Nociceptive long-term depression (LTD) and potentiation (LTP) of synaptic transmission in the spinal cord are considered key mechanisms underlying long-lasting changes of pain perception ('pain memory'). In a human pain model of LTP- and LTD-like bidirectional plasticity (Klein et al. 2004) we investigated, whether pain plasticity exhibits saturation following repeated application of conditioning low-frequency (LFS) or high-frequency electrical stimulation (HFS). LFS (1000 pulses at 1Hz) or HFS (5x1s trains at 100Hz, 10s train intervals) with a stimulus strength of 10x detection threshold were applied 3x with an interstimulus interval of 1h in 17 healthy subjects (two-way, cross-over). Perceptual changes in the stimulated pathway were tested by single electrical test stimuli at 10x detection threshold via the conditioning electrode. After the 1^st LFS train (LFS1) pain decreased significantly (pain-LTD; -17% vs. the control site, p<0.05). Pain further decreased after LFS2 (-35%, p<0.01 both vs. control and vs. LFS1) and LFS3 (-51%, p<0.001 vs. control and p<0.01 vs. LFS2). After the 1^st HFS train (HFS1) pain to electrical test stimuli increased significantly compared to an unconditioned control site (pain-LTP; +26%, p<0.01). Upon a 2^nd and 3^rd HFS train pain-LTP was not further enhanced (+26% and +24%, respectively; n.s. vs. HFS1). We concluded that pain-LTD showed no signs of response saturation. In contrast, the induction of pain-LTP saturated already after the first HFS. This suggests that in healthy humans the nociceptive system in the naïve state is more susceptible to pain reduction (i.e. analgesic effect) than to pain increase (i.e. hyperalgesic effect). A shift towards diminished saturation properties of pain-LTP induction may underlie some forms of chronic hyperalgesia.