Skip to main content
NCBI home page
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2013 Feb 1.
Published in final edited form as: Pain. 2011 Dec 6;153(2):463–472. doi: 10.1016/j.pain.2011.11.010

Differential Effects of Experimental Central Sensitization on the Time-course and Magnitude of Offset Analgesia

Katherine T Martucci 1, Marc D Yelle 1, Robert C Coghill 1
PMCID: PMC3264887  NIHMSID: NIHMS338334  PMID: 22154333

Summary

Despite observations of thermal hyperalgesia, mechanical allodynia and temporal alterations of offset analgesia, the magnitude of offset analgesia remains unaltered following capsaicin-heat and heat-only sensitization.

Pain perception is temporally altered during states of chronic pain and acute central sensitization, however, the mechanisms contributing to temporal processing of nociceptive information remain poorly understood. Offset analgesia is a phenomenon that reflects the presence of temporal contrast mechanisms for nociceptive information and can provide an end point to study temporal aspects of pain processing. In order to investigate whether offset analgesia is disrupted during sensitized states, 23 healthy volunteers provided real-time continuous visual analog scale (VAS) responses to noxious heat stimuli that evoke offset analgesia. Responses to these stimuli were evaluated during capsaicin-heat sensitization (45°C stimulus, capsaicin cream 0.1%) and heat-only sensitization (40°C stimulus, placebo cream). Capsaicin-heat sensitization produced significantly larger regions of secondary mechanical allodynia compared to heat-only sensitization. Although areas of mechanical allodynia were positively related to individual differences in heat pain sensitivity, this relationship was altered at later time points after capsaicin-heat sensitization. Heat hyperalgesia was observed in the secondary region following both capsaicin-heat and heat-only sensitization. Increased latencies to maximal offset analgesia and prolonged aftersensations were observed only in the primary regions directly treated by capsaicin-heat or heat alone. However, contrary to the hypothesis that offset analgesia would be reduced following capsaicin-heat sensitization, the magnitude of offset analgesia remained remarkably intact after both capsaicin-heat and heat-only sensitization in zones of both primary and secondary mechanical allodynia. These data indicate that offset analgesia is a robust phenomenon and engages mechanisms which interact minimally with those supporting acute central sensitization.

Keywords: offset analgesia, temporal sharpening, aftersensations, capsaicin-heat sensitization, thermal hyperalgesia, mechanical allodynia

1. Introduction

Chronic neuropathic pain involves symptoms of both mechanical allodynia and thermal hyperalgesia [38, 54, 17]. Moreover, pain perception is temporally altered in neuropathic pain [38, 10, 48, 12, 46]. Patients often report sensations of pain that long outlast the duration of applied mechanical or thermal stimuli [32, 24, 12], and exhibit altered temporal summation of pain [48, 12].

Although altered temporal summation of pain and aftersensations have been documented in pathological conditions and during acute central sensitization, temporal aspects of pain processing remain poorly characterized. Offset analgesia may provide a set of novel end points to assess pathophysiological temporal changes since it has been proposed to function as a temporal sharpening mechanism [14, 57]. This phenomenon occurs during dynamic noxious stimuli when a small incremental decrease in noxious stimulus intensity evokes a disproportionately large decrease in perceived pain ratings. The mechanisms supporting offset analgesia remain incompletely understood. Functional imaging studies indicate that offset analgesia activates the periaqueductal gray and other brain regions involved in the descending control of pain [6, 56]. However, offset analgesia may be initiated by dynamic responses of primary afferents, and could also involve spinal inhibitory processes that function to enhance the perception of decreased temperature.

Temporal alterations in pain are observed also in experimentally induced states of central sensitization involving application of capsaicin [51, 12]. The mechanisms of central sensitization are complex and include neurotransmitter induced increases in excitability of second order neurons, enlargement of spinal receptive fields, enhanced connectivity between peripheral nociceptors and central neurons, and depression of spinal inhibition [52, 55]. Central sensitization by capsaicin is diminished by administration of ketamine indicating involvement of N-methyl D-aspartate receptor (NMDA) mechanisms [33]. Additionally, capsaicin sensitization produces enhanced activation of brain regions involved in pain processing indicating a supraspinal component of central sensitization [16, 28, 27, 59, 29].

To test the hypothesis that offset analgesia would be disrupted during a state of experimentally induced central sensitization, continuous visual analog scale (VAS) responses from healthy volunteers were analyzed after inducing capsaicin-heat sensitization on the forearm. This is a well established model of experimental sensitization that involves the application of capsaicin cream and noxious heat stimuli to a small area of skin [36]. Following capsaicin-heat sensitization, the production of mechanical hyperalgesia outside of the directly treated region is indicative of central sensitization [53, 22]. Heat-only sensitization was also induced by application of a 40°C stimulus (5 minutes) and placebo cream during a separate session. Offset analgesia was induced by administration of a dynamic heat stimulus in which stimulus temperature decreased from 50°C to 49°C and was assessed both before and after induction of sensitization.

2. Methods

2.1. Subjects

The Institutional Review Board (IRB) at Wake Forest University School of Medicine approved all procedures used in this experiment. Written informed consent was obtained from all subjects, and all participants were free to withdraw from the study or painful stimulation at any time. All 25 subjects recruited for the study were healthy volunteers with no history of chronic pain or any neurological disorder. Two female subjects withdrew from the study since they could not tolerate the heat stimuli. Data from 23 healthy, pain-free subjects (14 females, 9 males, 26.3 ± 0.7 years, Mean ± SEM) were analyzed and are reported. The racial distribution consisted of 16 white, 2 black, 2 Asian, and 3 Hispanic. Subjects were asked to refrain from taking analgesics within 48 hours of the study sessions.

2.2. Capsaicin-Heat Sensitization

Each subject participated in two study sessions separated by a minimum of two days. One of the sessions served as the experimental session, when capsaicin cream was applied (capsaicin-heat sensitization) and the other day served as the blinded control using a placebo cream (heat-only sensitization). The order of the sessions was randomized across subjects. On the first day of the study, subjects were first introduced to the thermal stimuli with a training session of 32 heat stimuli (5 s duration, 35-49°C). Pre-sensitization testing was then administered with blocks of noxious heat stimuli (see below). Next capsaicin-heat sensitization was induced on a 30 × 30 mm2 area, designated as the primary region, in the center of the forearm using the methods adapted from Petersen and Rowbotham, 1999 [36]. A 45°C stimulus was applied for 5 minutes to preheat the skin (using a 30 × 30 mm2 probe, Medoc TSA II) and the region of pre-heating was outlined using a washable felt tip marker. Then capsaicin cream (Capsaicin 0.1%, CAPZASIN-HP, Chattem, Inc., USA) was applied to the same region, taking care to stay within the marked borders, and a transparent dressing (Tegaderm, Nexcare First Aid, 3M Consumer Health Care, USA) was carefully placed over the cream ensuring that none of the cream spread outside of the region. After 30 minutes, the capsaicin cream was removed and post-sensitization testing was administered using the same thermal stimulus paradigms (see below). A 40°C stimulus (5 minutes) was applied to the primary region 40 minutes after removal of the cream to ‘rekindle’ the sensitization and allow for additional blocks of sensory testing. The procedures for heat-only sensitization were identical to capsaicin-heat sensitization except for the use of a placebo cream (fragrance-free body moisturizer, Neutrogena Corp., USA) and a 40°C preheating stimulus instead of 45°C. Study days were randomized for capsaicin-heat or heat-only sensitization.

