Allodynia mediated by C-tactile afferents in human hairy skin

Viktig studie med alt om hudens c-fibre og deres relasjon til smerte (allodynia). Nevner at det er en samling av flere mekanoreseptorer i både muskel og hud som gir opphav smerte, ikke enkeltvis. 

We show that gentle tactile stimulation (vibration and brushing) of the hairy skin can exacerbate the underlying muscle pain (allodynia) evoked by infusion of hypertonic saline into the tibialis anterior muscle. This effect is dependent upon a low-threshold, mechanosensitive class of nerve fibres in the hairy skin known as C-tactile (CT) fibres. Knowledge of the role of CT fibres in allodynia increases our understanding of the mechanisms that underlie sensory-perceptual abnormalities – a common manifestation of clinical-pain states and neurological disorders.

We recently showed a contribution of low-threshold cutaneous mechanoreceptors to vibration-evoked changes in the perception of muscle pain. Neutral-touch stimulation (vibration) of the hairy skin during underlying muscle pain evoked an overall increase in pain intensity, i.e. allodynia. This effect appeared to be dependent upon cutaneous afferents, as allodynia was abolished by intradermal anaesthesia.
 Sustained muscle pain was induced by infusing hypertonic saline (HS: 5%) into tibialis anterior muscle (TA). Sinusoidal vibration (200 Hz–200 μm) was applied to the hairy skin overlying TA. Pain ratings were recorded using a visual analogue scale (VAS).
During tonic muscle pain (VAS 4–6), vibration evoked a significant and reproducible increase in muscle pain (allodynia) that persisted following compression of myelinated afferents. During compression block, the sense of vibration was abolished, but the vibration-evoked allodynia persisted.  In contrast, selective anaesthesia of unmyelinated cutaneous afferents abolished the allodynia, whereas the percept of vibration remained unaffected.
It is widely accepted that discriminative touch is mediated exclusively by large-diameter sensory fibres, whereas painful sensations are mediated by small-diameter fibres. Consistent with this view, selective microstimulation of a single large-diameter myelinated afferent in awake human subjects evokes a fundamental, innocuous (non-painful) sensation that has the quality of pressure, flutter or vibration according to the type of primary afferent excited (Ochoa & Torebjork, 1983Vallbo et al. 1984Macefield et al. 1990).
In addition to cutaneous nociceptors, which have high mechanical thresholds, there is another class of unmyelinated (C) fibre that has low mechanical thresholds. The existence of low-threshold unmyelinated afferents, termed C-mechanoreceptors, which respond to light touch of the skin, was documented long ago in the hairy skin of the cat and monkey (Zotterman, 1939Maruhashi et al. 1952Douglas & Ritchie, 1957Bessou et al. 1971). Although some investigators had suggested that C low-threshold mechanoreceptors (CLTMs) are vestigial (Kumazawa & Perl, 1977), recent studies have reported a class of unmyelinated fibres in the human hairy skin, known as C-tactile (CT) fibres, that responds to innocuous mechanical stimulation (Johansson et al. 1988Nordin, 1990Vallbo et al.1993).
The response properties of CT fibres have been described using a limited range of stimuli – most notably slowly moving, low-force, mechanical stimuli such as finger stroking and soft brushing (Nordin, 1990Vallbo et al. 19931999Lokenet al. 2009).
 It is this latter observation, together with the results of neuroimaging studies that have demonstrated that CT-mediated inputs project onto the insular cortex, which has underpinned the proposition of a CT-mediated emotional touch system (Olausson et al. 2002Cole et al. 2006;McGlone et al. 2007Olausson et al. 2008).  Intriguingly, in healthy subjects gentle brushing – known to elicit CT fibre responses – can evoke a neutral or even unpleasant sensation at the lowest brushing velocities (Loken et al. 2009), suggesting that gentle tactile stimulation can elicit opposing aspects of touch, i.e. predilection and aversion. A contribution of CT fibres to unpleasant touch has been suggested by recent work showing the activation of superficial dorsal horn neurons by gentle brushing of skin (Andrew, 2010Craig, 2010). Similarly, these fibres have been implicated in touch hypersensitivity after injury in mice (Seal et al. 2009).
