Abstract
P2X7 receptors (P2X7Rs) belong to a family of ATP-gated non-selective cation channels. Microglia represent a major cell type expressing P2X7Rs. The activation of microglial P2X7Rs causes the release of pro-inflammatory cytokines such as interleukin-1β (IL-1β). This response has been implicated in neuroinflammatory states in the central nervous system and in various diseases, including neuropathic pain. Thus, P2X7R may represent a potential therapeutic target. In the present study, we screened a chemical library of clinically approved drugs (1979 compounds) by high-throughput screening and showed that the Ca2+ channel blocker cilnidipine has an inhibitory effect on rodent and human P2X7R. In primary cultured rat microglial cells, cilnidipine inhibited P2X7R-mediated Ca2+ responses and IL-1β release. Moreover, in a rat model of neuropathic pain, the intrathecal administration of cilnidipine produced a reversal of nerve injury-induced mechanical hypersensitivity, a cardinal symptom of neuropathic pain. These results point to a new inhibitory effect of cilnidipine on microglial P2X7R-mediated inflammatory responses and neuropathic pain, proposing its therapeutic potential.
Highlights
Neuropathic pain is a chronic pain condition caused by nerve injury or diseases such as diabetes, cancer, fibromyalgia, chemotherapy, infection, and autoimmune diseases
To assess the effect of compounds on responses mediated by rat P2X7 receptors (P2X7Rs), we established a cell line, 1321N1 cells, that stably expressed rat P2X7R and measured intracellular Ca2+ increases induced by the P2X7R agonist BzATP using a highthroughput Ca2+ imaging apparatus
BzATP was confirmed in rP2X7R-1321N1 cells [30], but not in native 1321N1 cells
Summary
Neuropathic pain is a chronic pain condition caused by nerve injury or diseases such as diabetes, cancer, fibromyalgia, chemotherapy, infection, and autoimmune diseases. Neuropathic pain significantly impairs quality of life and is often resistant to known treatments, including opioids [1]. An increasing body of literature indicates that neuropathic pain is associated with the inflammatory milieu of the central nervous system (CNS) after nerve injury. Activated microglia are observed in the spinal cord and brain in diverse models of neuropathic pain, including peripheral nerve injury (PNI) [2,3,4], and are known to release various inflammatory mediators including proinflammatory cytokines, critically contributing to the development of neuroinflammatory milieu in the CNS, alongside behavioral pain hypersensitivity [5,6].
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
