Journal of Neurology, Neurosurgery, and Psychiatry 1988;51:28-34

Quantitative objective assessment of peripheralnociceptive C fibre functionN PARKHOUSE, PAMELA M LE QUESNE

From the Departments ofSurgical Studies and Neurological Studies, The Middlesex Hospital Medical School,London andMRC Toxicology Unit, Carshalton, Surrey, UK

SUMMARY A technique is described for the quantitative assessment of peripheral nociceptive Cfibre function by measurement of the axon reflex flare. Acetylcholine, introduced by electrophoresis,is used to stimulate a ring of nociceptive C fibre endings at the centre of which the increase in bloodflow is measured with a laser Doppler flowmeter. This flare (neurogenic vasodilatation) has beencompared with mechanically or chemically stimulated non-neurogenic cutaneous vasodilation. Theflare is abolished by local anaesthetic and is absent in denervated skin. The flare has been measuredon the sole of the foot of 96 healthy subjects; its size decreases with age in males, but not in females.

In recent years quantitative measurement of variousmodalities of peripheral sensation has come to beincreasingly important in both diagnosis and manage-ment of peripheral neuropathy.' 2 Although sensitivemethods are available for measuring mechano-receptor and thermal function, techniques suitable forclinical measurement of nociceptor function are lesssatisfactory. In early classical work on pain, Hardyet al3 used radiant heat as a stimulus amd morerecently heat-pain threshold has been measured usingthe more precisely controlled stimulus produced by aPeltier thermode.' A device for measuring mechani-cally induced pain was produced by Lynn and Perlsand used in the measurement of pain threshold indiabetics by Le Quesne and Fowler.6 The value of allthese techniques is limited by the particular problemsof subjective pain assessment.

During a study of sweating in diabetics using thetechnique developed by Low et al7 whereby axonreflex sweating was induced by electrophoresis ofacetylcholine, Ahmed and Le Quesne8 noted that incontrol and some diabetic subjects a spreading flaredeveloped, whereas in others the flare was absent.Lewis9 demonstrated that the spreading vaso-dilatation of the triple response was an axon reflexdepending on the integrity of nociceptor afferentnerves. Recently there has been a resurgence of inter-

Address for reprint requests: Dr Pamela M Le Quesne, MiddlesexHospital Medical School London WIN 8AA.

Received 27 March 1987. Accepted 8 June 1987

est in neurogenic inflammation and the vasoactivepeptides, particularly substance P, responsible for theaxon reflex flare.'0 Lembeck" has re-emphasised thedual role of the small C fibres forming Lewis's noci-fensor system, whereby stimulation of cutaneousnociceptor endings produces impulses which travelboth to the CNS to produce the sensation of pain andto axon collaterals to initiate neurogenic inflam-mation. By means of a technique for quantifying theflare response,'2 we have used the linking of the twofunctions in one fibre to provide an objectivemeasurement of peripheral pain pathways. Inaddition, we can measure neurogenic inflammation,whose impairment may be important in somediseases.The flare depends on a cutaneous vascular reaction.

This assumes that the vasculature is capable ofresponding to the vasodilator peptides released by theaxon reflex. To assess the capacity of the vessels todilate, use has been made of another component ofLewis's9 triple response, the direct local red reaction,which is independent of nerves. This reaction, whichcan be produced in a variety of ways and is confinedto the area stimulated, will reveal any intrinsic vascu-lar abnormality due for example to microangiopathyor occlusive vascular disease.

Methods

Apparatus and techniqueCapsule Stimulation and measurement were performedconcurrently using a small capsule applied to the skin (fig 1).This capsule is a modification of the one described by Low

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Quantitative objective assessment ofperipheral nociceptive C.fibre function

Fig I (a) Photograph ofcapsule; (b) diagram ofcapsuleshowing spread offlare both outwards and inwardsfrom thering ofstimulation.

et al7 to measure axon reflex sweating. It has two concentricchambers, each fitted with an inlet and outlet vent, and witha platinum wire electrode, which is used as the anode forelectrophoresis. The walls of the chambers are thick and thebase smooth so that double sided adhesive rings (3M) pro-duce a water tight seal with the skin, which was prepared bygentle cleansing. The probe of the laser Doppler flowmeterused for measuring blood flow is mounted vertically at thecentre of the capsule with the probe inserted to a distance of1 mm from the skin. The cathode for electrophoresis is a leadplate, 4 x 6cm, wrapped in saline soaked gauze andattached to the skin, previously cleansed with spirit, withmicropore tape. A constant current generator designed andbuilt at The Mayo Clinic was used to provide a 1 mA stimu-lus.

