulin‐1‐ErbB signaling promotes microglia activation contributing to mechanical allodynia of cyclophosphamide‐induced cystitis

“…23 Neuroinflammation has also been verified to function in visceral pain and chronic pain. 2 In our study, we found similar parallel changes in Nrg1-ErbB signaling, microglia status, and IL-1β expression in the SDH of the CYP-induced cystitis model. Neuroinflammation, which occurred at the spinal cord level, was shown to be attenuated by downregulation of Nrg1-ErbB signaling, leading to pain relief in the cystitis model.…”

“…Further, bidirectional signaling between glial cells and neurons, which are important circuits in neuroinflammation, facilitates the development of persistent pain . Neuroinflammation has also been verified to function in visceral pain and chronic pain . In our study, we found similar parallel changes in Nrg1‐ErbB signaling, microglia status, and IL‐1β expression in the SDH of the CYP‐induced cystitis model.…”

“…Neuroinflammation resulting from neuroglial and neuroimmune interactions can drive chronic pain via central sensitization, which can be induced and maintained by cytokines, chemokines, and other glia-produced mediators. 2 In addition, cyclophosphamide (CYP)induced chronic pain, which is thought to be a visceral neuropathic pain syndrome, may be initiated and maintained in part by neuroinflammation-leading central sensitization. 3 Our previous study showed that glia cell activation can contribute to allodynia in CYP-induced cystitis by releasing proinflammatory cytokines and inducing central sensitization at the spinal cord level.…”

Anti‐allodynic and anti‐inflammatory effects of 17α‐hydroxyprogesterone caproate in oxaliplatin‐induced peripheral neuropathy

“…50,51 After nervous system injury, glial cell activation and the production of proinflammatory mediators, such as the pro-inflammatory cytokines IL-1β, IL-18, IL-6 y TNFα, can directly modulate the activity of neurons and other glial cells, contributing to the development and maintenance of chronic pain. 50,51 In fact, modulating the neuroinflammatory process has emerged as a promising option for the treatment of neuropathic pain. 51 Interestingly, in the recent years, neuroinflammation has been proposed as a major mechanism underlying CIPN-associated pain.…”

“…50,51 In fact, modulating the neuroinflammatory process has emerged as a promising option for the treatment of neuropathic pain. 51 Interestingly, in the recent years, neuroinflammation has been proposed as a major mechanism underlying CIPN-associated pain. 10 In fact, we detected a significant increase in the mRNA levels of GFAP and Iba-1 (markers of satellite glial cells/astrocyes and microglila cells/macrophages, respectively), both in the lumbar DRG and dorsal spinal cord of animals receiving OXA.…”