Secondary hyperalgesia is mediated by heat‐insensitive A‐fibre nociceptors

Abstract

Secondary hyperalgesia refers to the increase in sensitivity to mechanical nociceptive stimuli delivered outside the area of tissue injury. Previous studies have suggested that secondary hyperalgesia is mediated by a specific class of myelinated nociceptors: slowly adapting A-fibre mechano- and heat-sensitive (AMH) type I nociceptors. Here, we tested this hypothesis by examining whether long-lasting heat stimuli, which are known to activate AMH-type I nociceptors, elicit enhanced responses when delivered to the area of secondary hyperalgesia induced by high frequency electrical stimulation of the skin (HFS). Before and 20 min after HFS, sustained 30 s radiant heat stimuli were delivered to the area of increased mechanical pinprick sensitivity while participants continuously rated intensity of perception using an online visual analog scale (0-100 mm). After HFS, no significant enhancement of heat perception was observed in the area of increased pinprick sensitivity. To establish that myelinated nociceptors actually contribute to the perception of sustained heat, we conducted a second experiment in which sustained heat stimuli were presented before and during an A-fibre nerve conduction block, achieved by applying a rubber band with weights which compresses the superficial radial nerve against the radius. During the block, heat perception was significantly reduced 17-33 s after the onset of the heat stimulus (before: mean = 53 mm, during: mean = 31 mm; P = 0.03), matching the response profile of AMH-type I nociceptors. These results support the notion that AMH-type I nociceptors contribute to the perception of sustained heat, but also show that these afferents do not mediate secondary hyperalgesia.

Event-related brain potentials elicited by high-speed cooling of the skin: A robust and non-painful method to assess the spinothalamic system in humans

“…All stimuli were clearly perceived, but the intensity of the elicited sensations was greater for large vs. small decreases in skin temperature, as well as for stimulation using a large vs. small stimulation surface. Previous studies have shown that cool perception is abolished during the presence of an A-fibre nerve compression block (Oliveiro et al, 2005; van den Broeke et al, 2016), which strongly suggests that cool sensation is mediated by cool-sensitive A-fibres. Moreover, electrophysiological recordings of single nerve fibers in primates have identified a subpopulation of cool-sensitive A-fibers that (1) discharge rapidly at the onset of cooling the skin, (2) respond more strongly for fast vs. slow rates of cooling, (3) do not respond or respond minimally to mechanical stimuli and (4) have their ongoing activity suppressed by rapid warming of the skin (Darian-Smith et al, 1973; Dubner et al, 1975; Kenshalo and Duclaux, 1977).…”

Quickly responding C‐fibre nociceptors contribute to heat hypersensitivity in the area of secondary hyperalgesia

“…; Van den Broeke et al . ). Studies have suggested that this heterotopic increase of mechanical pinprick sensitivity is abolished during A‐fibre nerve conduction blockade (Ziegler et al .…”

Neurogenic hyperalgesia: illuminating its mechanisms with an infrared laser

“…This dichotomy had been supported by several additional converging lines of evidence, including selective nerve blocks in healthy subjects and electrophysiological recordings from nociceptive afferents and nociceptive spinal neurons in monkeys (for discussion see: Van den Broeke et al . ; Henrich et al . ).…”

“…In this issue of The Journal of Physiology , André Mouraux and colleagues (Van den Broeke et al . ) have now investigated which type of A‐fibre nociceptor mediates the hypersensitivity to pinprick pain surrounding a site of HFS. Based on previous publications, there were two candidates left: mechano‐heat sensitive A‐fibre nociceptors (type I AMH) or heat‐insensitive high‐threshold mechanoreceptors (HTM).…”