Abstract
In the setting of injury, myelinated primary afferent fibers that normally signal light touch are thought to switch modality and instead signal pain. In the absence of injury, touch is perceived as more intense when firing rates of Aβ afferents increase. However, it is not known if varying the firing rates of Aβ afferents have any consequence to the perception of dynamic mechanical allodynia (DMA). We hypothesized that, in the setting of injury, the unpleasantness of DMA would be intensified as the firing rates of Aβ afferents increase. Using a stimulus-response protocol established in normal skin, where an increase in brush velocity results in an increase of Aβ afferent firing rates, we tested if brush velocity modulated the unpleasantness of capsaicin-induced DMA. We analyzed how changes in estimated low-threshold mechanoreceptor firing activity influenced perception and brain activity (functional MRI) of DMA. Brushing on normal skin was perceived as pleasant, but brushing on sensitized skin produced both painful and pleasant sensations. Surprisingly, there was an inverse relationship between Aβ firing rates and unpleasantness such that brush stimuli that produced low firing rates were most painful and those that elicited high firing rates were rated as pleasant. Concurrently to this, we found increased cortical activity in response to low Aβ firing rates in regions previously implicated in pain processing during brushing of sensitized skin, but not normal skin. We suggest that Aβ signals do not merely switch modality to signal pain during injury. Instead, they exert a high- and low-frequency-dependent dual role in the injured state, with respectively both pleasant and unpleasant consequences. NEW & NOTEWORTHY We suggest that Aβ signals do not simply switch modality to signal pain during injury but play a frequency-dependent and dual role in the injured state with both pleasant and unpleasant consequences. These results provide a framework to resolve the apparent paradox of how touch can inhibit pain, as proposed by the Gate Control Theory and the existence of dynamic mechanical allodynia.
Highlights
A major premise of the Gate Control Theory of Pain that Melzack and Wall (1965) proposed was that activation of myelinated low-threshold afferent fibers can inhibit pain.These authors postulated that the myelinated low-threshold mechanoreceptors (LTMs) that signal innocuous touch (Johnson and Hsiao 1992; Vallbo and Johansson 1984) can decrease the activity in ascending nociceptive pathways that is generated by small-diameter afferents
A LTMs increase their firing rate with increasing brush velocity (Ackerley et al 2014; Löken et al 2009). It follows that CLTM firing rates in response to varying brush velocity can be modeled as an inverted U-shaped function but that firing intensity in A fibers increases linearly with brush velocity
We reasoned that if A afferent activity is an important contributor to dynamic mechanical allodynia (DMA), changes in A firing rates, which are linear in relationship to brush velocity, should generate correlated percepts
Summary
A major premise of the Gate Control Theory of Pain that Melzack and Wall (1965) proposed was that activation of myelinated low-threshold afferent fibers can inhibit pain.These authors postulated that the myelinated low-threshold mechanoreceptors (LTMs) that signal innocuous touch (Johnson and Hsiao 1992; Vallbo and Johansson 1984) can decrease (by gating) the activity in ascending nociceptive pathways that is generated by small-diameter afferents. The mechanism through which normally innocuous stroking becomes painful is thought to result from a central sensitization process, in which there is an enhanced excitability of nociceptive dorsal horn neurons that makes them responsive to low-threshold mechanical stimuli (Cook et al 1987; Woolf 1983). Consistent with this hypothesis, intraneural microstimulation of A fibers in the area sensitized by capsaicin injection can evoke pain (so-called mechanical allodynia) (Torebjörk et al 1992). The fact that DMA cannot be evoked in patients lacking A fibers (Liljencrantz et al 2013; Treede and Cole 1993) is consistent with a necessary contribution of myelinated LTMs
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