Mechanical allodynia

Abstract

Mechanical allodynia (other pain) is a painful sensation caused by innocuous stimuli like light touch. Unlike inflammatory hyperalgesia that has a protective role, allodynia has no obvious biological utility. Allodynia is associated with nerve damage in conditions such as diabetes, and is likely to become an increasing clinical problem. Unfortunately, the mechanistic basis of this enhanced sensitivity is incompletely understood. In this review, we describe evidence for the involvement of candidate mechanosensitive channels such as Piezo2 and their role in allodynia, as well as the peripheral and central nervous system mechanisms that have also been implicated in this form of pain. Specific treatments that block allodynia could be very useful if the cell and molecular basis of the condition could be determined. There are many potential mechanisms underlying this condition ranging from alterations in mechanotransduction and sensory neuron excitability to the actions of inflammatory mediators and wiring changes in the CNS. As with other pain conditions, it is likely that the range of redundant mechanisms that cause allodynia will make therapeutic intervention problematic.

Fig. 1

Sensitization to pain. This graphical representation of the shift in pain thresholds during a pain state shows both enhanced response to noxious, normally painful, stimuli (hyperalgesia) and pain triggered by non-noxious stimuli (allodynia) like the gentle brush of the skin. These two painful states do not always coexist, and it is increasingly apparent that they are driven by distinct mechanisms in different sets of sensory neurons

Fig. 2

Signalling pathways for the sensitization of mechanosensitive sensory neurons. Different but interconnected pathways have been shown to contribute to the sensitization of mechanosensitive neurons, leading to allodynia. PKA and PKC are known to be important for neuronal excitability, notably through voltage-gated sodium channel modulation [12, 39], but more recently, they were also found to have an effect on mechanotransduction directly. Indeed, the low threshold mechano-gated channel Piezo2 has been shown to be positively modulated by PKC, PKA [9] and by the cAMP sensor EPAC1 [10]. EPAC1, but not EPAC2, enhances Piezo2 current by activating the G protein Rap1 when activated by cAMP. cAMP increases can be induced directly by the activation of GPCR coupled to Gs proteins (PGE₂ receptor EP₂, histamine H2 receptor, CALCRL receptor for CGRP, serotonin receptor 5-HT₄…) or indirectly via a calcium increase, induced either by an ion channel (TRPs, ASICs, P2Xs…) or by IP₃-mediated calcium increase following either activation of a PLC coupled tyrosine kinase receptor (e.g. neurotrophin receptors) or activation of a GPCR coupled to Gq proteins (PGE₂ receptor EP₁, histamine receptor H1, serotonin receptor 5-HT₂…). PLC activation will also result in DAG-mediated activation of PKC, which has also been shown to positively regulate Piezo2 channels [9]. However, PKA and PKC activation were found to have no effect on the human Piezo2 channel [10]. Therefore, further work is needed to clarify Piezo2 modulation by these signalling pathways. TRPC3 and TRPC6 channels were also found to be involved together in the generation of a low threshold mechanically activated current and to be essential for normal touch perception [34]. It is not known whether these channels are subject to the same positive regulation as Piezo2. Mechano-gated channels producing rapidly, intermediately and slowly adapting currents, yet to be identified, are also positively regulated by NGF and PKC [5]. In sensory neuron cultures, TrkA activation by NGF leads to transcription of new channels, and activated PKC promotes the insertion of the channels into the membrane to increase peak currents [2]