The leukotriene B4 receptors BLT1 and BLT2 form an antagonistic sensitizing system in peripheral sensory neurons [Signal Transduction]

Sensitization of the heat-activated ion channel Transient Receptor Potential Vanilloid 1 (TRPV1) through lipids is a fundamental mechanism during inflammation-induced peripheral sensitization. Leukotriene B4 is a proinflammatory lipid-mediator whose role in peripheral nociceptive sensitization is to date not well understood. Two major G-Protein-coupled receptors for Leukotriene B4 have been identified: the high affinity receptor BLT1 and the low affinity receptor BLT2. Transcriptional screening for the expression GProtein-coupled receptors in murine dorsal root ganglia showed that both receptors were among the highest expressed in dorsal root ganglia. Calcium imaging revealed a sensitization of TRPV1-mediated calcium increases in a relative narrow concentration range for Leukotriene B4 (100-200 nM). Selective antagonists and neurons from knockout mice demonstrated a BLT1-dependent sensitization of TRPV1-mediated calcium increases. Accordingly, Leukotriene B4 -induced thermal hyperalgesia was mediated through BLT1 and TRPV1 as shown using the respective knockout mice. Importantly, higher Leukotriene B4 concentrations (>0.5 μM) and BLT2 agonists abolished sensitization of the TRPV1-mediated calcium increases. Also, BLT2-activation inhibited protein kinase C- as well as protein kinase Amediated sensitization processes through the phosphatase calcineurin. Consequently, a selective BLT2-receptor agonist increased thermal and mechanical withdrawal thresholds during zymosan-induced inflammation. In accordance with these data immunohistochemical analysis showed that both Leukotriene B4 receptors were expressed in peripheral sensory neurons. Thus, the data show that the two Leukotriene B4 receptors have opposing roles in the sensitization of peripheral sensory neurons forming a self-restricting system.

from #AlexandrosSfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2l6JbH8
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