Central representation of cold-evoked pain relief in capsaicin induced pain: An event-related fMRI study

The termination of an unpleasant or painful somatic condition can produce a rewarding sense of relief, even if the stimulus that causes the termination is itself unpleasant or painful under normal circumstances. We aimed to identify central neural mechanisms of pain relief from capsaicin-elicited heat-hyperalgesia by administering cold stimuli. We hypothesized that cooling might facilitate endogenous descending inhibitory mechanisms. We compared intraindividual neural responses of 15 healthy male volunteers to cold (20, 0 °C), intermediate (30 °C) and heat stimuli (43 °C) on untreated vs. capsaicin-treated skin using event-related fMRI in a 2 × 4 factorial design. Thermal stimuli were applied at the right hand in two separate imaging sessions using a Peltier-element. Psychophysical ratings of the perceived valence and intensity (VAS: 1-100) were obtained after each stimulus. The 43 °C-stimulus was perceived as excessively painful on capsaicin-treated skin as opposed to an unpleasant sensation on normal skin. In contrast, the 0 °C-stimulus was perceived unpleasant when applied on untreated skin while subjects rated the same stimulus pleasant in the capsaicin-treated condition. When neural responses to the 0 °C-stimulus were compared between the untreated and capsaicin-treated skin condition there were stronger BOLD-responses in prefrontal cortex (PFC) and periaqueductal grey (PAG) which correlated with increasing perceived pleasantness (VAS). Based on a connectivity analysis which identified cold-dependent contributions of PFC activity with PAG in heat-hyperalgesia we propose that cold-induced pain relief partly results from activation of endogenous descending inhibition of nociception. The data illustrate that perception of nociceptive input may largely be determined by competing aversive-appetitive motivational states.