Offset analgesia: a temporal contrast mechanism for nociceptive information

Abstract

Temporal filtering of afferent information is an intrinsic component of the processing of numerous types of sensory information. To date, no temporal filtering mechanism has been identified for nociceptive information. The phenomenon of offset analgesia, the disproportionately large decrease in perceived pain following slight decreases in noxious thermal intensity, however, suggests the existence of such a mechanism. To test the hypothesis that a temporal filtering mechanism is engaged during noxious stimulus offset, subjects rated heat pain intensity while stimulus fall rates were varied from -0.5 to -5.0 degrees C/s. In the absence of a temporal filtering mechanism, pain intensity would be expected to decrease in direct proportion to the stimulus fall rate. However, psychophysical fall rates were considerably faster than stimulus fall rates, such that subjects reported no pain while stimulus temperatures were clearly within the noxious range (47.2 degrees C). In addition, paired noxious stimuli were presented simultaneously to determine if offset analgesia evoked by one stimulus could inhibit pain arising from a separate population of primary afferent neurons. Pain ratings were significantly lower than those reported from two constant 49 degrees C stimuli when offset analgesia was induced proximal to, but not distal to, a second noxious stimulus. These asymmetric spatial interactions are not readily explained by peripheral mechanisms. Taken together, these findings indicate that offset analgesia is mediated in part by central mechanisms and reflect a temporal filtering of the sensory information that enhances the contrast of dynamic decreases in noxious stimulus intensity.

Figure 1. End Points of the One Temperature Paradigm

Typical VAS ratings of pain (thick, solid line) are superimposed on stimulus temperature (thin, solid line). The VAS fall slope (dotted line) was derived from the VAS ratings alone, while the VAS latency and the temperature at VAS zero (dot-dash line) were calculated using both VAS and stimulus temperature.

Figure 2. Subjects Distinguish Differences in Perceived Pain Intensity using the Continuous VAS

During training sessions, subjects were presented with stimuli between 35°C–49°C. In the left panel, continuous VAS ratings (averaged across all subjects) from 5s stimuli are shown by stimulus temperature. In the right panel, average peak VAS ratings are shown for each stimulus temperature. Note that as stimulus temperature increases, peak VAS ratings increase exponentially (fit line) according to Price’s application of Steven’s power law (Stevens, 1957, 1970; Price et al., 1983, 1994).

Figure 3. Psychophysical Fall Rates are Largely Independent of Temperature Fall Rates

The mean continuous VAS ratings reported from each five second 50°C stimulus (stimulus fall rates varied from −0.5° C/s to −5.0° C/s) are shown together (overlay, A). Psychophysical ratings (thick line, averaged across all subjects) from each stimulus condition are shown in the insets (b–f) with their corresponding stimulus temperature trace (thin line).

Figure 4. Psychophysical Fall Rates For 48°C Stimuli

Psychophysical ratings (averaged across all subjects) for each stimulus fall rate are plotted together for 48°C stimuli. As was the case for 50°C stimuli (Fig. 3), VAS fall rates were largely independent of stimulus fall rates for 48°C stimuli.

Figure 5. Actual Psychophysical Fall Rates (dashed lines) are Significantly More Rapid than Expected Fall Rates (solid lines)

Expected fall rates were modeled using a linear relationship between the stimulus fall rate and perceived intensity fall rate. These expected data were plotted against observed VAS fall rates (averaged across subjects) for both 48°C and 50°C stimuli (a and b, respectively). Note that due to offset analgesia there is very little change in VAS fall rate regardless of stimulus fall rate. Additionally, at the fastest fall rate (−5.0°C/s) actual and expected fall rates begin to converge.

Figure 6. Temperatures at which VAS Ratings Returned to Zero and VAS Fall Latencies

The absolute stimulus intensity (no latency correction) when subjects first reported VAS ratings of zero is shown for 48°C and 50°C (a and b, respectively; means ± SEM). These data are shown with latency correction in c and d (means ± SEM). The latency taken for subjects to first respond to an initial decrease in stimulus intensity is shown for 48°C and 50°C (e and f, respectively; means ± SEM). The dashed line (a–d) denotes approximate pain threshold (a–d). * denotes statistically significant differences (p<0.05).

Figure 7. The Magnitude and Duration of Offset Analgesia

The continuous VAS ratings (averaged across all subjects) from each condition are shown together (overlay, a). In b-d, mean psychophysical ratings (thick lines) of each condition are shown at the bottom of the figure with their corresponding stimulus temperature trace (thin lines).

Figure 8. Interactions of Spatially Remote Stimuli with Offset Analgesia

The minimum VAS ratings during the time period following the change from 50°C (T2) to 49°C (T3) were averaged across all subjects (A, B, D, & E, means ± SEM) for both the three temperature stimulus trains and from time matched locations for constant 49°C stimuli. Percent analgesia was calculated by dividing the minimum VAS from the three temperature stimulus train by the minimum VAS from the constant 49°C for each series within subjects (C & F, means, ± SEM). A–C. Offset analgesia evoked simultaneously at two sites (b) does not summate beyond that evoked at one site (a) since the percent analgesia (c) was not different between conditions. D–F. Offset analgesia evoked by a proximal stimulus inhibits pain evoked by a distal noxious stimulus (d). However, a proximal noxious stimulus abolishes offset analgesia evoked at a distal location (e). Examination of the percent analgesia confirms these spatial interactions are asymmetric (f). Since these complex spatial interactions cannot be readily explained by a peripheral mechanism, offset analgesia must be, in part, mediated by central mechanisms. Abbreviations: 49°C - 49°C 30 second stimulus. 35°C-35°C 30 second stimulus. 3Temp - 49°C for 5 seconds, followed by 50°C for 5 seconds, followed by 49°C for 20 seconds. D and P represent Distal and proximal, respectively. N.S. symbolizes “not significant.”