The effects of ketamine on the temporal summation (wind-up) of the R(III) nociceptive flexion reflex and pain in humans

Abstract

Animal studies have suggested that the temporal summation of nociceptive inputs might play a significant role in the development of central sensitization (i.e., hyperexcitability of central nociceptive neurons) and hyperalgesia via the activation of N-methyl-D-aspartate receptors. To further analyze these processes in humans, we evaluated the effects of small systemic doses of ketamine on the temporal summation (i.e., wind-up) of both the nociceptive flexion (R(III)) reflex and sensations of pain in six healthy volunteers. The R(III) reflex was recorded from the biceps femoris and was elicited by electrical stimulation of the sural nerve. First, the recruitment (stimulus/response) curve for the reflex was built using stimuli up to the pain tolerance threshold (applied once every 6 s). A series of 15 stimuli was then applied once a second at an intensity of 1.2 times the reflex threshold. These procedures were performed both before and after the randomized IV injection of either 0.15 mg/kg ketamine or a placebo. The R(III) reflex threshold and its recruitment curve were not significantly altered after the injection of ketamine or placebo. By contrast, the significant increases (i.e., wind-up) in both the reflex responses and the sensations of pain observed during the higher frequency stimulation were significantly reduced after the administration of ketamine, but not placebo. This method might be useful for quantifying and analyzing the wind-up phenomenon and, thus, for studying the neurophysiological and pharmacological mechanisms underlying hyperalgesia in humans.

Implications: The wind-up phenomenon (i.e., the progressive increase of the responses induced by repetitive nociceptive stimuli) was characterized in humans by using electrophysiological recordings of the nociceptive flexion reflex. We showed that, as in animals, this phenomenon, which might represent an elementary form of the central sensitization involved in various painful syndromes, depends on the activation of N-methyl-D-aspartate receptors, because it was selectively reduced after the administration of ketamine.