Elsevier

Behavioural Brain Research

Volume 289, 1 August 2015, Pages 61-68
Behavioural Brain Research

Research report
Age-related differences in conditioned pain modulation of sensitizing and desensitizing trends during response dependent stimulation

https://doi.org/10.1016/j.bbr.2015.04.014Get rights and content

Highlights

  • Novel psychophysical test used dynamically changing levels of noxious stimulation.

  • This pain test assessed sensitization and desensitization within the same paradigm.

  • A conditioning stimulus enhanced sensitization and desensitization in older adults.

  • A conditioning stimulus decreased pain sensitivity of older and younger adults.

Abstract

The current study evaluated age differences in conditioned pain modulation using a test stimulus that provided the opportunity to evaluate changes in heat pain sensitivity, sensitization, and desensitization within the same paradigm. During this psychophysical test, pain intensity clamping uses REsponse Dependent STIMulation (REDSTIM) methodology to automatically adjust stimulus intensity to maintain a desired pain rating set-point. Specifically, stimulus intensity increases until a pre-defined pain rating (the setpoint) is exceeded, and then decreases until pain ratings fall below the setpoint, with continued increases and decreases dictated by ratings. The subjects are blinded in terms of the setpoint and stimulus intensities. Younger and older subjects completed two test sessions of two REDSTIM trials, with presentation of conditioning cold stimulation between the trials of one session but not the other. The results indicated that conditioning cold stimulation similarly decreased the overall sensitivity of younger and older subjects, as measured by the average temperature that maintained a setpoint rating of 20 (on a scale of 0–100). The conditioning stimulus also significantly enhanced sensitization following ascending stimulus progressions and desensitization following descending stimulus progressions in older subjects relative to younger subjects. Thus, older subjects experienced greater swings in sensitivity in response to varying levels of painful stimulation. These results are discussed in terms of control over pain intensity by descending central modulatory systems. These findings potentially shed new light on the central control over descending inhibition and facilitation of pain.

Introduction

Psychophysical studies of healthy adults have shown that a noxious conditioning stimulus reduces pain from a remote second stimulus [1], [2], [3]. The central systems activated by this paradigm, known as Conditioned Pain Modulation (CPM), can reduce experimentally-induced pain evoked by various types of stimulation, including thermal stimulation [4]. The mechanisms underlying desensitization by CPM are thought to involve spinal–medullary–spinal pathways and widespread inhibition of nociceptive wide dynamic range (WDR) neurons [5]. More recent research has revealed both excitatory and inhibitory influences on spinal nociceptive coding by projection systems descending from the brainstem [6], [7]. Importantly, these brainstem systems are controlled independently, so that an apparent loss of inhibition could result from enhanced sensitization, and reduced sensitization could appear to be enhanced inhibition. Thus, when attempting to elucidate mechanisms for altered pain sensitivity and/or abnormal pain, it is advantageous to evaluate both sensitization and desensitization.

A novel psychophysical procedure involving dynamically changing levels of stimulation designed to clamp (i.e., maintain) pain intensity near a desired set-point provides an opportunity to evaluate trends of sensitization and desensitization within the same paradigm [8], [9], [10]. This test, termed REsponse Dependent STIMulation (REDSTIM), involves computer-controlled adjustments of stimulus intensity (i.e., thermode temperature) to maintain a desired pain rating (setpoint). Pain intensity is monitored continuously with a real time electronic visual analogue scale (eVAS). Pain ratings oscillate around the setpoint in response to ascending and descending temperature changes (Fig. 1). For example, when pain ratings are below the setpoint (20 on a 0–100 scale), the stimulus temperature will increase until the pain ratings reach or exceed the setpoint. Conversely, when pain ratings exceed the setpoint, the stimulus temperature will decrease until the ratings reach or fall below the setpoint. Prior work has revealed that REDSTIM methodology establishes an average temperature that maintains the setpoint (overall sensitivity) and also reveals trends of sensitization following ascending series of stimulus intensities and desensitization following descending series of intensities. When pain ratings first exceed the setpoint and the stimulus temperature begins to decrease, the ratings continue to increase before descending (i.e., sensitization). Similarly, when pain ratings first drop below the setpoint and the stimulus temperature begins to rise, the ratings continue to descend before increasing (i.e., desensitization). These trends may reflect excitatory and inhibitory mechanisms of pain modulation [8].

