An Improved Model of Heat-Induced Hyperalgesia—Repetitive Phasic Heat Pain Causing Primary Hyperalgesia to Heat and Secondary Hyperalgesia to Pinprick and Light Touch

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.

Pain‐autonomic interaction: A surrogate marker of central sensitization

“…Repetitive heat pain stimulation induced a large area of secondary hyperalgesia to mechanical stimulation as reported previously (Jürgens et al, 2014). Pinprick hyperalgesia was indicated by a decreased MPT in the secondary area of hyperalgesia.…”

“…Central sensitization can be provoked experimentally by activating nociceptors in a sustained and intense fashion (Henrich, Magerl, Klein, Greffrath, & Treede, 2015;LaMotte, Shain, Simone, & Tsai, 1991;Sandkühler, 2009;Treede & Magerl, 2000;Treede, Meyer, Raja, & Campbell, 1992). Such paradigms include noxious heat stimulation, which produces robust mechanical hyperalgesia in the surrounding skin area (i.e., secondary hyperalgesia) (Jürgens, Sawatzki, Henrich, Magerl, & May, 2014;Petersen & Rowbotham, 1999). This is mediated by an "increased responsiveness of central nociceptive neurons to their normal or subthreshold afferent input" (Loeser & Treede, 2008).…”

Functional magnetic resonance imaging of the cervical spinal cord during thermal stimulation across consecutive runs

“…While pain ratings were not obtained during scanning, the subjects anecdotally reported an increase in their pain experience across the six runs, and temporary mild erythema was typically present over the stimulation site at the end of the study. Considering these findings and the stimulation protocol used in this study, some sensitization to the thermal stimuli across the runs likely occurred (Jurgens et al, 2014). To assess whether indicators of sensitization were present in the data, we looked for an increase in the number of active voxels and the average percent signal change of the active voxels across the runs.…”

“…From this, we identified a significant increase in the number of active voxels across the runs for the painful stimuli at the group level, which may reflect sensitization. Based on the stimulation protocol, both peripheral and central sensitization may have occurred (Jurgens et al, 2014). The increase in the spatial extent of the activity may be due to decreased thresholds of peripheral receptors and their central targets, the unmasking of silent receptors, and/or greater reflexive motor activity (Chan and Dallaire, 1989; Latremoliere and Woolf, 2009).…”

tDCS modulates cortical nociceptive processing but has little to no impact on pain perception

“…These stimuli were applied 3 times in a standardized order, and the participants were asked to give a pain rating for each stimulus on a numerical rating scale from 0 (no pain) to 100 (worst imaginable pain). Mechanical allodynia may occur as a physiological response to thermal pain [29]. To detect any potential influence of tDCS on pain processing, the modulation of mechanical allodynia was chosen as an additional secondary outcome measure.…”