Research ReportAn experimental model to measure excitatory and inhibitory pain mechanisms in humans
Introduction
In experimental pain research, several approaches have been used to induce and measure pain perception. The main reason to use experimental pain in healthy subjects and in patients is to obtain a better understanding of the excitatory and inhibitory mechanisms operating in different conditions. Outcomes such as pain threshold (PTh), pain tolerance (PTol) and mean pain perception are indicators of one's interpretation of nociceptive inputs. Different pain modalities (thermal, electrical, chemical), and also different stimuli duration (phasic, repetition at high or low frequency, tonic) are currently used to induce experimental pain. Experimental pain also allows us to safely mimic a clinical situation in healthy subjects or patients in order to verify their reaction to a nociceptive stimulation or an analgesic procedure. Of all the different methods, the tonic pain model has been thought to better mimic clinical pain (Rainville et al., 1992). Furthermore, the tonic pain model allows us to measure a greater number of variables related to nociception, such as temporal summation (TS) (Price and Dubner, 1977, Granot et al., 2006) and the effectiveness of endogenous pain control mechanisms (previously measured using a spatial summation model (Marchand and Arsenault, 2002) and a temporal summation model (Potvin et al., 2007).
Pain is a dynamic phenomenon under the influence of several excitatory and inhibitory endogenous pain control mechanisms. Excitatory mechanisms such as TS and central sensitization, associated with repetitive (Price and Dubner, 1977) or persistent stimulations (Granot et al., 2006) are critically involved in the development of chronic pain. Studying TS will help to better understand the mechanisms of central sensitization in humans and its potential role in the development and persistency of certain chronic pain conditions. Pain inhibitory mechanism, such as diffuse noxious inhibitory controls (DNIC), originally described by LeBars et al. (1979), is of particular interest since a deficit of this mechanism is associated with the development of chronic pain (Edwards, 2005). For example, a deficit of endogenous pain inhibition was found to play an important role in some chronic pain conditions like fibromyalgia (Julien et al., 2005, Kosek and Hansson, 1997, Lautenbacher and Rollman, 1997). This central pain control mechanism is triggered by persistent nociceptive afferents from nociceptive fibres (A-delta and C-fibres). Once activated, it inhibits nociceptive activity arising from the afferent primary fibres at multiple levels of the dorsal horn, resulting in diffuse pain inhibition. These descending pain pathways originate from the brainstem and have significant inhibitory actions on nociceptive activity, and thus, pain perception (LeBars et al., 1992). This form of analgesia is also known as counter-irritation induced analgesia.
DNIC analgesia is typically quantified by calculating the difference in pain ratings given before and after a painful conditioning stimulus; since the conditioning stimulus activates DNIC, pain perception following this conditioning stimulus should be lower than before the conditioning stimulus (Talbot et al., 1987, Edwards et al., 2003, Serrao et al., 2004, Ge et al., 2004, Ge et al., 2005, Goffaux et al., 2007). We previously developed a spatial summation paradigm to measure the effect of excitatory and inhibitory mechanisms in a single test (Marchand and Arsenault, 2002) and were able to demonstrate that the inhibitory component of the test was opioidergic (Julien, and Marchand, 2006). Other methods have been used, such as repetitive phasic pain (TS paradigm) (Edwards, and Fillingim, 2001; Sarlani and Greenspan, 2002). However, this method might be less sensitive than others since it failed to show the inhibitory effects of DNIC in healthy women (Staud et al., 2003). Recently, it was found that constant nociceptive stimulation (which is more relevant to clinical pain) yields comparable results to the classical repetitive phasic TS procedure (Granot et al., 2006). Finally, even if abundant literature has been published concerning DNIC, there is no agreement concerning the best and most reliable way to quantify the analgesic effect of the DNIC which is of great importance in pain research.
Considering the potential role of endogenous excitatory mechanisms such as TS and endogenous pain control mechanisms in the development and persistence of some chronic pain conditions, it is important to use experimental pain models that can give us as much information as possible on these mechanisms both in healthy subjects and also with different chronic pain populations. We previously used a spatial summation model to measure the interaction between excitatory and inhibitory mechanisms in healthy subjects (Marchand and Arsenault, 2002) and in patients (Julien et al., 2005). The spatial summation procedure consisted of two sessions, on two different days. Only few studies reported experimental protocols permitting to measure both excitatory and inhibitory pain mechanism in one relatively brief session (45 min) (Staud et al., 2003; Granot et al., 2008). Our protocol has the advantage of measuring temporal summation and DNIC using a tonic painful stimulus, which more closely mimics clinical pain (Rainville et al., 1992).
Therefore, the main objective of this study was to develop and test a relatively simple experimental design which would enable us to elicit and/or measure multiple nociceptive and analgesic mechanisms, such as TS, tonic pain perception, and the effect of DNIC in a single session.
Section snippets
Participants
After approval from the hospital review board, we collected data from 83 healthy volunteers, 42 men and 41 women (see Table 1). None of the participants was suffering from any known diseases and none was taking medications. The entire experimental procedure lasted about 60 min. The experiment took place at the Clinical Research Centre of the Sherbrooke University Hospital, Sherbrooke, Quebec, Canada. Subjects were recruited through local ads and were all French speaking community-dwelling
Discussion
In this study protocol, 2 min of tonic heat pain (ramp and hold technique) allowed to measure multiple nociceptive and pain-related phenomena including HPC, peak pain, mean pain perception and TS. Animal literature regarding the temporal recruitment of nociceptive afferents suggests that A-delta and C-fibre discharge rate is maximal during this time period. But throughout the 30 second period (peak pain period), the A-delta fibre discharge rate significantly decreases while the C-fibre
Pain perception
Pain perception was assessed during the experimental pain procedure using a computerized visual analogue scale (COVAS) linked to a 9 cm2 thermode (TSA II, NeuroSensory Analyser, Medoc Instruments1). This graduated intensity scale ranged from 0 (absolutely no pain) to 100 (worst pain imaginable). During the cold pressor test (CPT), pain intensity and pain unpleasantness were measured using a numerical pain rating
References (36)
- et al.
Visceral pain: gender differences in response to experimental and clinical pain
Eur. J. Pain
(2004) - et al.
Lack of sex differences in modulation of experimental intraoral pain by diffuse noxious inhibitory controls (DNIC)
Pain
(2005) - et al.
Effects of age on temporal summation and habituation of thermal pain: clinical relevance in healthy older and younger adults
J. Pain
(2001) - et al.
Individual differences in diffuse noxious inhibitory controls (DNIC): association with clinical variables
Pain
(2003) - et al.
A comparison of diffuse noxious inhibitory controls in men and women
Pain
(1999) - et al.
Sex differences in temporal characteristics of descending inhibitory control: an evaluation using repeated bilateral experimental induction of muscle pain
Pain
(2004) - et al.
Gender differences in pain modulation evoked by repeated injections of glutamate into the human trapezius muscle
Pain
(2005) - et al.
Descending analgesia—when the spine echoes what the brain expects
Pain
(2007) - et al.
Contact heat-evoked temporal summation: tonic versus repetitive-phasic stimulation
Pain
(2006) - et al.
Determinants of endogenous analgesia magnitude in a diffuse noxious inhibitory control (DNIC) paradigm: do conditioning stimulus painfulness, gender and personality variables matter?
Pain
(2008)