Molecular Mechanism Of Brain Regulation Of Chronic Pain

Chronic pain is a serious debilitating disease for which effective treatment is still lacking.Although acid-sensing ion channel 1a(ASIC1a)has been implicated in both peripheral and central processing of pain,the underlying mechanisms remain mysterious.Here,we show that ASIC1 a sensitizes central nociceptive processing in response to peripheral inflammation by promoting long-term potentiation(LTP)in anterior cingulate cortex(ACC)through increasing postsynaptic trafficking of AMPA receptors.Conditional deletion of ASIC1 a gene from ACC neurons in mice,especially the excitatory neurons there,not only reduced the probability of cortical LTP induction but also attenuated the inflammation-induced thermal and mechanical hypersensitivity without affecting basal pain sensation.Moreover,the inflammation-induced membrane trafficking of AMPA receptor subunit GluA1,but not that of NMDA receptor subunit GluN2 B,in ACC was blocked by the deletion of ASIC1 a.Mechanistically,the ASIC1a-regulated AMPA receptor trafficking and LTP in ACC are dependent on PKC?,which when ectopically expressed in ACC neurons,rescued the biochemical,electrophysiological and behavioral alterations seen in ASIC1 a null mice.Furthermore,while local administration of ASIC1 a agonist in ACC produced pain hypersensitivity in the absence of inflammation,the application of ASIC1 a inhibitors in ACC reversed the previously established inflammatory hyperalgesia in the chronic pain model.By linking ASIC1 a to AMPA receptor trafficking and synaptic potentiation through PKC? in ACC,our findings provide novel insights into central nociceptive processing.The demonstration that inhibiting ACC ASIC1 a reversed pain hypersensitivity further suggests that the ASIC1a-linked pathway presents a promising target for the treatment of chronic pain.