2.3. Mechanical Allodynia and Definition of Stimulus Regions

Areas of mechanical allodynia were assessed using a von Frey filament (2.0 g) at two time-points: after removal of the cream and after the rekindling stimulus (post-cream and post-rekindle respectively). Subjects were asked to report when the von Frey filament touching their skin felt “sharp or painful” compared to when the filament was applied to their skin before starting the experiment. The experimenter applied the von Frey filament in a radial fashion starting from the outermost region of the arm and advancing in linearly towards the center of the 1° region until subjects responded positively to the stimuli. Approximately 12 linear tracks were used for mapping of mechanical sensitivity, however, the number of stimuli varied according to subjects' sensitivities so that in some cases additional stimuli were applied until the region of secondary mechanical allodynia was clearly outlined. Positive responses were subsequently marked on the skin with a washable felt tip marker. At the end of each experimental session, the 30 × 30 mm2 region where heat and cream were applied and marked points of mechanical allodynia were traced onto a plastic transparent sheet. The transparencies were scanned to produce a digital image, and a custom-made program was used to calculate the areas of mechanical allodynia. Using this program the perimeter of allodynia was first defined by connecting the marks at the outermost edges of the allodynic zone. The area within this perimeter was then calculated. The primary region was defined as the 30 × 30 mm2 location on the arm where the preheating stimulus and cream were applied. The secondary region was defined as the area surrounding the primary region where subjects responded positively to von Frey stimuli (Fig. 2A).

Fig. 2. Primary and Secondary Regions of Mechanical Allodynia.

Fig. 2

Open in a new tab

A. Diagram of primary and secondary regions. The primary region (30 × 30 mm2 area, shaded square, 1°) where heat (45°C or 40°C heat-only, 5 minutes) and capsaicin or placebo cream (30 minutes) were applied. Rekindling heat stimuli (40°C for 5 minutes) were applied 40 minutes later. The region surrounding the primary region, where subjects perceived a 2.0 g von Frey filament as painful, was defined as the secondary region (2°) of sensitization. B. Areas of secondary mechanical allodynia to a 2.0 g von Frey filament mapped after removal of capsaicin / placebo cream (post-cream) and after application of the rekindling stimulus (post-rekindle), (Mean ± SEM). Significantly larger areas of secondary mechanical allodynia occurred at both testing time points after capsaicin-heat sensitization compared to heat-only sensitization (ANOVA, treatment effects, p = 0.0093). Areas of allodynia significantly increased between post-cream and post-rekindle time points after both capsaicin-heat and heat-only sensitization (ANOVA, time effects, p = 0.0003). VAS, Visual Analog Scale.

2.4. Areas of Mechanical Allodynia and Individual Differences in Thermal Sensitivity

Subjects' individual sensitivities (mean sensitivity to 49°C) were obtained during the initial training session. Since individual differences in sensitivity may contribute to the extent of central sensitization, mean VAS ratings to 49°C stimuli (5 s) were compared to areas of mechanical allodynia measured at post-cream and post-rekindle time points.

2.5. Thermal Stimulation and Pain Assessment

A 16 × 16 mm2 Peltier device (Medoc TSA II, Ramat Yishai, Israel) was attached to the ventral surface of the non-dominant forearm of the subject by a Velcro strap. The thermal probe was maintained at a baseline of 35°C (skin temperature).

Subjects were asked to give real-time ratings of their perceived pain intensity during all applied stimuli using a computerized visual analog scale (VAS, 0-10) (15 cm in length, verbal anchors of “no pain sensation” and “most pain sensation imaginable”) [39, 40, 37, 18]. Subjects were specifically instructed to rate only pain intensity, not temperature, on the VAS. Stimulus temperature and real-time VAS ratings were digitally recorded (100 Hz sample frequency) and analyzed using custom-made programs (PowerLab Data Acquisition System, ADInstruments; IDL). For all stimulus conditions, stimuli were separated by a minimum 30 s interstimulus interval and the thermal probe was moved after each stimulus to a distinct area of skin to reduce sensitization and/or habituation. Pain sensitivity does not vary with location on the ventral forearm [41], thus, psychophysical responses were minimally influenced by the application of stimuli to different sites along the proximal-distal axis of the forearm.

2.6. Noxious Thermal Stimulus Paradigms

Long duration thermal stimuli were used to assess altered thermal sensitivity, aftersensations and the magnitude and time-course of offset analgesia [14, 57]. The dynamic stimulus consisted of a three-temperature stimulus train (T1: 49°C [4-7 s], T2: 50°C [4-6 s], T3: 49°C [30 s]) (Fig. 1). The 1°C temperature decrease (−6°C / s) between the second temperature (T2) and the third temperature (T3) initiates offset analgesia. A constant temperature stimulus consisted of 49°C for 40 s duration. An additional three-temperature stimulus (T1: 49°C [6-8 s], T2: 50°C [5-9 s], T3: 35°C [30 s]) served as a dynamic control for expectation effects. Stimuli were presented in blocks of three, with each stimulus type (49-50-49°C, constant 49°C and 49-50-35°C control) presented once per block in pseudo-random order. During stimulation, subjects were asked to rate pain intensity in real-time (VAS) for each of the three stimulus types.

Fig. 1. Noxious Thermal Stimuli Paradigm End Points.

Fig. 1

Open in a new tab

A. Constant temperature stimulus (49°C, 40 s) end points: Peak VAS - the maximum VAS rating, and VAS End Latency - time from the end of the stimulus to the end of the VAS rating. B. Dynamic three-temperature stimulus (T1: 49°C [4-7 s], T2: 50°C [4-6 s], T3: 49°C [30 s]) end points: MaxT2 - the maximum VAS rating during the T2 time window of the 49-50-49°C stimulus, Min Offset - the minimum VAS rating following the T2-T3 decrease, Min Offset Latency - time from the T2-T3 shift to Min Offset, VAS End Latency 49-50-49°C - time from the end of the T3 stimulus to the end of the VAS rating. C. Control stimulus (T1: 49°C [6-8 s], T2: 50°C [5-9 s], T3: 35°C [30 s]) end points: MaxT2-35 - same as for 49-50-49°C stimulus, and Min 35 Latency - time from the end of the T2 stimulus to the end of the VAS rating. Since T1 and T2 durations were varied, 49-50-49°C and 49-50-35°C stimuli are temporally aligned to the start of the T2-T3 temperature decrease. VAS, Visual Analog Scale.

Pre-sensitization, three blocks of stimuli were administered to the forearm (9 stimuli total). Post-sensitization, five blocks of the three-temperature stimuli were administered, two blocks in the primary region and three blocks in the secondary region (15 stimuli total), with the last two of these blocks administered post-rekindling. Blocks of stimuli were pseudorandomly alternated between the primary and secondary regions, and the last two blocks post-rekindling included one in the primary and one in the secondary region. Stimuli administered to the secondary region were not presented immediately adjacent to the primary region, but rather, to locations within approximately 1 cm from the inner (edge of primary region) and outer borders of the secondary region. In the secondary region, stimuli of each block were typically presented adjacent to each other (ie. in a row).

