Evidence for a vasomotor cyclo‐oxygenase dependent mechanism of sensitization at the cutaneous level

Abstract

AIMSCurrent-induced vasodilation (CIV) is an axon-reflex response observed during monopolar current application such as iontophoresis. Cyclo-oxygenase derivates (COD) participate in CIV and act as sensitizing agents at the anodal level. Mechanisms involved during cathodal current application (CCA) are partially unknown. In a randomized double-blind crossover trial, we tested in 16 healthy subjects (i) the influence of the inter-stimulation interval (I-I) by comparing CIV following all-at-once 10 s CCA against 2 × 5 s CCA with intervals ranging from15 s-16 min and (ii) the participation of COD in CIV using 1 g aspirin or placebo intake. METHODSMeasurements were repeated 2 h and 14 days after treatment. Laser Doppler flowmetry assessed cutaneous blood flow, reported in multiples of baseline. RESULTSBefore treatment, peak vasodilation 10 min after the last current application (CVC stim2 ) increased compared with baseline whatever the I-I. Increase in CVC stim2 from baseline was greater for the 4 min (9.4 (5.3, 10.9) times; median (1 st percentile, 3 rd percentile)) and higher I-Is compared with all-at-once delivery (3.0 (2.1, 4.3) times, P < 0.05). The response was similar after placebo but aspirin abolished this vasodilation (increase by 1.2 (1.1, 1.3) times for all-at-once delivery and by 1.5 (1.3, 1.7) ± 0.3 times for 4 min interval, 2 h after aspirin intake) that recovered after 14 days. CONCLUSIONSThis confirms the participation of COD in CIV with CCA and their sensitizing action. This model can represent an attractive way to study the axon-reflex and sensitizing function of COD in humans. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Monopolar current applications (segmented or not) at the cutaneous level can elicit vasodilatation.• Cyclo-oxygenase derivates (probably prostaglandins) participate in this phenomenon and, during segmented current applications, can have a sensitizing effect on the nervous afferent stimulated. • This effect is well known at the anodal level but must be better described for cathodal current. WHAT THIS STUDY ADDS• Participation of cyclo-oxygenase derivates was confirmed for cathodal segmented current application.• A minimal interval must be respected between two current applications to observe the sensitizing effect of cyclooxygenase derivates.• This model is useful to study the sensitizing function of cyclo-oxygenase derivates in humans.

Sensory nerves contribute to cutaneous vasodilator response to cathodal stimulation in healthy rats

“…Indeed both capsazepine and amiloride could block impulse conduction in sensory nerves (Hayes et al, 2007), thereby attenuating CGRP and substance P release (Franco-Cereceda et al, 1993;Santicioli et al, 1993;Zhong and Wang, 2007). Moreover capsazepine, CGRP8-37 and the NK1 antagonist L703,606 could reduce prostacyclin production (Gallicchio et al, 2006;Harada et al, 2003;Mizutani et al, 2009) and we demonstrated that prostacyclin plays a major role in cathodal CIV in rats (Gohin et al, 2011), as recently confirmed in humans (Mahe et al, 2015). Although each drug is selective for a channel or receptor, it may not be specific in its action, given a plausible explanation for the large decrease in cathodal CIV observed for each individual blockade.…”

Neurovascular microcirculatory vasodilation mediated by C-fibers and Transient receptor potential vanilloid-type-1 channels (TRPV 1) is impaired in type 1 diabetes

“…We hypothesize that this overexpression could be linked to hypofunction of TRPV-1 that would induce a diminished microvascular peak response in our T1D patients, but this remains to be studied. In our study we also used the cathodal CIV, a second axon reflex test that is partially mediated by prostaglandins 28 . This test is based on the anodal CIV test that has been widely used and studied in the literature 29 30 .…”

“…The current application was delivered on the active probe in two consecutive 5-second applications separated by 4 minutes28. For CIV, we studied the late-plateau response.…”

“…Transdermal iontophoresis of deionized water was performed with an iontophoresis chamber (LI 611, Perimed Jarfalla, Sweden) and corresponded to the cathode. The current application was delivered on the active probe in two consecutive 5-second applications separated by 4 minutes 28 . For CIV, we studied the late-plateau response.…”