Saad S. Nagi

Allodynia mediated by C‐tactile afferents in human hairy skin

Non‐technical summary  What triggers a realignment of sensations, e.g. a stimulus that is perceived as non‐painful in intact skin, but evokes pain in sunburned skin, is yet to be ascertained. This phenomenon is clinically termed allodynia. 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.

Cav3.2-expressing low-threshold C fibres in human hairy skin contribute to cold allodynia--a non-TRPV1- and non-TRPM8-dependent phenomenon.

Abstract It is generally agreed that cold allodynia is a consequence of impaired (A&dgr;-fibre-mediated) central inhibition of C-nociceptive inputs. However, it is also known that C polymodal nociceptors are not activated at innocuous low temperatures. Recently, we demonstrated the contribution of C-tactile fibres to tactile allodynia. In this study, we investigated whether this, or a related, C-fibre class contributes to cold allodynia. In 30 healthy and 3 chronic pain subjects, a series of normally innocuous localised thermal stimuli were applied to the skin overlying a painful tibialis anterior muscle (induced by infusion of hypertonic saline). The effects of thermal stimulation on muscle pain were observed before and after compression blockade of myelinated fibres. Furthermore, intradermal capsaicin, menthol and TTA-A2 were used for desensitisation of TRPV1, TRPM8, and T-type calcium (Cav3.2) channels, respectively. Before muscle pain, all thermal stimuli were reported as nonpainful regardless of whether myelinated fibres were conducting or not. During muscle pain, dynamic skin cooling (32°C → 20°C) evoked significant and reproducible increases in the overall pain intensity (allodynia). This increase was short lived and locked to the dynamic phase of cooling with pain levels returning to baseline during sustained cooling. Dynamic warming (32°C → 39°C) had no effect on pain levels. Cold allodynia persisted after nerve compression and TRPV1 and TRPM8 desensitisation but was abolished by localised Cav3.2 blockade. In clinical subjects, C-fibre-mediated allodynia was observed without the need for experimental pain-producing manipulations. In conclusion, cold allodynia represents a non-TRPV1- and non-TRPM8-dependent phenomenon, which is mediated by low-threshold Cav3.2-expressing C fibres.

C-tactile Fibers Contribute to Cutaneous Allodynia After Eccentric Exercise

UNLABELLED We recently showed that during acute muscle pain, C-tactile (CT) fibers mediate allodynia in healthy human subjects. In this study, we pursued the following questions: Do CTs contribute to allodynia observed in delayed onset muscle soreness (DOMS)? Is CT-mediated allodynia reproducible in a clinical pain state? In 30 healthy subjects, DOMS was induced in anterior compartment muscles of the leg by repeated eccentric contractions. DOMS was confirmed by mapping the emergence of tender points (decreased pressure pain thresholds). Furthermore, we measured pressure pain thresholds in a clinical subject who presented with activity-triggered heel pain but no resting pain. Cutaneous vibration (sinusoidal; 200 Hz-200 μm)--an otherwise innocuous stimulus--was applied to anterolateral leg before exercise, during DOMS, and following recovery from DOMS. The peripheral origin of allodynia was determined by employing conduction blocks of unmyelinated (intradermal anesthesia) and myelinated (nerve compression) fibers. In DOMS state, there was no resting pain, but vibration reproducibly evoked pain (allodynia). The blockade of cutaneous C fibers abolished this effect, whereas it persisted during blockade of myelinated fibers. In the clinical subject, without exposure to eccentric exercise, vibration (and brushing) produced a cognate expression of CT-mediated allodynia. These observations attest to a broader role of CTs in pain processing. PERSPECTIVE This is the first study to demonstrate the contribution of CT fibers to mechanical allodynia in exercise-induced as well as pathological pain states. These findings are of clinical significance, given the crippling effect of sensory impairments on the performance of competing athletes and patients with chronic pain and neurological disorders.

Slow brushing reduces heat pain in humans

C‐tactile (CT) afferents are unmyelinated low‐threshold mechanoreceptors optimized for signalling affective, gentle touch. In three separate psychophysical experiments, we examined the contribution of CT afferents to pain modulation.

Psychophysical Investigations into the Role of Low-Threshold C Fibres in Non-Painful Affective Processing and Pain Modulation

We recently showed that C low-threshold mechanoreceptors (CLTMRs) contribute to touch-evoked pain (allodynia) during experimental muscle pain. Conversely, in absence of ongoing pain, the activation of CLTMRs has been shown to correlate with a diffuse sensation of pleasant touch. In this study, we evaluated (1) the primary afferent fibre types contributing to positive (pleasant) and negative (unpleasant) affective touch and (2) the effects of tactile stimuli on tonic muscle pain by varying affective attributes and frequency parameters. Psychophysical observations were made in 10 healthy participants. Two types of test stimuli were applied: stroking stimulus using velvet or sandpaper at speeds of 0.1, 1.0 and 10.0 cm/s; focal vibrotactile stimulus at low (20 Hz) or high (200 Hz) frequency. These stimuli were applied in the normal condition (i.e. no experimental pain) and following the induction of muscle pain by infusing hypertonic saline (5%) into the tibialis anterior muscle. These observations were repeated following the conduction block of myelinated fibres by compression of sciatic nerve. In absence of muscle pain, all participants reliably linked velvet-stroking to pleasantness and sandpaper-stroking to unpleasantness (no pain). Likewise, low-frequency vibration was linked to pleasantness and high-frequency vibration to unpleasantness. During muscle pain, the application of previously pleasant stimuli resulted in overall pain relief, whereas the application of previously unpleasant stimuli resulted in overall pain intensification. These effects were significant, reproducible and persisted following the blockade of myelinated fibres. Taken together, these findings suggest the role of low-threshold C fibres in affective and pain processing. Furthermore, these observations suggest that temporal coding need not be limited to discriminative aspects of tactile processing, but may contribute to affective attributes, which in turn predispose individual responses towards excitatory or inhibitory modulation of pain.