Beep tones attenuate pain following Pavlovian conditioning of an endogenous pain control mechanism

Abstract

Heterotopic noxious counter-stimulation (HNCS) is commonly used to study endogenous pain control systems. The resulting pain inhibition is primarily based on spinal cord-brainstem loops. Recently, functional imaging studies have shown that limbic structures like the anterior cingulate cortex and amygdala are also implicated. Since these structures are involved in learning processes, it is possible that the HNCS-induced pain inhibition may depend on specific cues from the environment that have been associated with pain reduction through associative learning. We investigated the influence of Pavlovian conditioning on HNCS-induced pain inhibition in 32 healthy subjects by using a differential conditioning paradigm in which two different acoustic stimuli were either repeatedly paired or unpaired with HNCS. Series of noxious electrical pulse trains delivered to the non-dominant foot served as test stimuli. Diffuse noxious inhibitory control (DNIC)-like effects were induced by concurrent application of tonic HNCS (immersion of the contralateral hand in ice water). Subjective pain intensity and pain unpleasantness ratings and electromyographic recordings of the facial corrugator muscle and the nocifensive RIII flexion reflex were used to measure changes in pain sensitivity. HNCS induced significant pain and reflex inhibitions. In the post-conditioning phase, only the paired auditory cue was able to significantly reduce pain perceptions and corrugator muscle activity. No conditioned effect could be observed in RIII reflex responses. Our results indicate that the functional state of endogenous pain control systems may depend on associative learning processes that, like in the present study, may lead to an attenuation of pain perception. Similar albeit opposite conditioning of pain control mechanisms may significantly be involved in the exacerbation and chronification of pain states.

Figure 1. Experimental protocol.

Abbreviations: HNCS = heterotopic noxious counter-stimulation, UCR = unconditioned response, CS = conditioned stimulus, CS– = unpaired conditioned stimulus, CS+ = paired conditioned stimulus, CR = conditioned response, TG = test group (N₁ = 16), CG = control group (N₂ = 16), BL = baseline. (A) Stimulus presentations during the pre-conditioning, conditioning and post-conditioning phases (see further details in the text. (B) Electrical stimulation sequences delivered over each stimulation block.

Figure 2. Psychophysical and psychophysiological data of the test group (N₁ = 16) and the control group (N₂ = 16) during pre-conditioning HNCS (BL2) and post-conditioning CS−/CS+ trials (3 CS– trials; 3 CS+ trials).

Pre-conditioning BL2 values were contrasted to pre-conditioning BL1 values (1 trial for each BL). Post-conditioning CS−/CS+ values were contrasted to post-conditioning BL3 values. (A) Pain intensity decrease relative to BL. (B) Reduction in pain unpleasantness relative to BL. (C) Inhibition of corrugator muscle activity relative to BL. (D) Overall magnitude RIII reflex inhibition relative to BL. Abbreviations: TG = test group, CG = control group, HNCS = heterotopic noxious counter-stimulation, BL = baseline, CS– = unpaired conditioned stimulus, CS+ = paired conditioned stimulus, Δ % = percent difference. Results were based on absolute values and were presented as percent difference measures. Arithmetic mean and standard error of the mean (AM ± SEM) were used as measures for central tendency and variability. For the differences between test phase effects, p-values of *p<0.05 and **p<0.005 were considered as significant and highly significant.