Mechanism of Neuropathic pain
Neuropathic pain is a chronic pathological pain caused by damage or dysfunction of the nervous system, and it affects tens of millions of people worldwide. Clinical symptoms of this devastating disorder include allodynia, a pain sensation caused by non-noxious stimuli, and hyperalgesia, an exaggerated pain sensation caused by noxious stimuli. Such pain hypersensitivity is partly attributed to the enhanced excitability of pain-transmitting neurons at the spinal cord level, called central sensitization. Results of studies to date indicate that spinal cord microglia activation plays a critical role in the development of central sensitization; peripheral nerve injury induces microglia activation and proliferation in the spinal cord dorsal horn where the injured nerve innervates. Upon activation, spinal cord microglia express various pain-mediating proinflammatory molecules such as TNF-α, IL-1β, and BDNF. These pain mediators in turn enhance the excitability of pain-transmitting neurons in the spinal cord, leading to central sensitization. However, how peripheral nerve injury induces microglia activation in the spinal cord, which is anatomically remote from the injury site, remains unclear.
Relationship between microglia and neuropathic pain
Various microglia-activating molecules, including ATP, fractalkine, cathepsin S (Ctss) and colony stimulating factor-1 (CSF-1) have been implicated in nerve injury-induced spinal cord microglia activation in previous studies. Recently, we discovered that GT1b in the spinal cord functions as an endogenous agonist of TLR2, which activates microglia and triggers the induction of proinflammatory genes that contribute to central sensitization and the neuropathic pain. Our studies will expand our understanding of the precise mechanism and relationship between microglia and neuropathic pain.
Neuro-glia communication
Microglia, innate immune cells of CNS, plays a critical role in synapse pruning. Several studies showed that direct microglia-synapse interaction (MHC class 1, complement cascade proteins) and multiple soluble factors (BDNF, ATP) from microglia regulate synapses suggesting that the microglial activation and its releasing factors in spinal cord may have critical role in neuropathic pain. However, little is known about the involvement of microglia in spinal synapse remodeling. We hypothesize that peripheral nerve injury-induced spinal synapse remodeling is regulated by microglia, and we are probing the potential target molecules involved in regulation (elimination and protection) of synapse.