The overall maximum VAS ratings from constant 49°C stimuli (Peak VAS) and maximum VAS ratings during the T2 time window of 49-50-49°C stimuli (MaxT2) and 49-50-35°C stimuli (MaxT2-35) were examined for changes in sensitivity to constant and dynamic stimuli, respectively. It was expected that Peak VAS and MaxT2 variables would increase following capsaicin-heat sensitization indicating the presence of heat hyperalgesia.

The magnitude of offset analgesia was calculated from real-time VAS ratings to 49-50-49°C stimuli. The minimum VAS rating within the window of time from the T2-T3 transition until the end of the T3 stimulus was identified as Min Offset. The magnitude of offset analgesia was calculated as a within-stimulus measure by calculating the difference between MaxT2 and Min Offset values. This raw difference, found separately for each dynamic 49-50-49°C stimulus, allowed for a direct assessment of the magnitude of offset analgesia while avoiding the possible confound of between-stimulus variability.

Temporal changes in offset analgesia were evaluated by calculating the latency from the T2-T3 temperature shift to the time point of Min Offset (0.01 s resolution) in the dynamic 49-50-49°C stimulus (Min Offset Latency). For comparison, temporal changes were also assessed in the 49-50-35°C stimuli following the T2-T3 temperature decrease (Min 35 Latency). Aftersensations were assessed initially from real-time VAS ratings to constant 49°C stimuli (40 s) by calculating the latency for VAS ratings to return to zero, signifying the end of the pain felt by the subject (VAS End Latency). Aftersensations were also assessed at the end of 49-50-49°C stimuli (VAS End Latency 49-50-49°C).

2.7. Statistics

Post-stimulus VAS ratings of 49°C stimuli (5 s) obtained during the training session were averaged to provide a sensitivity measure for each subject. Next, a linear regression was used to assess the relationship between area of secondary mechanical allodynia (cm2, post-cream and post-rekindle, capsaicin-heat and heat-only sensitization) and mean sensitivity to 49°C (VAS).

Real-time VAS end points were averaged within-subjects for each condition (heat-only sensitization and capsaicin-heat sensitization), and time / region of thermal stimulation (pre-sensitization, post-sensitization primary, and post-sensitization secondary). These means were analyzed using two-way repeated measures analysis of variance (ANOVA) to find effects for time / region, treatment, and time / region by treatment interaction (p = 0.05). All analyses used JMP Software (JMP Statistical Software, SAS Institute Inc., Cary, NC, USA).

2.7.1. Thermal Hyperalgesia – Order Effects Analysis

Peak VAS values from constant stimuli (49°C, 40 s) applied post-sensitization were analyzed for order effects to ensure that hyperalgesia was not a product of the repetition of test stimuli (N=19 subjects for this analysis since the exact order of stimulus presentation could not be determined for 4 subjects). Since a total of 5 post-sensitization stimuli were presented in both primary (2) and secondary (3) regions in random order, these values were ranked for the order in which they were applied, and a two-way repeated measures analysis of variance (ANOVA) was used to assess effects of time and treatment. Analyses were performed separately for primary and secondary regions.

3. Results

3.1. Areas of Mechanical Allodynia

Mechanical sensitivity was assessed after removal of either capsaicin or placebo cream (post-cream) and at a later time point after application of a 40°C rekindling stimulus in the primary region (post-rekindle). Subjects displayed mechanical allodynia to von Frey stimulation in both primary and secondary regions following capsaicin-heat and heat-only sensitization. Areas of allodynia to mechanical stimuli were significantly larger following capsaicin-heat sensitization compared to heat-only sensitization (ANOVA, treatment effects, p = 0.0093, Fig. 2B). Areas of mechanical allodynia increased over the duration of each session (post-cream vs. post-rekindle) following both capsaicin-heat and heat-only sensitization (ANOVA, time effects, p = 0.0003).

3.2. Capsaicin-Heat Sensitization Alters the Relationship between Areas of Mechanical Allodynia and Heat Pain Sensitivity at the Later Time Point

Following heat-only sensitization areas of mechanical allodynia for both time points (post-cream and post-rekindle) were correlated with subjects' individual heat pain sensitivity (mean sensitivity to 49°C, R2 = 0.3439, p = 0.0105; R2 = 0.2449, p = 0.0368; respectively, Fig. 3). Following capsaicin-heat sensitization, however, the post-cream areas were correlated with individual sensitivity (R2 = 0.2876, p = 0.0218) whereas post-rekindle areas were not (R2 = 0.0088, p = 0.7101).

Fig. 3. Areas of Mechanical Allodynia vs. Individual Differences in Thermal Sensitivity.

Fig. 3

Open in a new tab

Subjects' average VAS ratings to 49°C (5 s) were significantly related to areas of mechanical allodynia at both time points after heat-only sensitization, but only for the early time point after capsaicin-heat sensitization. VAS, Visual Analog Scale.

3.3. Changes in Thermal Sensitivity

3.3.1. Hyperalgesia to Constant Long-Duration Stimuli (Peak VAS)

Peak VAS values, the maximum VAS rating from constant 49°C stimuli, significantly increased in the primary and secondary regions following both capsaicin-heat and heat-only sensitization [ANOVA, time / region effects p = 0.0011 (pre vs. primary p = 0.0009, pre vs. secondary p = 0.0028), treatment effects not significant p = 0.2016, time / region by treatment interaction not significant p = 0.2040 (pre vs. primary interaction p = 0.444, pre vs. secondary interaction p = 0.2165), Fig. 4A, 4B].

Fig. 4. Alterations in Thermal Sensitivity: Peak VAS and MaxT2.

Fig. 4

Open in a new tab

A. PeakVAS values, maximum VAS ratings from the constant stimulus (49°C, 40 s), significantly increased following both capsaicin-heat and heat-only sensitization [heat-only sensitization pre (HP), heat-only sensitization post-primary (H1), heat-only sensitization post-secondary (H2), capsaicin-heat sensitization pre (CHP), capsaicin-heat sensitization post-primary (CH1), capsaicin-heat sensitization post-secondary (CH2); ANOVA, time / region effects p = 0.0011 (pre vs. primary p = 0.0009, pre vs. secondary p = 0.0028), treatment effects not significant p = 0.2016, time / region by treatment interaction not significant p = 0.2040] (Mean ± SEM). B. Real-time continuous VAS data to constant 49°C stimuli (Mean ± SEM). C. MaxT2 values, the maximum VAS rating during the T2 time window of the experimental three-temperature stimulus (49-50-49°C), were not significantly altered following capsaicin-heat and heat-only sensitization. However, the direction of change was opposite after capsaicin-heat sensitization compared to heat-only sensitization as indicated by a significant interaction effect [ANOVA, time / region effects not significant p = 0.3856, treatment effects not significant p = 0.1101, time / region by treatment interaction effects p = 0.0061 (pre vs. primary interaction p = 0.0178, pre vs. secondary interaction p = 0.0026) ] (Mean ± SEM). Significant interaction effects denoted by **. D. Real-time continuous VAS data to 49-50-49°C stimuli (Mean ± SEM). E. MaxT2-35 values, maximum VAS ratings from the T2 time window of control stimuli (49-50-35°C), showed significant effects of treatment with values increasing following the heat-only condition but remaining constant following capsaicin-heat sensitization (ANOVA, time / region effects not significant p = 0.3130, treatment effects p = 0.0298, time / region by treatment interaction effects not significant p = 0.2446). F. Real-time continuous VAS data to 49-50-35°C control stimuli (Mean ± SEM). Since T1 and T2 durations were varied, 49-50-49°C and 49-50-35°C stimuli are temporally aligned to the start of the T2-T3 temperature decrease. VAS, Visual Analog Scale.

