Windup leads to characteristics of central sensitization

Abstract

Central sensitization refers to enhanced excitability of dorsal horn neurons and is characterized by increased spontaneous activity, enlarged receptive field (RF) areas, and an increase in responses evoked by large and small caliber primary afferent fibers. Sensitization of dorsal horn neurons often occurs following tissue injury and inflammation and is believed to contribute to hyperalgesia. Windup refers to the progressive increase in the magnitude of C-fiber evoked responses of dorsal horn neurons produced by repetitive activation of C-fibers. In the present study, we tested the hypothesis that windup leads to central sensitization. Recordings were made from rat nociceptive dorsal horn neurons classed as wide dynamic range. Windup was produced by conditioning stimuli in a train of 12 electrical pulses (0.5 ms duration) applied to the RF at intensities three times the threshold for excitation of C-fibers and at a frequency of 0.5 Hz. Single electrical stimuli applied outside the RF never evoked responses except when delivered following conditioning stimulation inside the RF, indicating an expansion of the RF following windup. C-Fiber conditioning stimuli applied outside the RF also increased the response evoked by a single stimulus and increased the total number of spikes evoked by a train of electrical stimuli delivered inside the RF. Although both A- and C-fibers were activated, conditioning stimuli did not alter subsequent responses evoked by stimulation of A-fibers. Enhanced responsivity to C-fiber input following windup produced by stimulation inside the RF at a frequency of 0.5 Hz could be maintained for approximately 100 s by stimuli delivered at 0.1 Hz, a frequency that itself cannot produce windup. It is concluded that neuronal events leading to windup also produce some of the classical characteristics of central sensitization including expansion of RFs and enhanced responses to C- but not A-fiber stimulation. Thus, windup may be a useful tool to study mechanisms underlying certain characteristics of central sensitization related to C-fiber activity.