A Translational Study of the Effects of Ketamine and Pregabalin on Temporal Summation of Experimental Pain

Abstract

Central sensitization is often seen in chronic pain. A relevant and potent mechanism of central sensitization is the central integration of nociceptive impulses. Temporal summation in humans and the wind-up process in animals share common features of central integration. This preclinical and clinical translational study investigated the effect of ketamine and pregabalin on temporal summation (TS) and wind-up of wide dynamic range (WDR) neurons of nociceptive electrical stimuli in healthy volunteers and rats. This 3-way crossover study included healthy male volunteers (n = 18) receiving 3 doses of 300 mg pregabalin (orally) over 2 days, ketamine (intravenous loading dose 0.5 mg/kg followed by 9 μg/kg per minute for 20 mins) on the first day, or placebo. The pain detection thresholds to repetitive electrical cutaneous and suprathreshold responses stimulation were assessed.In male Sprague-Dawley rats (n = 30), WDR neuron recordings after electrical stimulation were obtained before and after 15 minutes of intravenous infusion pregabalin (0.127, 0.42, and 1.27 mg/kg per minute) and ketamine (0.006, 0.02, 0.06, and 0.2 mg/kg per minute). In the human study, ketamine compared with placebo significantly increased the TS pain detection threshold (P < 0.001) and significantly reduced suprathreshold pain responses (P < 0.001). In rats, the highest dose of ketamine significantly inhibited the wind-up response of the WDR neurons (P = 0.014). Pregabalin affected neither of the parameters in TS and WDR responses. It was shown that TS shares common features with wind-up of WDR neurons and that pregabalin does not affect this component of central sensitization.