Neural processing of cold-induced pain relief in heat allodynia (fMRI study)

Background: Thermal (heat) allodynia or hyperalgesia is a core symptom of neuropathic pain syndromes resulting from sensitization of peripheral C-fiber afferents (primary hyperalgesia). Neural processing in the brain is distinctly different in capsaicin-induced thermal allodynia, when compared to perceptionally identical pain intensities elicited by thermal stimuli on normal skin. The goal of this study was to identify central neural mechanisms of pain relief from primary hyperalgesia by using thermal cooling. We hypothesized that cooling might fascilitate endogenous descending inhibitory mechanisms.

Methods: We directly compared intraindividual neuronal responses of 15 healthy male volunteers (mean age 27.7±6.2 years) to cold (20°, 0°C) and warm/heat stimuli (30°, 43°) on capsaicin (2.5%) sensitized vs. normal skin using event-related fMRI (2×4 factorial design). Thermal stimuli (Pelthier-element, Medoc TSA II) were applied at the back of the right hand in two separate imaging sessions. Psychophysical ratings were obtained after each stimulus to relate stimulus elicited activations to different perceptional qualities (painful, unpleasant and pleasant) and levels (visual analogue scale, VAS, 1–100).

Results: The 43° stimulus was perceived as excessively painful (79.8±5.2) on the sensitized skin as opposed to a non-painful unpleasant sensation on the normal skin (37.4±7.9). In contrast, the 0° stimulus was perceived as unpleasant when applied on the normal skin (61.2±8.4) while subjects rated the same stimulus as highly pleasant in the capsaicin treated condition (53.4±5.2).

Common neural responses (irrespective of skin sensitization) for all thermal stimuli were found in the thalamus. Categorical comparison of neural responses to the 43° stimulus between the normal and sensitized skin condition revealed activation in SI, SII, ACC, anterior insula, prefrontal cortex and cerebellar vermis consistent with previous fMRI studies on heat allodynia. Cooling (0°) of capsaicin-sensitized skin, compared to stimulation on normal skin, elicited prefrontal cortex and periaqueductal grey (PAG) activation, which strongly correlated with the perception of pleasantness (VAS).

Conclusion: We propose that cold-induced pain relief in primary hyperalgesia not only results from peripheral antiinflammatory mechanisms but also from activation of endogenous descending inhibition of nociception.