Constitutive cyclooxygenase-2 is involved in central nociceptive processes in humans

Abstract

Background: Prostaglandins play a major role in inflammation and pain. They are synthesized by the two cyclooxygenase (COX) isoforms: COX-1, which is expressed constitutively in many cell types, and COX-2, which is induced at the site of inflammation. However, unlike peripheral tissues, COX-2 is expressed constitutively in the central nervous system and may play a role in nociceptive processes. The current study aimed to investigate the role of constitutive COX-2 in the spinal transmission of nociceptive signals in humans.

Methods: The authors used 12 healthy volunteers to compare the effects of the specific COX-2 inhibitor sodium parecoxib (1 mg/kg) or placebo, administered intravenously in a double-blind and crossover fashion, on the electrophysiologic recordings of the nociceptive flexion (RIII) reflex. The RIII reflex is an objective psychophysiologic index of the spinal transmission of nociceptive signals and was recorded from the biceps femoris after electrical stimulation of the sural nerve. Two experiments, 7 days apart, were conducted in each volunteer. On each experimental day, the effects of parecoxib or placebo were tested on (1) the RIII reflex threshold, (2) the stimulus-response curves of the reflex up to the tolerance threshold (frequency of stimulation: 0.1 Hz), and (3) the progressive increase of the reflex and pain sensations (i.e., "windup" phenomenon) induced by a series of 15 stimulations at a frequency of 1 Hz (intensity 20% above RIII threshold).

Results: Parecoxib, but not placebo, significantly reduced the slope of the stimulus-response curve, suggesting a reduction in the gain of the spinal transmission of nociceptive signals. By contrast, the windup phenomenon was not significantly altered after administration of parecoxib or placebo.

Conclusions: This study shows that constitutive COX-2 modulates spinal nociceptive processes and that the antiinflammatory and antinociceptive actions of COX-2 inhibitors are not necessarily related.

Figure 1

A) Experimental set-up for recording the RIII reflex. The sural nerve (sn) was stimulated behind the lateral malleolus, using a pair of surface electrodes. The electrical responses were recorded (rec) from the ipsilateral biceps femoris muscle (bi) using a pair of surface electrodes. An example of an RIII reflex response, and the corresponding full-wave rectified signal, are shown in the upper part of the figure. B) individual example of RIII reflex responses with increasing intensity of stimulation of the sural nerve at 0.1 Hz.

Figure 2

Comparisons of the area under the recruitment curves (AUC) from the control baseline period (CONT), and 20, 40, 60 and 80 minutes after the administration of (A) parecoxib (black columns), or (B) placebo (hatched columns). A significant reduction in the recruitment curve was observed from 20 to 60 minutes after the administration of parecoxib but not with the placebo. Data are means ± SEMs. * = P<0.05, **= P<0.01.

Figure 3

Effects of administration of placebo or parecoxib on the shape of the recruitment curves for the RIII reflex at baseline (A), and 20 (B), 40 (C) 60 (D) and 80 (E) minutes after the administration of placebo or parecoxib. Reflex responses are expressed as a percentage of the maximum response obtained when building the control curve. A progressive reduction of the slope of the recruitment curve was observed from 20 minutes after the administration of parecoxib.

Figure 4

Effects of placebo and parecoxib on the wind-up of the RIII reflex. Each reflex response was expressed as a percentage of the first response in the series.