Neurogenic hyperalgesia: illuminating its mechanisms with an infrared laser

Most people have experienced minor accidental burn injuries at some point in their lifetime. Fortunately, most first and second degree burns heal without scars, and hence the painful experience may end up being the worst aspect of the accident. In addition to being painful during the injuring stimulus, there is enhanced pain sensitivity (hyperalgesia) at the injured site (primary hyperalgesia) and in surrounding skin (secondary hyperalgesia) both of which outlast the injury for many hours. Whereas primary hyperalgesia is readily explained by peripheral sensitization of nociceptive nerve terminals in injured skin (e.g. via phosphorylation of the TRPV1 heat transduction channel), the mechanisms of secondary hyperalgesia have been more enigmatic, since peripheral sensitization is strictly limited to the injured tissue region.

Secondary hyperalgesia is induced by nociceptive input signals that reach the spinal cord and not by the injury itself. This has led to the term ‘neurogenic hyperalgesia’ (Baumann et al. 1991), which can be induced by injury, by injection of the TRPV1 agonist capsaicin or by high‐frequency electrical stimulation (HFS) of superficial nociceptive nerve terminals. It was recently confirmed that also HFS induces neurogenic hyperalgesia via activation of TRPV1‐positive nociceptive afferents (Henrich et al. 2015).

In contrast to primary hyperalgesia, where hypersensitivity occurs to both heat and mechanical stimuli, secondary hyperalgesia is characterized by hypersensitivity to mechanical stimuli only (Raja et al. 1984), which includes hypersensitivity to pinpricks and pain evoked by brushing (dynamic mechanical allodynia). The conspicuous absence of heat hypersensitivity in neurogenic hyperalgesia indicates that its mechanisms in the central nervous system require an interaction of at least two afferent pathways (Fig. 1): nociceptors that induce it (TRPV1‐positive, mostly C‐fibres) and nociceptors that mediate the amplified pain sensitivity (TPPV1‐negative A‐fibres). 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. 2016; Henrich et al. 2015).

Figure 1. Pain amplification in neurogenic hyperalgesia .

Neurogenic hyperalgesia is induced by strong input from nociceptors that express the capsaicin receptor TRPV1 and that are activated by actual or simulated tissue damage (burn, capsaicin injection, high‐frequency electrical stimulation). Secondary hyperalgesia is mediated by the resulting amplification of input from adjacent uninjured skin that is carried by low‐threshold (LTM) and high‐threshold mechanoreceptors (HTM), leading to dynamic mechanical allodynia and pinprick hyperalgesia.

In this issue of The Journal of Physiology, André Mouraux and colleagues (Van den Broeke et al. 2016) 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). Both nociceptors respond to pinprick, while type I AMHs also respond to heat stimuli of long duration. The heat transduction mechanism in type I AMHs is still unknown, but seems to be independent of TRPV1.

They used a feedback‐controlled laser stimulator to apply stepped heat stimuli that were adjusted to the responsivity of type I AMHs: temperature‐controlled heat stimuli of 1°C above the individual threshold temperature and 30 s duration were applied to skin surrounding the HFS site within an area that had previously been mapped as hyperalgesic to pinprick stimuli. While pinprick sensation was almost doubled after HFS, heat pain sensitivity did not change significantly. In a separate experiment with a compression block of the superficial radial nerve, the authors verified that the reaction times to both pinprick and short duration heat stimuli were increased from the A‐fibre range to the C‐fibre range and that in response to their long duration heat stimulus pain intensity was reduced by about 20% by the A‐fibre block within an appropriate time window where type I AMHs respond to this stimulus. These findings suggest that A‐fibre nociceptors contribute to pinprick pain and to long‐lasting heat pain, but the differential facilitation after HFS indicates that they are mediated by different subtypes.

This study closes a small but important gap in our knowledge about the pathophysiology of secondary hyperalgesia by providing evidence on the subtype of A‐fibre nociceptors, the input of which is centrally facilitated in secondary hyperalgesia. Figure 1 shows the proposed spinal circuitry of central sensitization of spinal neurons with receptive fields in the zone of secondary hyperalgesia. These spinal nociceptive neurons are also sensitized to input from low‐threshold mechanoreceptors, which leads to the phenomenon of dynamic mechanical allodynia (touch‐evoked pain). Although dynamic mechanical allodynia has fascinated researchers for many decades, pinprick hyperalgesia as studied by André Mouraux and colleagues is more prevalent in both experimental and clinical data, and hence their paper deserves to be read and quoted by all researchers with an interest in the plasticity of the nociceptive system.

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Competing interests

None declared.