In a recent pilot study we found that innocuous tactile stimulation (vibration) of hairy skin intensified the underlying muscle pain (allodynia), and that this effect appeared to be dependent upon cutaneous mechanoreceptors as the allodynia was abolished by intradermal anaesthesia (Nagi et al. 2009).
The ambiguity in the literature about the contribution of different fibre classes to allodynia may be attributed in part to the use of a single-compartment model in which innocuous and noxious stimuli are applied to the same or adjacent regions of skin. Such an approach can lead to uncertainty as to whether any change in pain perception reflects peripheral sensitization of nociceptive fibres and/or an altered central convergence of innocuous and noxious inputs.
The muscle is physically separated from the skin by sheet-like fascia and each is supplied by separate vascular and nerve supplies (O’Rahilly & Muller, 1986Berry et al. 1995;Salmons, 1995Gibson et al. 2009). Within the hairy skin it is known that such low-amplitude vibratory stimuli are preferentially encoded by hair follicle afferents at low frequencies (~5 Hz to 100 Hz) and by Pacinian corpuscle receptors at high frequencies (~50 Hz to 1000 Hz: Merzenich & Harrington, 1969Mahns et al. 2006). Although the response properties of CT fibres to vibratory stimulation remain untested, low-threshold mechanical sensitivity has been demonstrated using soft brushing (Vallbo et al. 1999Olausson et al. 2002;Loken et al. 2009).
We have shown that innocuous cutaneous vibration can increase the intensity of underlying muscle pain, induced by intramuscular infusion of hypertonic saline, and that this effect (i) persists during compression blockade of myelinated fibres but (ii) is abolished by selective anaesthesia of unmyelinated cutaneous afferents. Thus, vibration-evoked allodynia is evidently dependent upon intact C fibre inputs from the skin, and that these C-fibres have a low mechanical threshold (they responded to 200 μm vibration).
Vibration was described as non-painful by all subjects prior to the induction, and following cessation, of muscle pain. Our observations clearly implicate the mechanically sensitive C-tactile (CT) fibres in mediating this vibration-evoked allodynia. In contrast to earlier work, our psychophysical data indicate that the mechanical sensitivity of CT fibres need not be limited to slowly moving stimuli, as allodynia was evoked by vibration following blockade of myelinated afferents.
Using the same data presented by Loken et al.(2009) an alternative explanation can be advanced, namely that C-fibre and large-diameter afferents are activated in parallel during brush stroking, with a sense of pleasantness emerging when large-diameter responsiveness exceeds that of C-fibres.
In our study, brushing stimulation – at reportedly pleasant speeds – evoked allodynia during muscle pain. Thus, it is the concurrent activation of muscle nociceptors during hypertonic saline infusion and cutaneous mechanoreceptors during brushing (and vibratory) stimulation that leads to the allodynia.
In our study, brushing stimulation – at reportedly pleasant speeds – evoked allodynia during muscle pain. Thus, it is the concurrent activation of muscle nociceptors during hypertonic saline infusion and cutaneous mechanoreceptors during brushing (and vibratory) stimulation that leads to the allodynia. The use of differential nerve blocks to avoid the co-activation of multiple fibre classes during tactile stimulation – an ambiguity that has plagued earlier studies – confirms the role of CT fibres in mediating allodynia. Hence, it is the complement of active sensory fibres, rather than the activation of a single class of afferents, which determines the perceptual outcome of activating CT fibres. 
Neuroimaging studies have shown differential representation of pleasant and painful tactile stimuli in certain areas of the brain involved in emotional processing (insular, orbitofrontal and anterior cingulate cortices: Olausson et al. 2002Rolls et al. 2003). However, cortical activation evoked by a neutral tactile stimulus predominantly activates the discriminative-cognitive areas, the primary and secondary somatosensory cortices.
The qualia of touch may have evolved mainly in a social context to create a useful construct of the world, e.g. to predict whether the intent behind another’s action was benign or sinister; synthesized with the sense of ‘self’, these inputs subserve reflective self-awareness that characterizes humans as immensely social creatures (Ramachandran, 2004).

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