The Role of Store-Operated Calcium Channels in Peripheral Sensitization

Chronic pain is a common and debilitating condition that afflicts more than 100 million Americans and is often poorly managed. Peripheral and central sensitization processes are believed to play key roles in the pathogenesis of chronic pain. However, candidate molecules involved in these processes remain unclear. Store-operated calcium channels (SOCs) are highly calcium-selective channels mediating calcium entry in various cell types. We have reported that SOC inhibition by YM-58483 attenuates chronic pain. Our previous study showed that SOCs are expressed in dorsal horn neurons and play a critical role in central sensitization. However, it remains elusive whether SOCs contribute to peripheral sensitization. Here we demonstrate that SOCs are expressed in dorsal root ganglion (DRG) neurons and that both STIM1 and STIM2 are important components mediating SOC entry (SOCE). While Orai1 is the only subunit mediating SOCE in most cell types, we found that Orai1 and Orai3 are responsible for SOCE in DRG neurons. Importantly, SOC activation by thapsigargin increases neuronal excitability, which is abolished by double knockdown of Orai1/3. To further determine the peripheral mechanisms of SOCs in inflammatory pain, we generated carrageenan- and CFA-induced pain models and found that Orai1 is involved in carrageenan- and CFA-induced inflammatory pain. Moreover, we demonstrate that SOC function in DRG neurons is potentiated by PGE2, an important inflammatory mediator, which was mediated through EP1 and its downstream PKC cascade. Orai1 deficiency completely abolished PGE2-induced SOCE increase in DRG neurons. Consistently, PGE2-induced pain hypersensitivity is significantly attenuated in Orai1KO mice compared with wildtype littermates. Taken together, our findings suggest that SOCs exert an excitatory action in DRG neurons and are important in peripheral sensitization during chronic pain. Our study also provides new insights into how PGE2 mediates inflammatory pain.