The Role Of Monocyte Chemoattractant Protein-1(MCP-1) In Inducing And Maintaining Of Inflammatory Pain

The therapy of inflammatory pain induced by tissue injury poses a challenge in clinic. The mechanisms underlying inflammatory pain are very important to develop effective therapies. Many mechanisms have been found in inducing and maintaining of inflammatory pain. In this study, we find monocyte chemoattractant protein-1 (MCP-1) and its receptor CCR2 are involved in increasing the excitability of DRG nociceptive neurons of complete Freund's adjuvant (CFA)-induced inflammatory rats. Besides the peripheral nociceptive receptors, MCP-1 might modulate the transmission of pain signals in the dorsal horn of the spinal cord, which might contribute to the maintaining of inflammatory pain. In conclusion, we investigated the roles of MCP-1/CCR2 signaling in the peripheral sensitization of DRG nociceptive neurons in CFA-induced inflammatory rats and in the modulation of central sensitization in substantia gelatinosa (laminaâ…¡) neurons of the spinal cord in normal rats. The results prove a new target for inflammatory pain therapy. The following are the main findings:1. MCP-1 faciliates pain behavior of the inflammatory rats(1). Behavioral study showed that MCP-1 could enhance spontaneous pain behavior and facilitate mechanical pain behavior in CFA-induced inflammatory rats. The lifting time of hind paw lasted longer after a subcutaneous injection of MCP-1.MCP-1 injection also reduced the mechanical pain threshold.2. The expression of MCP-1 and CCR2 are increased in the DRG of CFA-induced inflammatory rats(1).Real-time PCR results showed that expression of MCP-1 mRNA were up-regulated in DRG of CFA-induced inflammatory rats.(2). Western blot results showed that CCR2 proteins were also up-regulated in DRGs of CFA-induced inflammatory rats.3. MCP-1 enhances the excitability of DRG nociceptive neurons. (1). Whole cell patch clamp recordings showed that MCP-1 enhanced the excitability of DRG nociceptive neurons in CFA-induced inflammatory rats, which manifested as inducing the depolarization and spontaneous discharge, and increasing the number of action potentials induced by current threshold stimulation. Furthermore, MCP-1 could enhance the amplitude and shift leftward the activation curve of TTX-sensitive sodium current, but it had no effect on TTX-resistant sodium current and potassium current.4. MCP-1 modulates the synaptic transmission of nociceptive information in the dorsal horn of spinal cord in normal rats.(1). Behavioral study showed that intrathecal injection of MCP-1 could induce pain behavior in normal rats.(2). Whole cell patch clamp recordings in spinal cord slice showed that MCP-1 could enhance the frequency and amplitude of spontaneous excitatory postsynaptic currents (sEPSCs), and decrease the frequency and amplitude of spontaneous inhibitory postsynaptic currents (sIPSCs) of the SG neurons. Further research indicated that MCP-1 increased AMPA,NMDA currents and decreased GABA currents.In conclusion, we investigated the roles of MCP-1/CCR2 signaling in the regulation of peripheral nociceptive receptors in inflammatory rats and the transmission of pain signals in spinal cord in normal rats. The results indicated that MCP-1/CCR2 signaling played an important role in the inducing and maintaining of inflammatory pain by enhancing the excitability of peripheral DRG nociceptive neurons, facilitating the excitatory synaptic transmission and decreasing the inhibitory synaptic transmission of the SG neurons.