PAIN MEDICINE Anesthesiology 2010; 113:1392–1405 Copyright © 2010, the American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins Spinal Cord Stimulation-induced Analgesia Electrical Stimulation of Dorsal Column and Dorsal Roots Attenuates Dorsal Horn Neuronal Excitability in Neuropathic Rats Yun Guan, M.D., Ph.D.,* Paul W. Wacnik, Ph.D.,† Fei Yang, Ph.D.,‡ Alene F. Carteret, M.S.,§ Chih-Yang Chung, M.D.,‡ Richard A. Meyer, M.S., Srinivasa N. Raja, M.D.# ABSTRACT Background: The sites of action and cellular mechanisms by which spinal cord stimulation reduces neuropathic pain re- main unclear. Methods: We examined the effect of bipolar electrical-con- ditioning stimulation (50 Hz, 0.2 ms, 5 min) of the dorsal column and lumbar dorsal roots on the response properties of spinal wide dynamic range (WDR) neurons in rats after L5 spinal nerve injury. The conditioning stimulation intensity was set at the lowest current that evoked a peak antidromic sciatic A/-compound action potential without inducing an A- or C-compound action potential. Results: Within 15 min of the dorsal column or root condi- tioning stimulation, the spontaneous activity rate of WDR neurons was significantly reduced in nerve-injured rats. Con- ditioning stimulation also significantly attenuated WDR neuronal responses to mechanical stimuli in nerve-injured rats and inhibited the C-component of the neuronal response to graded intracutaneous electrical stimuli applied to the re- ceptive field in nerve-injured and sham-operated rats. It is noteworthy that dorsal column stimulation blocked windup of WDR neuronal response to repetitive intracutaneous elec- trical stimulation (0.5 Hz) in nerve-injured and sham-oper- ated rats, whereas dorsal root stimulation inhibited windup only in sham-operated rats. Therefore, stimulation of puta- tive spinal substrates at A-fiber intensities with parameters similar to those used by patients with spinal cord stimulators attenuated established WDR neuronal hyperexcitability in the neuropathic condition and counteracted activity-depen- dent increase in neuronal excitability (i.e., windup). Conclusions: These results suggest a potential cellular mecha- nism underlying spinal cord stimulation–induced pain relief. This in vivo model allows the neurophysiologic basis for spinal cord stimulation–induced analgesia to be studied. S PINAL cord stimulation is an effective neuromodulatory technique for managing a variety of chronic pain condi- tions, particularly neuropathic pain, which is often refractory to current pharmacotherapies. 1–3 Yet, the biologic basis for the effectiveness of spinal cord stimulation in treating neu- ropathic pain is unclear. Differences in lead design, stimula- tion mode, and intensity-selecting criteria also present barri- ers to correlating previous findings in experimental animals with mechanisms underlying therapeutic effects in patients. * Assistant Professor, ‡ Postdoctoral Fellow, § Research Assistant, # Professor, Department of Anesthesiology and Critical Care Medi- cine,  Professor, Department of Neurosurgery, Johns Hopkins Uni- versity, School of Medicine, Baltimore, Maryland. † Senior Scientist, Department of Neuromodulation Research, Medtronic, Inc., Minne- apolis, Minnesota. Received from the Division of Pain Medicine, Department of Anesthesiology and Critical Care Medicine, Johns Hopkins Univer- sity, Baltimore, Maryland. Submitted for publication April 21, 2010. Accepted for publication July 29, 2010. Supported by Medtronic, Inc. (Minneapolis, Minnesota). Address correspondence to Dr. Guan: Division of Pain Medicine, Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, 720 Rutland Avenue, Ross 351, Baltimore, Maryland 21205. yguan1@jhmi.edu. Information on purchasing re- prints may be found at www.anesthesiology.org or on the masthead page at the beginning of this issue. ANESTHESIOLOGY’s articles are made freely accessible to all readers, for personal use only, 6 months from the cover date of the issue.  This article is accompanied by an Editorial View. Please see: Linderoth B, Meyerson BA: Spinal cord stimulation: Exploration of the physiological basis of a widely used ther- apy. ANESTHESIOLOGY 2010; 113:1265–7.  Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are available in both the HTML and PDF versions of this article. Links to the digital files are provided in the HTML text of this article on the Journal’s Web site (www.anesthesiology.org). What We Already Know about This Topic ❖ Spinal cord stimulation is frequently applied to treat neuro- pathic pain, but its site and mechanisms of action are unclear. What This Article Tells Us That Is New ❖ Bipolar electrical stimulation at the dorsal column or lumbar dorsal roots attenuated dorsal horn neuronal hyperexcit- ability in nerve-injured rats and inhibited short-term neuro- nal sensitization. 1392 Anesthesiology, V 113 • No 6 • December 2010