ng that they may represent independent aspects albeit related to the same underlying process of central sensitization which suggests that the administration of repetitive heat pain using this paradigm is comparable to other potent inducers of experimental primary and secondary hyperalgesia, such as burn pain or capsaicin. Likewise, allodynia mediated by heterosynaptic sensitization to the central input of A-beta fibres was observed in both the central and the peripheral zone following repetitive heat pain. Recently, different methods of heat-induced central sensitization were meta-analysed with two main conclusions: first, various models of noxious heat reliably induce central sensitization, and second, the most reliable results were observed with strong sustained stimulation resulting in first degree burns, sometimes even skin blistering. Our model provides similar thermal stimulation but likely more vigorous input from heat-sensitive nociceptors resulting from the phasic discharge to pulsating stimulation. At the same time, intermittent cooling avoids cumulation of thermal energy to damaging levels in the tissue and ensuing burn injury thus increasing the safety margin for this stimulus type. Notably, this model of repetitive heat pain stimulation induced a significantly more long-lasting type of hyperalgesia than other 22441874 varieties of heat conditioning that have been published previously e.g.. Rather they share the sustained time course of hyperalgesia 
models like high-dose intracutaneous capsaicin injection, high-frequency electrical stimulation, or experimental skin incision , suggesting that it may induce the long-term potentiation type of central sensitization. An additional advantage is the induction of a prominent and long-lasting primary heat hyperalgesia, thus allowing the parallel study of primary and secondary hyperalgesia mechanisms in the same model. Repetitive application of noxious heat stimuli elicited a profound significant increase in all primary and secondary modalities except for pain sharpness. Pain sharpnessreflected by ratings of adjectives like cutting, tearing, shooting, sharp, and stabbing, is the perceptual correlate of A-delta fibre activation, which is related to 17594192 reflex withdrawal, while pain rhythmicitycomprising characteristics such as nagging, hot, radiating and pulsating relates to C-fibre activation. The latter may directly be related to higher affective load, however, more complex central mechanisms cannot be ruled out. As predicted from previous human BS-181 site studies, the preemptive administration of acetaminophen in a proof-of-concept trial conducted in a small cohort of subjects changed pain ratings to repetitive heat stimuli and to painful pinpricks only marginally indicating poor analgesic efficacy. In contrast, the area of secondary pinprick hyperalgesia decreased significantly in the acetaminophen group. These findings support the notion that acetaminophen is a rather weak NSAID analgesic with some, but limited peripheral action on primary afferents. In contrast, it may be a quite powerful inhibitor of hyperalgesia of the secondary hyperalgesia type, which is related to a heterosynaptic mechanism of spinal central sensitization. This corroborates previous findings in an intracutaneous electrical hyperalgesia model and reports on the efficacy of acetaminophen on laser-evoked pain in panretinal photocoagulation and mechanical experimental pain involving hyperalgesia to blunt pressure 109. In line with prev
