This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in Web of Science Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Dutton, R. C. Articles by Carstens, E. Search for Related Content PubMed Articles by Dutton, R. C. Articles by Carstens, E. Related Collections Mechanisms Pain Mechanisms Preclinical Pharmacology Pharmacology

---

ANESTHETIC PHARMACOLOGY

Temporal and Spatial Determinants of Sacral Dorsal Horn Neuronal Windup in Relation to Isoflurane-Induced Immobility

Robert C. Dutton, MD^*, Jason M. Cuellar, PhD, Edmond I. Eger, II, MD^*, Joseph F. Antognini, MD, and Earl Carstens, PhD

From the *Department of Anesthesia and Perioperative Care, University of California, San Francisco; Department of Anesthesia, Stanford University School of Medicine; Department of Anesthesiology and Pain Medicine; and Section of Neurobiology, Physiology and Behavior, University of California, Davis, California.

Address correspondence and reprint requests to E. Carstens, Section of Neurobiology, Physiology and Behavior, University of California, Davis, 1 Shields Ave., Davis, CA 95616. Address e-mail to eecarstens{at}ucdavis.edu.

BACKGROUND: Windup is a progressive increase in response of dorsal horn neurons to repetitive C-fiber stimulation that may underlie temporal summation of pain. We investigated the frequency- and intensity-dependency of windup, and the effects of isoflurane and N-methyl-d-aspartate (NMDA) receptor blockade, to determine if they parallel the influence of temporal and spatial summation of noxious stimuli on anesthetic requirements.

METHODS: We recorded responses of rat sacral dorsal horn neurons to 20-s trains of electrical tail stimulation at different frequencies (0.3–10 Hz) and intensities (0.8–5 x stimulus threshold) during delivery of 0.7 to 1.3 minimum alveolar anesthetic concentration isoflurane. Summed responses (area under the curve [AUC] windup), initial response, absolute windup (AUC minus 20 times the initial response), and slope of windup were quantified.

RESULTS: Increases in stimulus intensity and frequency progressively increased AUC windup (P < 0.01 for both) and correlated with isoflurane concentrations required for immobility (R² = 0.98 and 0.97, respectively). Increasing the isoflurane concentration significantly suppressed each measure of windup elicited by low-intensity and low-frequency, but not high-intensity and high-frequency stimulus trains. The initial response magnitude significantly correlated with slope of windup across stimulus intensities and isoflurane concentrations. The NMDA receptor antagonist MK801 significantly reduced windup (to 53%; P < 0.05) at 1 Hz.

CONCLUSION: Windup of dorsal horn neurons at low stimulus intensities and frequencies increases isoflurane requirements for immobility via a NMDA receptor-dependent mechanism. At high stimulus intensities and frequencies, windup was resistant to isoflurane consistent with larger anesthetic requirements for immobility.