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1 Anesthetiology, Yale University School of Medicine, New Haven, Connecticut, United States
2 Pharmacology, Yale University School of Medicine, New Haven, Connecticut, United States
3 Pediatrics, Yale University Sch Med, New Haven, Connecticut, United States
4 Anesthesiology, Yale School of Medicine, New Haven, Connecticut, United States
* To whom correspondence should be addressed. E-mail: robert.lamotte{at}yale.edu.
Previous experimental results from our laboratory demonstrated that monocyte chemoattractant protein-1 (MCP-1) depolarizes or increases the excitability of nociceptive neurons in the intact dorsal root ganglion (DRG) after a chronic compression of the DRG (CCD) -- an injury that upregulates neuronal expression of both MCP-1 and mRNA for its receptor, CCR2. We presently explore the ionic mechanisms underlying the excitatory effects of MCP-1. MCP-1 (100 nM) was applied, after CCD, to acutely dissociated small DRG neurons with nociceptive properties. Under current clamp, the proportion of neurons depolarized was similar to that previously observed for CCD-treated neurons in the intact ganglion though the magnitude of depolarization was greater. MCP-1 induced a decrease in rheobase by 44±10% and some cells became spontaneously active at resting potential. Action potential width at a voltage equal to 10% of the peak height was increased from 4.94 ±0.23 to 5.90 ±0.47 msec. In voltage clamp, MCP-1 induced an inward current in 27 of 50 neurons held at -60 mV which increased with concentration over the range of 3 to 300 nM (EC50 = 45nM). The MCP-1 induced current was not voltage dependent and had an estimated reversal potential of -27mV. In addition, MCP-1 inhibited a voltage-dependent, non-inactivating outward current, presumably a delayed rectifier type K+ conductance. We conclude that MCP-1 enhances excitability in CCD neurons by, at least, two mechanisms: 1) activation of a non-voltage-dependent depolarizing current with characteristics similar to a non-selective cation conductance and 2) inhibition of a voltage-dependent outward current.
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