Peak VAS values were also used to assess effects of stimulus order on changes in sensitivity over time. This was to ensure that the repetition of long-duration test stimuli was not responsible for heat hyperalgesia. No increases in pain intensity ratings over time were detected. Instead, significant reductions in pain intensity ratings to repeated test stimuli occurred over time in the primary region, but not in the secondary region (Primary Region: effects of time p = 0.0414, effects of treatment p = 0.7749, time by treatment interaction p = 0.0382; Secondary Region: effects of time p = 0.2472, effects of treatment p = 0.0632, time by treatment interaction p = 0.6074) (Fig. 5).

Fig. 5. Order Analysis of Repeated Thermal Stimuli.

Fig. 5

Open in a new tab

A. Peak VAS for the primary region revealed significant habituation to repeated thermal stimulation (effect of time p = 0.0414, effect of treatment not significant p = 0.7749, time by treatment interaction p = 0.0382). B. Peak VAS for the secondary region (3 blocks of stimuli) showed no significant changes in sensitivity due to repeated application of heat stimuli (effect of time not significant p = 0.2472, effect of treatment not significant p = 0.0632, time by treatment interaction not significant p = 0.6074). VAS, Visual Analog Scale. (Mean ± SEM).

3.3.2. Anti-Hyperalgesia to Dynamic Thermal Stimuli (MaxT2)

In contrast to the hyperalgesia observed for constant (49°C) stimuli, alterations in heat sensitivity occurred differently for the dynamic 49-50-49°C stimuli. MaxT2 values were not significantly altered in the primary or secondary region, and there was no significant effect of treatment. A significant time / region by treatment interaction effect was observed, however, and this was due to the opposite directionality of changes following capsaicin-heat sensitization compared to heat-only sensitization [ANOVA, time / region effects not significant p = 0.3856, treatment effects not significant p = 0.1101, time / region by treatment interaction effects p = 0.0061 (pre vs. primary interaction p = 0.0178, pre vs. secondary interaction p = 0.0026), Fig. 4C, 4D]. These findings were confirmed by the results from analyses of MaxT2-35 values for control stimuli (49-50-35°C). No significant alterations were observed across time / region (p = 0.3130), however, a significant effect of treatment was observed with values increasing following the heat-only condition but remaining constant following capsaicin-heat sensitization (p = 0.0298). The time / region by treatment interaction effects were not significant (p = 0.2446) (Fig. 4E, 4F).

3.4. Magnitude of Offset Analgesia

Under baseline conditions, offset analgesia was observed in the averaged realtime VAS ratings to the dynamic 49-50-49°C stimuli. The Magnitude Offset Analgesia was calculated by subtracting Min Offset values from MaxT2 values for each 49-50-49°C stimulus. Magnitude Offset Analgesia values were positive pre-sensitization, before capsaicin-heat or heat-only sensitization was administered, indicating the presence of offset analgesia at baseline (Fig. 6A).

Fig. 6. Magnitude Offset Analgesia and Min Offset.

Fig. 6

Open in a new tab

A. Magnitude Offset Analgesia was calculated within the experimental three-temperature stimuli by the subtraction of MaxT2 - Min Offset variables and was not altered by capsaicin-heat or heat-only sensitization conditions, or time / region of stimulation (ANOVA, time / region effects not significant p = 0.5640, treatment effects not significant p = 0.0860, time / region by treatment interaction effects not significant p = 0.8167) (Mean ± SEM). B. Min Offset values were not significantly altered following capsaicin-heat or heat-only sensitization, but showed a trend for an interaction effect [ANOVA, time / region effects not significant p = 0.4481, treatment effects not significant p = 0.8699, time / region by treatment interaction not significant p = 0.0716 (pre vs. primary p = 0.0874, pre vs. secondary p = 0.0330) ] (Mean ± SEM). VAS, Visual Analog Scale.

Magnitude Offset Analgesia was not significantly altered following capsaicin-heat or heat-only sensitization in either region (ANOVA, time / region effects not significant p = 0.5640, treatment effects not significant p = 0.0860, time / region by treatment interaction effects not significant p = 0.8167, Fig. 6A).

Min Offset values were not significantly altered by capsaicin-heat or heat-only sensitization, but showed a trend for an interaction effect [ANOVA, time / region effects not significant p = 0.4481, treatment effects not significant p = 0.8699, time / region by treatment interaction p = 0.0716 (pre vs. primary interaction p = 0.0874, pre vs. secondary interaction p = 0.0330), Fig. 6B].

3.5. Temporal Alterations

3.5.1. Increased Latency of Offset Analgesia in the Primary Region

Temporal changes in offset analgesia were assessed from real-time VAS data of dynamic 49-50-49°C stimuli. Min Offset Latency, the latency to minimum VAS ratings following the T2-T3 temperature decrease for dynamic 49-50-49°C stimuli, was significantly increased following both capsaicin-heat and heat-only sensitization. However, post-hoc analyses revealed that this increase was significant in the primary, but not in the secondary region [ANOVA time / region effects p = 0.0066 (pre vs. primary p = 0.0006, pre vs. secondary p = 0.4907), treatment effects not significant p = 0.4705, time / region by treatment interaction p = 0.9693, Fig. 7A]. Min 35 Latency, the latency from the end of the stimulus (T2) to the end of the VAS rating for control stimuli (49-50-35°C), was not significantly altered under any condition (ANOVA time / region effects p = 0.6065, treatment effects p = 0.2780, time / region by treatment interaction p = 0.5485) (Fig. 7B).

Fig. 7. Temporal Alterations of Offset Analgesia and Control Stimuli.

Fig. 7

Open in a new tab

A. Min Offset Latency, the latency to minimum VAS ratings following the T2-T3 temperature decrease for experimental three-temperature stimuli (49-50-49°C), increased in the primary region following both capsaicin-heat and heat-only sensitization [ANOVA time / region effects p = 0.0066 (pre vs. primary p = 0.0006, pre vs. secondary p = 0.4907), treatment effects not significant p = 0.4705, time / region by treatment interaction not significant p = 0.9693]. B. Min 35 Latency, for the 49-50-35°C stimuli, was calculated as the time from the end of the T2 (50°C) stimulus to the end of VAS ratings (VAS = 0), and was not significantly altered under any condition (ANOVA time / region effects p = 0.6065, treatment effects p = 0.2780, time / region by treatment interaction p = 0.5485). VAS, Visual Analog Scale. (Mean ± SEM).

