Abstract
This study tested a modified experimental model of heat-induced hyperalgesia, which improves the efficacy to induce primary and secondary hyperalgesia and the efficacy-to-safety ratio reducing the risk of tissue damage seen in other heat pain models. Quantitative sensory testing was done in eighteen healthy volunteers before and after repetitive heat pain stimuli (60 stimuli of 48°C for 6 s) to assess the impact of repetitive heat on somatosensory function in conditioned skin (primary hyperalgesia area) and in adjacent skin (secondary hyperalgesia area) as compared to an unconditioned mirror image control site. Additionally, areas of flare and secondary hyperalgesia were mapped, and time course of hyperalgesia determined. After repetitive heat pain conditioning we found significant primary hyperalgesia to heat, and primary and secondary hyperalgesia to pinprick and to light touch (dynamic mechanical allodynia). Acetaminophen (800 mg) reduced pain to heat or pinpricks only marginally by 11% and 8%, respectively (n.s.), and had no effect on heat hyperalgesia. In contrast, the areas of flare (−31%) and in particular of secondary hyperalgesia (−59%) as well as the magnitude of hyperalgesia (−59%) were significantly reduced (all p<0.001). Thus, repetitive heat pain induces significant peripheral sensitization (primary hyperalgesia to heat) and central sensitization (punctate hyperalgesia and dynamic mechanical allodynia). These findings are relevant to further studies using this model of experimental heat pain as it combines pronounced peripheral and central sensitization, which makes a convenient model for combined pharmacological testing of analgesia and anti-hyperalgesia mechanisms related to thermal and mechanical input.
Highlights
In previous studies, our group developed a repetitive nociceptive heat stimulation paradigm, which resulted in acute and pronounced intra-session sensitization and simultaneously an sustained inter-session habituation lasting for weeks related to activation of endogenous pain control [1,2,3]
The stimulus protocol involved the administration of repetitive noxious heat stimuli using a thermode, which were delivered in 10 blocks of 6 brief stimuli with a temperature of 48uC each
Tonic administration of heat leading to mild skin burns is known to induce hyperalgesia to punctate mechanical stimuli surrounding the site of primary hyperalgesia [5] similar to changes observed after intra- or epidermal application of capsaicin [6], or repetitive intra- or epidermal electrical stimulation [7]
Summary
Our group developed a repetitive nociceptive heat stimulation paradigm, which resulted in acute and pronounced intra-session sensitization and simultaneously an sustained inter-session habituation lasting for weeks related to activation of endogenous pain control [1,2,3]. The stimulus protocol involved the administration of repetitive noxious heat stimuli using a thermode, which were delivered in 10 blocks of 6 brief stimuli with a temperature of 48uC each. This standardized protocol of repetitive heat pain (RHP) was administered daily for 8 consecutive days. The common molecular denominator in these models is a strong input in capsaicin-sensitive nociceptors bearing the TRPV1 receptor Strong input in these mostly peptidergic nociceptive primary afferents causes central sensitization of spinal neurons to input from capsaicin-insensitive nociceptive A-delta fibres [8,9,10,11]. Since established burn injury models are not completely safe and sometimes induce manifest tissue injuries (second degree burn) [14], which makes mechanistic interpretations difficult, we strived to improve this method by a train repeated brief heat stimuli rather than sustained high level heat as has been used previously
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