MCP-1 Enhances Excitability of Nociceptive Neurons in Chronically Compressed Dorsal Root Ganglia

1 Department of Anesthesiology, 2 Department of Pharmacology, and 3 Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut Submitted 1 March 2006; accepted in final form 6 June 2006 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, although 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 ms. 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 (EC 50 = 45 nM). The MCP-1–induced current was not voltage dependent and had an estimated reversal potential of –27 mV. In addition, MCP-1 inhibited a voltage-dependent, noninactivating 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 nonvoltage-dependent depolarizing current with characteristics similar to a nonselective cation conductance and 2 ) inhibition of a voltage-dependent outward current. Address for reprint requests and other correspondence: R. H. LaMotte, Department of Anesthesiology, Yale University School of Medicine, New Haven, CT 06510 (E-mail: robert.lamotte{at}yale.edu )