3.5.2. Painful Aftersensations in the Primary Region

The presence of aftersensations was assessed from real-time VAS data of constant, dynamic and control stimuli. VAS End Latency, the latency from the end of the stimulus to the end of the VAS rating for constant 49°C stimuli (40 s), was significantly increased following both capsaicin-heat and heat-only sensitization. Post-hoc analyses revealed that these increases were significant in the primary region but not in the secondary region [ANOVA time / region effects p = 0.0038 (pre vs. primary p = 0.0206, pre vs. secondary p = 0.7543), treatment effects p = 0.2716, time / region by treatment interaction p = 0.7110, Fig. 8A]. Additionally, VAS End Latency 49-50-49°C, the latency from the end of the stimulus (T3) to the end of the VAS rating for dynamic stimuli (49-50-49°C), displayed a high degree of variability especially in the primary region following capsaicin-heat sensitization, however, was also not significantly altered (ANOVA time / region effects p = 0.5674, treatment effects p = 0.3211, time / region by treatment interaction p = 0.1443) (Fig. 8B).

Fig. 8. Painful Aftersensations in the Primary Region to Constant but not Dynamic Stimuli.

Fig. 8

Open in a new tab

A. VAS End Latency, the latency to the end of VAS ratings for constant 49°C stimuli, showed a main effect of time / region with significantly increased latency in the primary region after both capsaicin-heat and heat-only sensitization [ANOVA time / region effects p = 0.0038 (pre vs. primary p = 0.0206, pre vs. secondary p = 0.75430), treatment effects p = 0.2716, time / region by treatment interaction p = 0.7110]. B. VAS End Latency 49-50-49°C, was calculated as the latency from the end of the T3 stimulus to the end of VAS ratings, and showed a high degree of variability, however, was not significantly altered (ANOVA time / region effects p = 0.5674, treatment effects p = 0.3211, time / region by treatment interaction p = 0.1443). VAS, Visual Analog Scale. (Mean ± SEM).

4. Discussion

The capsaicin-heat sensitization model produces a centrally sensitized state in healthy humans, and it was therefore hypothesized that offset analgesia would be altered by central changes induced during capsaicin-heat sensitization. Changes in sensitivity to both mechanical and thermal stimuli were observed following both capsaicin-heat and heat-only sensitization, consistent with successful generation of central sensitization. Responses to heat stimuli were temporally altered in the primary region under conditions of capsaicin-heat and heat-only sensitization. However, contrary to the main hypothesis, the magnitude of offset analgesia remained notably unaltered following both capsaicin-heat and heat-only sensitization.

4.1. Mechanical Allodynia

Mechanical hyperalgesia that occurs outside of the directly treated region, or secondary region, is evidence of central sensitization [23, 15, 20]. The present results confirm previous evidence that large, stable regions of mechanical allodynia are produced by capsaicin-heat sensitization [36, 7]. Heat-only sensitization produced smaller regions of mechanical allodynia, which is not surprising since regions of mechanical hyperalgesia remain consistent across conditions of combined topical capsaicin-heat, heat alone, and topical capsaicin alone [7]. The combination of capsaicin-heat produced larger areas of secondary mechanical allodynia compared to heat-only sensitization. Further, areas of mechanical allodynia increased over time following both capsaicin-heat and heat-only sensitization. This may have been due to the application of the rekindling stimulus, repeated application of test stimuli and / or the progression of sensitization, since regions of mechanical allodynia have been shown to expand over time after capsaicin injection [50].

Pain sensitivity varies considerably between individuals [3]. Areas of mechanical allodynia following heat-only sensitization were correlated with individual differences in heat pain sensitivity, with more sensitive subjects exhibiting larger regions of mechanical allodynia. In the capsaicin-heat sensitization session, however, this correlation disappeared post-rekindling due to substantial enlargement of areas of allodynia in the individuals with less heat pain sensitivity. Thus, at the later time point after capsaicin-heat sensitization, observed regions of mechanical allodynia may be more related to the effects of capsaicin (as opposed to heat) than at the earlier time point. Moreover, it is suggested that hyperalgesia to mechanical and thermal stimuli are mediated by distinct mechanisms [45, 52, 49]. The observed correlation of thermal sensitivity and areas of mechanical hypersensitivity is therefore surprising and suggests that these two stimulus modalities may share a common mechanism during acute but not later stages of induced central sensitization.

4.2. Changes in Thermal Sensitivity

Thermal hyperalgesia occurs in the region where capsaicin and heat sensitizing stimuli are directly applied [4, 2, 19], as well as in the region surrounding a burn injury or application of topical capsaicin alone [34, 58]. Although secondary heat hyperalgesia can occur following central sensitization [58], this may be the first report of heat hyperalgesia in the secondary region produced by capsaicin-heat sensitization specifically. In the present study, hyperalgesia to Constant 49°C stimuli (Peak VAS) occurred in primary and secondary regions after capsaicin-heat and heat-only sensitization. Notably, additional analyses indicated that the hyperalgesia was not produced by the repeated application of long-duration heat stimuli. Therefore the changes in sensitivity were due to the sensitization procedures. In contrast, analysis of MaxT2 values (49-50-49°C and 49-50-35°C stimuli) revealed that secondary hyperalgesia to heat occurred following heat-only sensitization but not following capsaicin-heat sensitization. The anti-hyperalgesic effect produced by capsaicin-heat sensitization indicates that analgesia in the primary region reduced sensitivity to thermal stimuli in the secondary region as well. Studies report conflicting observations of altered heat sensitivity outside of the directly treated region following application of capsaicin alone (topical or injection) or heat (burn injury) [15, 42, 52, 1, 34, 9]. This may be due to mixed effects of sensitization as well as fatigue of sensory afferents since paradoxical decreases in activity are also known to occur following application of sensitizing stimuli [31, 11, 35]. The present observations indicate that secondary thermal hyperalgesia may vary due to complex sensitizing / desensitization effects of capsaicin, and that dynamic phases of stimulation may be more susceptible to an anti-hyperalgesic effect of capsaicin than stimuli of constant temperature.

4.3. Offset Analgesia and Capsaicin-Heat Sensitization

The study of temporal processing of nociceptive information has mainly focused on temporal summation of pain and aftersensations [21, 26, 12, 47, 44, 13]. Offset analgesia has been proposed to function as a temporal contrast mechanism that sharpens awareness of decreases in noxious thermal temperature [14], and has been shown to involve central mechanisms [6, 56]. While the specific mechanisms that subserve offset analgesia are unknown, it was hypothesized that experimentally induced central sensitization would diminish offset analgesia by disruption of central inhibitory mechanisms. Contrary to expectations, the magnitude of offset analgesia was not altered following capsaicin-heat sensitization. Further, the present data indicate that sensitization of central neurons sufficient to produce secondary mechanical and thermal hyperalgesia does not abolish offset analgesia. NMDA activity plays a substantial role in central sensitization [33]. Recent evidence shows that offset analgesia is not altered by administration of ketamine [30], a NMDA antagonist. Thus the present findings of the preservation of offset analgesia during acute central sensitization caused by capsaicin are consistent with the observation that the mechanisms supporting offset analgesia are NMDA independent.

