Protein Kinase C Lambda Mediates Acid-Sensing Ion Channel la-Dependent Cortical Synaptic Plasticity and Pain Hypersensitivity.

Chronic pain is a serious debilitating disease for which effective treatment is still lacking. Acid-sensing ion channel la (ASICla) has been implicated in nociceptive processing at both peripheral and spinal neurons. However, whether ASIC 1 a also contributes to pain perception at the supraspinal level remains elusive. Here, we report that ASICla in ACC is required for thermal and mechanical hypersensitivity associated with chronic pain. ACC-specific genetic deletion or pharmacological blockade of ASICla reduced the probability of cortical LTP induction and attenuated inflammatory thermal hyperalgesia and mechanical allodynia in male mice. Using cell type-specific manipulations, we demonstrate that ASICla in excitatory neurons of ACC is a major player in cortical LTP and pain behavior. Mechanistically, we show that ASICla tuned pain-related cortical plasticity through protein kinase C A-mediated increase of membrane trafficking of AMPAR subunit GluAl in ACC. Importantly, postapplication of ASICla inhibitors in ACC reversed previously established nociceptive hypersensitivity in both chronic inflammatory pain and neuropathic pain models. These results suggest that ASIC 1 a critically contributes to a higher level of pain processing through synaptic potentiation in ACC, which may serve as a promising analgesic target for treatment of chronic pain. [ABSTRACT FROM AUTHOR]