Behavioral assessment of temporal summation in the rat: sensitivity to sex, opioids and modulation by NMDA receptor antagonists

Abstract

Temporal summation of pain reflects a perceived increase in nociceptive sensitivity following repeated noxious stimulation that can last for approximately 15 s-2 min. This short-lasting change in nociceptive sensitivity has been used as a model to examine factors that influence the central processing of pain and the mechanisms underlying some chronic pain conditions. The purpose of this study was to develop a behavioral procedure to induce temporal summation in rats and determine the sensitivity of temporal summation (i.e., decrease tail-withdrawal latency following repeated presentations of a nociceptive thermal stimulus) to various parametric manipulations, sex, modulation by the N-methyl-D-aspartate (NMDA) receptor system, and sensitivity to reversal by opioids. The magnitude of temporal summation generally decreased with increases in the inter-nociceptive stimulus interval, and increased with increases in both the nociceptive stimulus intensity and the number of nociceptive stimulus presentations. Temporal summation was short-lived, evident 3.0 s after the final nociceptive stimulus presentation, but not after 30 s. Males displayed slightly higher levels of temporal summation than females. The non-competitive NMDA antagonists ketamine (3.0-30 mg/kg), dizocilpine (0.03-0.1 mg/kg) and dextromethorphan (10-30 mg/kg) attenuated the level of temporal summation at doses that failed to produce antinociceptive effects (warm water tail-withdrawal procedure). In an antinociception procedure, the opioids morphine (3.0-10 mg/kg), buprenorphine (0.3-3.0 mg/kg), butorphanol (3.0-30 mg/kg) and spiradoline (10-30 mg/kg) were more potent in males, whereas these opioids were equally potent and effective in reducing the level of temporal summation in males and females. These findings suggest a number of similarities in the characteristics and receptor modulation of temporal summation in humans and rats, and that in this model of chronic pain there are no sex differences in opioid potency.