Capsaicin sensitization produces a set of complex sensory changes beyond mechanical allodynia. Analgesic effects can be produced by desensitization of C-fibers [31]. The lack of thermal hyperalgesia to the dynamic stimuli following capsaicin-heat sensitization indicates that some desensitization may have occurred, and this may have potentially masked a minor portion of alterations in offset analgesia. However, offset analgesia may be altered under another form of central sensitization that does not involve the mechanisms that support capsaicin sensitization.

4.4. Alterations in the Time-course of Offset Analgesia and Aftersensations

Altered temporal processing of pain is classically observed as symptoms of enhanced or diminished temporal summation of pain and painful aftersensations. These symptoms have been observed in states of chronic pain and following capsaicin injection [24, 51, 48, 12]. In the present study, painful aftersensations were also observed. VAS End Latency values (amount of time for ratings to reach VAS 0 after the stimulus end) increased in the primary region after both capsaicin-heat and heat-only sensitization. Similarly, aftersensations from the 50°C T2 stimulus may have delayed offset analgesia since Min Offset Latency values increased in the primary region. Thus, direct application of capsaicin-heat as well as heat-only produced responses that continued past the normal end of the stimuli, possibly by a peripheral effect of sensitization of primary afferents. These results further indicate that while the magnitude of offset analgesia is resilient to disruption, the temporal profile of offset analgesia is susceptible to alterations in primary afferent activity.

4.5. Limitations

Heat-only sensitization unexpectedly produced long lasting secondary thermal hyperalgesia. At this point it is unclear how much of this effect is due to a nocebo effect or true sensitization caused by an innocuous warm stimulus. Future studies using such sham-sensitization procedures may wish to include testing of additional unsensitized regions to characterize potential nocebo effects. Nonetheless, the observation of enhanced mechanical allodynia following capsaicin-heat sensitization compared to heat-only sensitization indicates that more pronounced central sensitization occurred following capsaicin-heat sensitization. An additional limitation of the present study was the complex effects of capsaicin: a combination of afferent sensitization and desensitization which is likely responsible for previous conflicting reports of secondary thermal hyperalgesia. Also, the extent of hyperalgesia depended on whether constant or dynamic stimuli were tested, further indicating that the central effects of capsaicin-heat sensitization are highly variable and require additional investigation.

4.6. Conclusions

Capsaicin-heat sensitization was expected to disrupt offset analgesia. Although peripheral, spinal and supraspinal changes have been observed following capsaicin-heat sensitization [52, 43, 29], the magnitude of offset analgesia remained highly consistent across treatment conditions and both primary and secondary regions. This indicates that the mechanisms subserving offset analgesia are largely independent of peripheral and central processes affected by capsaicin-heat sensitization. Alterations in the time-course of offset analgesia were observed in the primary region indicating that peripheral mechanisms may be involved in the initial signaling of temperature change. However, importantly, the magnitude of offset analgesia was not altered under any condition, even in the primary region. Therefore other mechanisms may subserve the main component of offset analgesia. Cool-sensitive primary afferents have been shown to exhibit marked increases in discharge frequency during the offset of a noxious heat stimulus [8], and this may be sufficient to trigger inhibition of heat pain. Additionally, in glabrous skin of the monkey, warm fiber responses are suppressed following a 1°C decrease from a maintained baseline temperature of 39°C; analogous suppression of nociceptors may occur to decreases in the noxious range and contribute to offset analgesia [5]. Local mechanisms of spinal cord inhibitory circuitry [25] as well as supraspinal descending control from brainstem (PAG / RVM) regions may account for offset analgesia [6, 56]. Further investigation of offset analgesia may elucidate additional mechanisms supporting temporal processing of nociceptive information and, in turn, aspects of how tactile and thermal stimuli are abnormally perceived in neuropathic pain.

Acknowledgments

Supported by NIH grants DA20168 (RCC) and DA026278 (KTM).

Footnotes

Authors have no conflicts of interest to disclose.

Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

References

  • 1.Ali Z, Meyer RA, Campbell JN. Secondary hyperalgesia to mechanical but not heat stimuli following a capsaicin injection in hairy skin. Pain. 1996;68(2-3):401–411. doi: 10.1016/s0304-3959(96)03199-5. [DOI] [PubMed] [Google Scholar]
  • 2.Baumann TK, Simone DA, Shain CN, LaMotte RH. Neurogenic hyperalgesia: the search for the primary cutaneous afferent fibers that contribute to capsaicin-induced pain and hyperalgesia. J Neurophysiol. 1991;66(1):212–227. doi: 10.1152/jn.1991.66.1.212. [DOI] [PubMed] [Google Scholar]
  • 3.Coghill RC, McHaffie JG, Yen YF. Neural correlates of interindividual differences in the subjective experience of pain. Proc Natl Acad Sci U S A. 2003;100(14):8538–8542. doi: 10.1073/pnas.1430684100. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Culp WJ, Ochoa J, Cline M, Dotson R. Heat and mechanical hyperalgesia induced by capsaicin. Cross modality threshold modulation in human C nociceptors. Brain. 1989;112(Pt 5):1317–1331. doi: 10.1093/brain/112.5.1317. [DOI] [PubMed] [Google Scholar]
  • 5.Darian-Smith I, Johnson KO, LaMotte C, Shigenaga Y, Kenins P, Champness P. Warm fibers innervating palmar and digital skin of the monkey: responses to thermal stimuli. J Neurophysiol. 1979;42(5):1297–1315. doi: 10.1152/jn.1979.42.5.1297. [DOI] [PubMed] [Google Scholar]
  • 6.Derbyshire SW, Osborn J. Offset analgesia is mediated by activation in the region of the periaqueductal grey and rostral ventromedial medulla. Neuroimage. 2009;47(3):1002–1006. doi: 10.1016/j.neuroimage.2009.04.032. [DOI] [PubMed] [Google Scholar]
  • 7.Dirks J, Petersen KL, Dahl JB. The heat/capsaicin sensitization model: a methodologic study. J Pain. 2003;4(3):122–128. doi: 10.1054/jpai.2003.10. [DOI] [PubMed] [Google Scholar]
  • 8.Dodt E, Zotterman Y. The discharge of specific cold fibres at high temperatures; the paradoxical cold. Acta Physiol Scand. 1952;26(4):358–365. doi: 10.1111/j.1748-1716.1952.tb00917.x. [DOI] [PubMed] [Google Scholar]
  • 9.Drummond PD, Blockey P. Topically applied capsaicin inhibits sensitivity to touch but not to warmth or heat-pain in the region of secondary mechanical hyperalgesia. Somatosens Mot Res. 2009;26(4):75–81. doi: 10.3109/08990220903296761. [DOI] [PubMed] [Google Scholar]
  • 10.Eide PK, Jorum E, Stenehjem AE. Somatosensory findings in patients with spinal cord injury and central dysaesthesia pain. J Neurol Neurosurg Psychiatry. 1996;60(4):411–415. doi: 10.1136/jnnp.60.4.411. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Fuchs PN, Campbell JN, Meyer RA. Secondary hyperalgesia persists in capsaicin desensitized skin. Pain. 2000;84(2-3):141–149. doi: 10.1016/s0304-3959(99)00194-3. [DOI] [PubMed] [Google Scholar]
  • 12.Gottrup H, Kristensen AD, Bach FW, Jensen TS. Aftersensations in experimental and clinical hypersensitivity. Pain. 2003;103(1-2):57–64. doi: 10.1016/s0304-3959(02)00415-3. [DOI] [PubMed] [Google Scholar]
  • 13.Granot M, Granovsky Y, Sprecher E, Nir RR, Yarnitsky D. Contact heat-evoked temporal summation: tonic versus repetitive-phasic stimulation. Pain. 2006;122(3):295–305. doi: 10.1016/j.pain.2006.02.003. [DOI] [PubMed] [Google Scholar]
  • 14.Grill JD, Coghill RC. Transient analgesia evoked by noxious stimulus offset. J Neurophysiol. 2002;87(4):2205–2208. doi: 10.1152/jn.00730.2001. [DOI] [PubMed] [Google Scholar]
  • 15.Hardy JD, Wolff HG, Goodell H. Experimental evidence on the nature of cutaneous hyperalgesia. J Clin Invest. 1950;29(1):115–140. doi: 10.1172/JCI102227. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Iadarola MJ, Berman KF, Zeffiro TA, Byas-Smith MG, Gracely RH, Max MB, Bennett GJ. Neural activation during acute capsaicin-evoked pain and allodynia assessed with PET. Brain. 1998;121(Pt 5):931–947. doi: 10.1093/brain/121.5.931. [DOI] [PubMed] [Google Scholar]
  • 17.Jensen TS, Gottrup H, Sindrup SH, Bach FW. The clinical picture of neuropathic pain. Eur J Pharmacol. 2001;429(1-3):1–11. doi: 10.1016/s0014-2999(01)01302-4. [DOI] [PubMed] [Google Scholar]
  • 18.Koyama Y, Koyama T, Kroncke AP, Coghill RC. Effects of stimulus duration on heat induced pain: the relationship between real-time and post-stimulus pain ratings. Pain. 2004;107(3):256–266. doi: 10.1016/j.pain.2003.11.007. [DOI] [PubMed] [Google Scholar]
  • 19.LaMotte RH, Lundberg LE, Torebjork HE. Pain, hyperalgesia and activity in nociceptive C units in humans after intradermal injection of capsaicin. J Physiol. 1992;448:749–764. doi: 10.1113/jphysiol.1992.sp019068. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.LaMotte RH, Shain CN, Simone DA, Tsai EF. Neurogenic hyperalgesia: psychophysical studies of underlying mechanisms. J Neurophysiol. 1991;66(1):190–211. doi: 10.1152/jn.1991.66.1.190. [DOI] [PubMed] [Google Scholar]
  • 21.LaMotte RH, Torebjork HE, Robinson CJ, Thalhammer JG. Time-intensity profiles of cutaneous pain in normal and hyperalgesic skin: a comparison with C-fiber nociceptor activities in monkey and human. J Neurophysiol. 1984;51(6):1434–1450. doi: 10.1152/jn.1984.51.6.1434. [DOI] [PubMed] [Google Scholar]
  • 22.Latremoliere A, Woolf CJ. Central sensitization: a generator of pain hypersensitivity by central neural plasticity. J Pain. 2009;10(9):895–926. doi: 10.1016/j.jpain.2009.06.012. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.Lewis T. Experiments relating to cutaneous hyperalgesia and its spread through somatic nerves. Clinical Science. 1936;2(4):373–423. [Google Scholar]
  • 24.Lindblom U. Assessment of Abnormal Evoked Pain in Neurological Pain Patients and Its Relation to Spontaneous Pain - a Descriptive and Conceptual-Model with Some Analytical Results. Advances in Pain Research and Therapy. 1985;9:409–423. [Google Scholar]
  • 25.Lu Y, Perl ER. A specific inhibitory pathway between substantia gelatinosa neurons receiving direct C-fiber input. J Neurosci. 2003;23(25):8752–8758. doi: 10.1523/JNEUROSCI.23-25-08752.2003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26.Magerl W, Wilk SH, Treede RD. Secondary hyperalgesia and perceptual wind-up following intradermal injection of capsaicin in humans. Pain. 1998;74(2-3):257–268. doi: 10.1016/s0304-3959(97)00177-2. [DOI] [PubMed] [Google Scholar]
  • 27.Maihofner C, Handwerker HO. Differential coding of hyperalgesia in the human brain: a functional MRI study. Neuroimage. 2005;28(4):996–1006. doi: 10.1016/j.neuroimage.2005.06.049. [DOI] [PubMed] [Google Scholar]
  • 28.Maihofner C, Schmelz M, Forster C, Neundorfer B, Handwerker HO. Neural activation during experimental allodynia: a functional magnetic resonance imaging study. Eur J Neurosci. 2004;19(12):3211–3218. doi: 10.1111/j.1460-9568.2004.03437.x. [DOI] [PubMed] [Google Scholar]
  • 29.Moulton EA, Pendse G, Morris S, Strassman A, Aiello-Lammens M, Becerra L, Borsook D. Capsaicin-induced thermal hyperalgesia and sensitization in the human trigeminal nociceptive pathway: an fMRI study. Neuroimage. 2007;35(4):1586–1600. doi: 10.1016/j.neuroimage.2007.02.001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30.Niesters M, Dahan A, Swartjes M, Noppers I, Fillingim RB, Aarts L, Sarton EY. Effect of ketamine on endogenous pain modulation in healthy volunteers. Pain. 2011;152(3):656–663. doi: 10.1016/j.pain.2010.12.015. [DOI] [PubMed] [Google Scholar]
