The Potentiation Of TRPV1 By Chemokine MCP-1 And The Intracellular Signaling Mechanisms

MCP-1 (monocyte chemoattractant protein-1) is one of the CC chemokine subfamily members. The expression of MCP-1 was increased in neurons and glial cells after the nerve injuries,inflammation or other pathological changes. MCP-1 can directly enhance the excitability of neurons.As a new member of the family,MCP-1-1 is considered to be an important new mediator that produces pain.TRPV1 is an thermal non-selective cation channel which mainly expresses in small or medium neurons and unmyelinated C fibers or Aδnerve fibers of the dorsal root ganglia, trigeminal ganglia. The accumulated evidences demonstrate that TRPV1 is a very important pain mediators mediating pain sensitivity.The purpose of this research is to investigate the modulation of TRPV1 by MCP-1 in an animal pain model of the chronically compressed dorsal root ganglia (CCD). The main results are as follows:1 As assessed by Real-time PCR, the mRNA expression of TRPV1 was increased in CCD-injured dorsal root ganglia (DRG). The co-expression of CCR2, the cognate receptor for MCP-1 TRPV1 was found DRG neurons in the DRG tissue slices by immunofluorescence method.2. Spontaneous pain behavior test showed that MCP-1 enhanced capsaicin-induced flinching. The paw lifting time per minute (PLTPM) in CCD rats received a con-injection of MCP-1 with capsaicin is significantly higher than that received a single injection of capsaicin.3. The whole-cell patch-clamp recordings demonstrated the enhancement by MCP-1 of membrane depolarization and inward current amplitude induced by capsaicin in acutely isolated CCD neurons. Also, the free intracellular calcium that entry through the TRPV1 channels from the extracellular fluid was increased by MCP-1 in the acutely isolated CCD neurons as assessed by the ratio Ca²⁺ imaging system.4. The enhanced effects of MCP-1 on TRPV1 in CCD neurons was eliminated by U73122, an inhibitor of PLC. After the pretreatment of CCD neurons with U73122, The intracellular free calcium coming via the TRPV1 channels was not increased by MCP-1.In conclusion, the enhancement by MCP-1 of TRPV1 function in CCD neurons, as revealed by a larger depolarization or inward current induced by capsaicin and a higher level of free intarcellular calcium via TRPV1 channels might contribute to hyperalgesia in CCD rats.