The role of heterosynaptic facilitation in long-term potentiation (LTP) of human pain sensation.

Long-term potentiation (LTP) of nociceptive synaptic transmission induced by high-frequency electrical stimulation (HFS) predominantly modulates natural somatosensory perceptions mediated by Adelta- and Abeta-fibers in humans at the site of conditioning stimulation. The relative contribution of homo- and heterosynaptic mechanisms underlying those perceptual changes remained unclear. We therefore compared changes of the somatosensory profile between a conditioned skin site (homotopic zone) and an area adjacent to conditioning HFS (heterotopic zone). HFS of the ventral forearm in 24 healthy subjects (mean pain 41/100) led to an abrupt increase of pain to single electrical test stimuli (pain at baseline 13/100) delivered through the same electrode (homotopic pain LTP; +81%, p<0.001). Pain LTP was accompanied by similar changes to natural stimuli at both the homo- and heterotopic zones: a significant decrease of pain threshold and an increase of pain sensation to suprathreshold pinprick stimuli (punctate mechanical hyperalgesia; p<0.001) as well as pain to light tactile stimuli (dynamic mechanical allodynia; p<0.01). Changes at the heterotopic zone were about 30% less than at the homotopic conditioned zone, but they were highly correlated between both zones for suprathreshold painful stimuli (r=0.85-0.90) and for pain thresholds (r=0.51-0.66). Moreover, a small decrease of thresholds to blunt pressure was found at both zones (p<0.05). Pain summation (windup ratio), mechanical detection threshold as well as vibration detection threshold remained unchanged. Because none of the changes in sensory parameters was unique for the site of conditioning stimulation, these data suggest that heterosynaptic interactions are the predominant mechanism of LTP in nociceptive pathways.