  • 31.Nolano M, Simone DA, Wendelschafer-Crabb G, Johnson T, Hazen E, Kennedy WR. Topical capsaicin in humans: parallel loss of epidermal nerve fibers and pain sensation. Pain. 1999;81(1-2):135–145. doi: 10.1016/s0304-3959(99)00007-x. [DOI] [PubMed] [Google Scholar]
  • 32.Noordenbos W. Pain: problems pertaining to the transmission of nerve impulses which give rise to pain. Amsterdam, New York: Elsevier; 1959. pp. 1–182. [Google Scholar]
  • 33.Park KM, Max MB, Robinovitz E, Gracely RH, Bennett GJ. Effects of intravenous ketamine, alfentanil, or placebo on pain, pinprick hyperalgesia, and allodynia produced by intradermal capsaicin in human subjects. Pain. 1995;63(2):163–172. doi: 10.1016/0304-3959(95)00029-R. [DOI] [PubMed] [Google Scholar]
  • 34.Pedersen JL, Kehlet H. Secondary hyperalgesia to heat stimuli after burn injury in man. Pain. 1998;76(3):377–384. doi: 10.1016/S0304-3959(98)00070-0. [DOI] [PubMed] [Google Scholar]
  • 35.Peng YB, Ringkamp M, Meyer RA, Campbell JN. Fatigue and paradoxical enhancement of heat response in C-fiber nociceptors from cross-modal excitation. J Neurosci. 2003;23(11):4766–4774. doi: 10.1523/JNEUROSCI.23-11-04766.2003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36.Petersen KL, Rowbotham MC. A new human experimental pain model: the heat/capsaicin sensitization model. Neuroreport. 1999;10(7):1511–1516. doi: 10.1097/00001756-199905140-00022. [DOI] [PubMed] [Google Scholar]
  • 37.Price DD, Bush FM, Long S, Harkins SW. A comparison of pain measurement characteristics of mechanical visual analogue and simple numerical rating scales. Pain. 1994;56(2):217–226. doi: 10.1016/0304-3959(94)90097-3. [DOI] [PubMed] [Google Scholar]
  • 38.Price DD, Long S, Huitt C. Sensory testing of pathophysiological mechanisms of pain in patients with reflex sympathetic dystrophy. Pain. 1992;49(2):163–173. doi: 10.1016/0304-3959(92)90139-3. [DOI] [PubMed] [Google Scholar]
  • 39.Price DD, McGrath PA, Rafii A, Buckingham B. The validation of visual analogue scales as ratio scale measures for chronic and experimental pain. Pain. 1983;17(1):45–56. doi: 10.1016/0304-3959(83)90126-4. [DOI] [PubMed] [Google Scholar]
  • 40.Price DD, McHaffie JG, Larson MA. Spatial summation of heat-induced pain: influence of stimulus area and spatial separation of stimuli on perceived pain sensation intensity and unpleasantness. J Neurophysiol. 1989;62(6):1270–1279. doi: 10.1152/jn.1989.62.6.1270. [DOI] [PubMed] [Google Scholar]
  • 41.Quevedo AS, Coghill RC. An illusion of proximal radiation of pain due to distally directed inhibition. J Pain. 2007;8(3):280–286. doi: 10.1016/j.jpain.2006.09.003. [DOI] [PubMed] [Google Scholar]
  • 42.Raja SN, Campbell JN, Meyer RA. Evidence for different mechanisms of primary and secondary hyperalgesia following heat injury to the glabrous skin. Brain. 1984;107(Pt 4):1179–1188. doi: 10.1093/brain/107.4.1179. [DOI] [PubMed] [Google Scholar]
  • 43.Sang CN, Gracely RH, Max MB, Bennett GJ. Capsaicin-evoked mechanical allodynia and hyperalgesia cross nerve territories. Evidence for a central mechanism. Anesthesiology. 1996;85(3):491–496. doi: 10.1097/00000542-199609000-00007. [DOI] [PubMed] [Google Scholar]
  • 44.Sarlani E, Grace EG, Reynolds MA, Greenspan JD. Sex differences in temporal summation of pain and aftersensations following repetitive noxious mechanical stimulation. Pain. 2004;109(1-2):115–123. doi: 10.1016/j.pain.2004.01.019. [DOI] [PubMed] [Google Scholar]
  • 45.Simone DA, Sorkin LS, Oh U, Chung JM, Owens C, LaMotte RH, Willis WD. Neurogenic hyperalgesia: central neural correlates in responses of spinothalamic tract neurons. J Neurophysiol. 1991;66(1):228–246. doi: 10.1152/jn.1991.66.1.228. [DOI] [PubMed] [Google Scholar]
  • 46.Staud R, Robinson ME, Price DD. Temporal summation of second pain and its maintenance are useful for characterizing widespread central sensitization of fibromyalgia patients. J Pain. 2007;8(11):893–901. doi: 10.1016/j.jpain.2007.06.006. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 47.Staud R, Robinson ME, Vierck CJ, Jr, Price DD. Diffuse noxious inhibitory controls (DNIC) attenuate temporal summation of second pain in normal males but not in normal females or fibromyalgia patients. Pain. 2003;101(1-2):167–174. doi: 10.1016/s0304-3959(02)00325-1. [DOI] [PubMed] [Google Scholar]
  • 48.Staud R, Vierck CJ, Cannon RL, Mauderli AP, Price DD. Abnormal sensitization and temporal summation of second pain (wind-up) in patients with fibromyalgia syndrome. Pain. 2001;91(1-2):165–175. doi: 10.1016/s0304-3959(00)00432-2. [DOI] [PubMed] [Google Scholar]
  • 49.Sumikura H, Andersen OK, Drewes AM, Arendt-Nielsen L. Spatial and temporal profiles of flare and hyperalgesia after intradermal capsaicin. Pain. 2003;105(1-2):285–291. doi: 10.1016/s0304-3959(03)00243-4. [DOI] [PubMed] [Google Scholar]
  • 50.Sumikura H, Miyazawa A, Yucel A, Andersen OK, Arendt-Nielsen L. Secondary heat hyperalgesia detected by radiant heat stimuli in humans: evaluation of stimulus intensity and duration. Somatosens Mot Res. 2005;22(3):233–237. doi: 10.1080/08990220500262778. [DOI] [PubMed] [Google Scholar]
  • 51.Torebjork HE, Lundberg LE, LaMotte RH. Central changes in processing of mechanoreceptive input in capsaicin-induced secondary hyperalgesia in humans. J Physiol. 1992;448:765–780. doi: 10.1113/jphysiol.1992.sp019069. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 52.Treede RD, Meyer RA, Raja SN, Campbell JN. Peripheral and central mechanisms of cutaneous hyperalgesia. Prog Neurobiol. 1992;38(4):397–421. doi: 10.1016/0301-0082(92)90027-c. [DOI] [PubMed] [Google Scholar]
  • 53.Woolf CJ. Evidence for a central component of post-injury pain hypersensitivity. Nature. 1983;306(5944):686–688. doi: 10.1038/306686a0. [DOI] [PubMed] [Google Scholar]
  • 54.Woolf CJ, Mannion RJ. Neuropathic pain: aetiology, symptoms, mechanisms, and management. Lancet. 1999;353(9168):1959–1964. doi: 10.1016/S0140-6736(99)01307-0. [DOI] [PubMed] [Google Scholar]
  • 55.Woolf CJ, Salter MW. Neuronal plasticity: increasing the gain in pain. Science. 2000;288(5472):1765–1769. doi: 10.1126/science.288.5472.1765. [DOI] [PubMed] [Google Scholar]
  • 56.Yelle MD, Oshiro Y, Kraft RA, Coghill RC. Temporal filtering of nociceptive information by dynamic activation of endogenous pain modulatory systems. J Neurosci. 2009;29(33):10264–10271. doi: 10.1523/JNEUROSCI.4648-08.2009. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 57.Yelle MD, Rogers JM, Coghill RC. Offset analgesia: a temporal contrast mechanism for nociceptive information. Pain. 2008;134(1-2):174–186. doi: 10.1016/j.pain.2007.04.014. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 58.Yucel A, Andersen OK, Nielsen J, Arendt-Nielsen L. Heat hyperalgesia in humans: assessed by different stimulus temperature profiles. Eur J Pain. 2002;6(5):357–364. doi: 10.1016/s1090-3801(02)00022-8. [DOI] [PubMed] [Google Scholar]
  • 59.Zambreanu L, Wise RG, Brooks JC, Iannetti GD, Tracey I. A role for the brainstem in central sensitisation in humans. Evidence from functional magnetic resonance imaging. Pain. 2005;114(3):397–407. doi: 10.1016/j.pain.2005.01.005. [DOI] [PubMed] [Google Scholar]

RESOURCES