Targeting astrocyte signaling for chronic pain.
Clinical management of chronic pain after nerve injury (neuropathic pain) and tumor invasion (cancer pain) is a real challenge due to our limited understanding of the cellular mechanisms that initiate and maintain chronic pain. It has been increasingly recognized that glial cells, such as microglia and astrocytes in the CNS play an important role in the development and maintenance of chronic pain. Notably, astrocytes make very close contacts with synapses and astrocyte reaction after nerve injury, arthritis, and tumor growth is more persistent than microglial reaction, and displays a better correlation with chronic pain behaviors. Accumulating evidence indicates that activated astrocytes can release pro-inflammatory cytokines (e.g., interleukin [IL]-1β) and chemokines (e.g., monocyte chemoattractant protein-1 [MCP-1]/also called CCL2) in the spinal cord to enhance and prolong persistent pain states. IL-1β can powerfully modulate synaptic transmission in the spinal cord by enhancing excitatory synaptic transmission and suppressing inhibitory synaptic transmission. IL-1β activation (cleavage) in the spinal cord after nerve injury requires the matrix metalloprotease-2. In particular, nerve injury and inflammation activate the c-Jun N-terminal kinase in spinal astrocytes, leading to a substantial increase in the expression and release of MCP-1. The MCP-1 increases pain sensitivity via direct activation of NMDA receptors in dorsal horn neurons. Pharmacological inhibition of the IL-1β, c-Jun N-terminal kinase, MCP-1, or matrix metalloprotease-2 signaling via spinal administration has been shown to attenuate inflammatory, neuropathic, or cancer pain. Therefore, interventions in specific signaling pathways in astrocytes may offer new approaches for the management of chronic pain.
Gao
Yong-Jing
YJ
Department of Anesthesiology, Sensory Plasticity Laboratory, Pain Research Center, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA. yjing@zeus.bwh.harvard.edu
Ji
Ru-Rong
RR
D000818:Animals; D001253:Astrocytes / Q000473:pathology / Q000502:physiology*; D002908:Chronic Disease; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000502:physiology; D010146:Pain / Q000473:pathology*; D059408:Pain Management
D016207:Cytokines