SCIENTIFIC COMMENTARIES Translating synaptic plasticity into sensation

The nociceptive system is endowed with powerful mechanisms to modify its own responsiveness to noxious stimuli, ranging from complete analgesia, e.g. in stressful fight or flight situations (Willer et al., 1981) to pronounced hyperalgesia, e.g. to better protect inflamed or injured tissue (Sandkühler, 2013). Changes in synaptic strength are a versatile and powerful means to modulate nociception on demand (Sandkühler, 2009). Opioids, for example, temporarily depress synaptic strength in nociceptive pathways while injuries, trauma and inflammation may lead to synaptic long-term potentiation (LTP) (Ikeda et al., 2006) that amplifies pain. Human studies are the gold standard for assessing one of the most important endpoints of nociception, the perception of pain (Treede et al., 1999). However, in human studies it is, in striking contrast to in vitro or animal studies, notoriously difficult to identify the cellular elements that induce and/or express neuronal plasticity. In this issue of Brain, RolfDetlef Treede and his colleagues use a spectrum of experimental tools to selectively block or activate subgroups of primary afferent nerve fibres in healthy volunteers to elegantly pinpoint the neuronal elements that either trigger or mediate LTP-like amplification of pain perception (Henrich et al., 2015). An array of needle contact electrodes was used on one forearm for selective electrical stimulation of the most superficial nerve endings in the skin, which are from fine unmyelinated Cand myelinated A -fibre nociceptors. Topical application of capsaicin was used to temporarily desensitize a subgroup of cutaneous Cfibre terminals that express the TRPV1 receptor, and which mediate heat-pain (Cavanaugh et al., 2009). Finally, a well-controlled local compression of the radial nerve in one hand was used to reversibly block the myelinated A-fibres that mediate tactileand cold perception. With these tools at hand the authors were able to study the relative importance of the various fibre types for LTP-like pain amplification after conditioning high-frequency electrical stimulation of fine cutaneous afferents. The conditioning stimulation protocol was adapted from in vitro and animal experiments in which synaptic LTP was studied in nociceptive pathways. This experimental congruence invites conclusions about potential synaptic mechanisms that may underlie changes in pain perception. Conditioning high-frequency electrical stimulation immediately and temporarily induced a pain sensation at the stimulation site. Furthermore, conditioning stimulation also triggered a long-lasting amplification of the pain intensity elicited by single electrical test stimuli applied via the same array of electrodes. This lasting effect was labelled ‘homotopic pain-LTP’ as it was induced at the site of conditioning stimulation and considerably outlasted the period of conditioning. Interestingly, in the surrounding area of skin outside the array of stimulation electrodes, pain sensitivity to mechanical pinprick stimuli also increased for prolonged periods of time (heterotopic pain-LTP). When light stroking stimuli were applied to the skin adjacent to the electrode array on the forearm, the volunteers reported slightly painful sensations before conditioning stimulation. After conditioning, the same stroking stimuli were perceived as significantly stronger. This indicates that dynamic mechanical allodynia was induced by conditioning highfrequency stimulation of cutaneous C-fibre afferents. The key experiments were then conducted by evaluating the impact of two different types of nerve blocks. The experimental data suggest that all types of nociceptive nerve fibres, i.e. TRPV1-positive and TRPV1negative Cand A-fibres, contribute to the pain sensation elicited by conditioning electrical high-frequency stimulation. This is, of course, to be expected from a non-selective electrical stimulus. Interestingly however, the various afferent fibre types differentially contributed to the induction of homoversus heterotopic pain-LTP. For homotopic pain-LTP at the site of conditioning stimulation, the evidence suggests that only C-fibres— either TRPV1-positive or TRPV1negative—but not A-fibres contributed BRAIN 2015: 138; 2463–2470 | 2463