Glial mechanisms in control of pain

Zhi-Qi Zhao

Institute of Neurobiology, Institutes of Brain Science & The State Key Laboratory of Medical Neurobiology, Fudan University, China

Increasing evidence has testified that glial cells are powerful modulators of pain. Our evidence reveals that glia-expressed P2X7purinergicreceptors play a crucial role in tetanic stimulation of sciatic nerve-induced spinal long-term potentiation (LTP) and tolerance to morphine analgesia. I. P2X7 expressed in glia may be a signal molecule contributing to spinal LTP. P2X7 antagonists prevented the induction of spinal LTP in bothin vivoand the spinal cord slicein vitroand partially alleviated behavioral allodynia. Down-regulation of P2X7 with targeting P2X7 siRNA blocked the induction of spinal LTP and partially inhibited allodynia. P2X7 co-localized with microglial marker OX-42, but not with astrocytic marker GFAP or neuronal marker NeuN. Further, P2X7 antagonist inhibited tetanically sciatic stimulation-induced up-regulations of Iba-1, p38, IL-1β and GluR1. These results suggest that the P2X7 in microglia contributes the induction of spinal LTP and persistent pain through p38–IL-1β–GluR1 signaling pathway.II.Morphine loses analgesic potency after repeated administration. The previous studies have explored that glia is involved in morphine tolerance and P2X7 is implicated in neuron–glia communication and chronic pain. We recently demonstrated that P2X7 colocalized with the OX42, but not the GFAP, in the spinal cord. The protein level of spinal P2X7 was upregulated after chronic morphine. P2X7 inhibitor or targeting P2X7 siRNA significantly attenuated the loss of morphine analgesic potency, P2X7 upregulation, and microglial activation. These results suggest that spinal P2X7 is involved in the induction of neuropathic pain–associated spinal LTP and tolerance to morphine analgesiaand may be a new target for control of pain.