The effects of preferential A- and C-fibre blocks and T-type calcium channel antagonist on detection of low-force monofilaments in healthy human participants

Abstract

BackgroundA myriad of studies have argued that tactile sensibility is underpinned exclusively by large myelinated mechanoreceptors. However, the functional significance of their slow-conducting counterparts, termed C-low threshold mechanoreceptors (C-LTMRs), remains largely unexplored. We recently showed the emergence of brush- and vibration-evoked allodynia in human hairy and glabrous skin during background muscle pain. The allodynia persisted following the preferential blockade of myelinated fibres but was abolished by the preferential blockade of cutaneous C fibres, thereby suggesting a pathway involving hairy skin C-LTMRs and their functional counterparts in glabrous skin in this phenomenon. In the present study, we tested the effects of preferential A- and C-fibre conduction blocks and pharmacological blockade of T-type calcium channel Cav3.2 (expressed selectively on small-fibre LTMRs) on monofilament detection thresholds in healthy participants by compression, low-dose intradermal anaesthesia (xylocaine 0.25 %) and selective T-channel antagonist, TTA-A2.ResultsWe found that all participants could detect monofilament contacts (as low as 1.6 mN) within the innocuous tactile range regardless of the preferential blockade of myelinated fibres. Furthermore, during the compression block no subject reported a switch in modality from touch to pain. That is, the low-force monofilament contacts were always perceived as non-painful. However, there was a small but significant elevation of monofilament thresholds (~2 mN) in the glabrous skin following the compression block. Importantly, no differences were found in the thresholds across hairy and glabrous regions while the myelinated fibres were conducting or not. The preferential blockade of C fibres in the glabrous skin (with myelinated fibres intact) also resulted in a small but significant elevation of tactile thresholds. Furthermore, the use of T-channel blocker in the glabrous skin during compression block of myelinated fibres resulted in complete abolition of monofilament sensibility within the innocuous tactile range (tested up to ~20 mN).ConclusionsThese observations suggest that C-LTMRs need not be regarded as a redundant tactile system, but appear to complement normal large-myelinated-fibre tactile function. Convergent findings in glabrous and hairy skin lend support for an underlying system of innocuous mechanoreception with Cav3.2-expressing unmyelinated fibres.

Slow brushing reduces heat pain in humans

“…Recently, it was shown in mice that VGLUT3 (vesicular glutamate transporter)-expressing C-LTMRs release TAFA4 protein when activated, and intrathecal administration of TAFA4 reverses hyperalgesia. Conversely, in mice, low-threshold T-type calcium channel, Cav3.2, is a selective marker for small diameter mechanoreceptors expressing VGLUT3/TAFA4/tyrosine hydroxylase and, more importantly, a conditional knockout of Cav3.2 on C-LTMRs resulted in the attenuation of mechanical and cold allodyniaan observation confirmed in humans by the use of a peripheral T-channel antagonist (Francois et al, 2015;Nagi et al, 2015;Samour et al, 2015). Likewise, GINIP, a Ga1-interacting protein, expressed on nonpeptidergic C fibres (including C-LTMRs) has been shown to modulate the GABAergic inhibition of nociceptive transmission at the spinal level (Gaillard et al, 2014).…”

“…In the current study, vibration frequency and stroking velocity parameters were set based on previous electrophysiological data (Wessberg et al, 2003;L€ oken et al, 2009;Ackerley et al, 2014) on the responsiveness of CT afferents defining them as being optimal or sub-optimal. A recent study showed that skin indentation with monofilament contacts, a stimulus which activates both Ab and CT afferents (Cole et al, 2006;Nagi et al, 2015), produces analgesia when delivered simultaneously with infrared laser heat (Mancini et al, 2014). Interestingly, other studies have argued an intensity-dependent effect of stroking, as it tapered off with an increase in laser strength from a barely detectable condition to pain threshold and above (Kakigi and Shibasaki, 1992;Nahra and Plaghki, 2003).…”

Why does a cooled object feel heavier? Psychophysical investigations into the Weber’s Phenomenon

“…It is worth noting that the C cold fibres and C-LTMRs are both responsive to skin cooling, and while the former have been found to be mechanically insensitive, the latter have been implicated in ‘crude’ detection of low-force punctate mechanical stimuli [18, 28]. The residual incidence of WP following compression blockade—when the cooled stimulus was presented second (66.7 ± 5.5%)—suggests that the C-LTMRs can contribute to tactile–thermal interactions.…”

“…In a subsequent experimental sitting, the myelinated fibres of the ulnar nerve were preferentially blocked using compression of the ulnar nerve by placing a small metal slab just proximal to the medial epicondyle of humerus [16, 18]. This was successfully achieved in 9 of the 11 subjects—the block failed to take effect in one subject and another failed to show up for the experiment.…”

Heantos-4, a natural plant extract used in the treatment of drug addiction, modulates T-type calcium channels and thalamocortical burst-firing

“…Pan T-type blockers that block burst-firing in both VB [18] and TRN [31] neurons have been shown to suppress seizures in animal models of absence epilepsy [31, 58], prevent seizure kindling in a model of complex-partial seizures [59], and suppress tonic-clonic seizures [60]. In terms of pain signalling, pan T-type antagonists have shown efficacy in reducing pain sensation in both animal models [54, 61–63] and humans [64, 65]. T-type calcium currents underlying burst-firing and slow oscillations in the thalamocortical system have been extensively linked to non-REM sleep [6].…”