Abstract
Chronic pain is a serious debilitating disease for which effective treatment is still lacking. Acid-sensing ion channel 1a (ASIC1a) has been implicated in nociceptive processing at both peripheral and spinal neurons. However, whether ASIC1a also contributes to pain perception at the supraspinal level remains elusive. Here, we report that ASIC1a in ACC is required for thermal and mechanical hypersensitivity associated with chronic pain. ACC-specific genetic deletion or pharmacological blockade of ASIC1a 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 ASIC1a in excitatory neurons of ACC is a major player in cortical LTP and pain behavior. Mechanistically, we show that ASIC1a tuned pain-related cortical plasticity through protein kinase C λ-mediated increase of membrane trafficking of AMPAR subunit GluA1 in ACC. Importantly, postapplication of ASIC1a inhibitors in ACC reversed previously established nociceptive hypersensitivity in both chronic inflammatory pain and neuropathic pain models. These results suggest that ASIC1a 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.SIGNIFICANCE STATEMENT Chronic pain is a debilitating disease that still lacks effective therapy. Ion channels are good candidates for developing new analgesics. Here, we provide several lines of evidence to support an important role of cortically located ASIC1a channel in pain hypersensitivity through promoting long-term synaptic potentiation in the ACC. Our results indicate a promising translational potential of targeting ASIC1a to treat chronic pain.
Highlights
Chronic pain is a challenging clinical problem seriously affecting millions of people everyday (Holmes, 2016)
Postapplication of Acid-sensing ion channel 1a (ASIC1a) inhibitors in ACC reversed previously established nociceptive hypersensitivity in both chronic inflammatory pain and neuropathic pain models. These results suggest that ASIC1a 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
ASIC1a is not required for LTD induction in ACC We investigated the effect of ASIC1a deletion/inhibition on cingulate LTD, another form of synaptic plasticity induced by low-frequency stimulation (LFS) (Liu and Zhuo, 2014)
Summary
Chronic pain is a challenging clinical problem seriously affecting millions of people everyday (Holmes, 2016). The current treatment for chronic pain is not very effective (Woolf, 2010; Yekkirala et al, 2017). The most widely used analgesics for chronic pain are opioids and aspirin-like nonsteroidal anti-. Received Jan. 24, 2019; revised May 12, 2019; accepted May 14, 2019. Dr Cheng-Chang Lien for kindly providing the ASIC1a KO and ASIC1a flox/flox used in the current study; Dr Alexander M. Dr Yuan-Xiang Tao, Dr Hui Lu, and Dr Wei Lu for valuable comments on earlier versions of the manuscript; and Shaoli Wang, Fan Zhao, Dr Yang Tian, and Dr Ning Song for technical assistance
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