The REDSTIM procedure may be considered a modification of staircase methods such as stimulus titration, which has been utilized for some time to track thresholds for pain detection [11]. The REDSTIM method is a modification of these procedures with an important advantage. During threshold tracking, subjects are aware that transitions between ascending and descending series are dictated by pain threshold. This presents the opportunity to prevent presentation of painful stimuli by responding early in ascending series, driving thresholds toward stimulus detection rather than pain detection. During REDSTIM trials, the subjects are not aware of transitions between ascending and descending series, as is apparent from ascending and descending trends (see Fig. 1).

The primary aim of this study was to evaluate the capability of the central inhibitory mechanisms activated during CPM to modulate overall pain sensitivity and trend-induced sensitization and desensitization during prolonged REDSTIM in healthy older and younger adults. We hypothesized that conditioning stimulation would reduce overall pain sensitivity during REDSTIM in younger adults (i.e., increase the average temperature at which the setpoint was maintained), coupled with enhanced desensitization and/or reduced sensitization. However, previous studies show that older adults can exhibit no effect of CPM [12], [13], [14] or increased thermal pain [4], [16], [17], [18] during or following exposure to a painful conditioning stimulus, in contrast to pain reduction for younger subjects. Therefore, we hypothesized that older adults would exhibit no change in overall pain sensitivity during REDSTIM following conditioning stimulation, coupled with increased sensitization and/or reduced desensitization. A secondary aim of this study was to evaluate age differences in pain sensitivity, sensitization, and desensitization during REDSTIM at baseline. Previous investigations have indicated that sensitivity to suprathreshold painful stimulation does not change with age [4], [19], [20], [21]; therefore, we hypothesized no age differences in overall sensitivity, sensitization or desensitization at baseline.

Section snippets

Participants

Twenty-four healthy younger adults (age = 23.62 years, SD = 3.96; range: 20–34; 8 Female) and nineteen healthy older adults (age = 64.04 years, SD = 7.13; range: 55–77; 13 Female) participated in this study. A recent study showed that adults 55 years and older have reduced CPM [4]; therefore, we are including adults 55 years and older in our older adult group. The racial composition of the younger group was 6 Caucasian, 6 Hispanic, 8 Asian Americans, 2 African Americans, and 2 other. The older adult

Subject characteristics

A chi-square test indicated that sex distribution differed between age groups, p = .033. No significant differences existed between older and younger subjects on Mental Health status on the SF-36 (younger adults = 84.32 ± 12.95, older adults = 81.47 ± 10.93). However, younger subjects self-reported significantly better physical health status on the SF-36 compared to older subjects (younger adults = 90.17 ± 10.48, older adults = 80.73 ± 18.85). In comparison with national Normative Data of the SF-36, these data

Discussion

This study evaluated CPM and age-related effects with a novel and sophisticated psychophysical procedure that provides the opportunity to evaluate trends of desensitization and sensitization within the same paradigm. Pain intensity clamping with the use of REDSTIM methodology to evaluate suprathreshold pain sensitivity offers advantages compared to traditional psychophysical tests. Specifically, participants are blinded to stimulus parameters (i.e., thermode temperature) and are free from

Conflict of interest

Andre Mauderli is an officer of Neuroanalytics Corportation. There are no other conflicts of interest, or any financial interests, to report with regard to this work for any of the other authors.

Author and contributions

JLR, APM, and CJV made substantial contributions to the conception or design of the work and interpretation of the data for the work.

KMN and YCA made substantial contributions to the acquisition, analysis, and interpretation of data for the work.

All authors listed aided in drafting the work or revising it critically for important intellectual content, gave final approval of the version to be published, and agreed to be accountable for all aspects of the work in ensuring that questions related

Acknowledgments

This research was supported by NIH-NIA Grant R01AG039659 (J.L.R.) and NIH Grant T32 T32NS045551-06 (K.M.N.).

References (38)

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