The laser Doppler flowmeter A PF2 laser Dopplerflowmeter linked to a BBC chart recorder was used to mea-sure the changes in superficial cutaneous blood flow. A nar-row laser light beam is transmitted through a fibre opticcable to the probe head and penetrates the skin to a depth of1-5 mm. The coherent light is scattered in the tissues; the raysscattered by moving red blood cells undergo a frequencyshift according to the Doppler principle. The backscatteredlight travels back through a separate fibre optic channel to aphotodetector which produces an output linearly related tothe flux of red cells i.e. the number of cells times their veloc-ity. This output signal is fed to the pen recorder. The signal,expressed in mV rather than conventional flow units, is anindirect measure of blood flow but a close correlation hasbeen obtained between laser Doppler flux and red cell veloc-ity determined by direct capillary microscopy.13The laser Doppler signal is sensitive to small changes in

flow; sympathetic arousal stimuli cause clearly detectablechanges. Movement of the subject or the probe causes anabrupt artefact which is easily distinguishable from physio-logically induced changes. Measurements have generallybeen made on the 12 kHz scale with a gain of x 3 and a timeconstant of 1 5 s.

Procedure Measurements were made after 30 minutesacclimatisation in a warm room maintained at 26°C in orderto reduce sympathetic vasoconstrictor tone and to enablecomparison with data from neuropathic patients in whomlimb temperature is often higher than in healthy subjects.The skin temperature was 34-35 C° throughout the test.To produce the axon reflex flare, the outer ring was filled

with 10% acetylcholine (ACh) and, when the Doppler signalwas stable, a current of 1 mA was passed for 5 min throughthe outer chamber. The flare produced spreads both out-wards, where it is visible, and inwards where it is measuredby the probe (fig lb).For the direct, chemically induced non-neurogenic reac-

tion, the central well was filled with either 10% ACh or 1%pilocarpine, and a stimulus of 1 mA applied for 5 minthrough the central chamber.A direct, mechanically induced red reaction was produced

by making a firm stoke with a spring loaded dermograph,which produces a pressure of 2 5 N. The flux was measuredwith the probe at the same site before and after stimulation.

Results

Characteristics of the vascular reactionsTypical findings in a control subject are shown infig 2. The increasing laser Doppler flux recorded fromthe centre of the capsule during electrophoresis ofACh from the outer ring is shown in fig 2a. This is theaxon reflex flare. Pilocarpine was then electro-phoresed from the central wall under the laserDoppler probe and the further rise in flux duringdevelopment of the non-neurogenic direct reaction isseen. This non-neurogenic reaction is the same fol-lowing electrophoresis of either pilocarpine or AChfrom the central well, although pilocarpine, unlikeACh, does not in addition produce a flare. The direct

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30

20r 0

> 15E

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0.lo-

0o

o,) 5

0 L

Firr

IACh 1mA) Pilo(1mA)*Outer ring .Centre,.. . . . . . . . .0 2 4 6 8 10 12

Time (min)Fig 2 Laser Dopplerflux (mV): (a) and (b)sole offoot ofJ.H. (F, aged 44). (a) during eleofacetylcholine (ACh) from outer ring, followepilocarpinefrom central well; (b) afirm strokemade with a dermograph at an adjacent site andplaced over the area of visible vasodilatation.

red reaction following a firm strokemograph is shown for the same patient irdirect mechanically induced red reactiosmaller than the pilocarpine reaction, incmaximal vasodilatation is not producedcedure.The classical stimulus for the flare is

histamine. The flux recorded from ainduced flare is shown in fig 3b. It is simnitude to the ACh-induced flare recordadjacent site of the forearm of the sz(fig 3a).The specificity of ACh as a stimulus

was demonstrated by comparing it withlack of reaction to electrophoresis of salinwith the rapid increase in flux during eleiof ACh can be seen in fig4a.The neurogenic origin of the axon refli

demonstrated by examining locally aiskin. Five ml 1% lignocaine were injectedthe subcutaneous tissue to minimise lo(which would itself produce a flare. The tried out after an area of approx 4 sq cm Iinsensitive. The results are shown in fig 4bno increase in flux when ACh was electfrom the outer ring, but non-neurogenicinduced vasodilatation occurred whenwas electrophoresed from the central well.

Further confirmation of the neurogeni

Parkhouse, Le Quesnethe axon reflex flare was obtained by examiningtotally denervated skin. Surgically transferred freeflaps, consisting of skin and subcutaneous tissue on avascular pedicle, were examined at a time when com-plete nerve degeneration must have occurred. Theaxon reflex flare to ACh was absent in the skin of suchflaps, along with all other sensory modalities. Thedirect red reaction to mechanical stimulation wasunaffected. There was, however, some slight reduc-

f tion in the non-neurogenic direct pilocarpineI ~~response.

n stroke Passage of I mA current produces, in most sub-jects, a-prickling sensation. Increasing the current to apainful intensity (usually 2 mA) did not increase themagnitude of the vasodilatation (fig 4c).

In order to investigate the influence of chronic, , ischaemia on the vascular reactions on the sole of the0 2 4 foot, five subjects with clinical evidence of severe

major arterial disease in the lower limbs were studied.The flare was absent in two and reduced in three. The

recordedfrom non-neurogenic reaction to both pilocarpine and actrophorests firm stoke were also reduced. All reactions wered by absent in the patient with the most severely ischaemicwas then legthe probe

Control dataData have been obtained on the two types of vascular

with a der- reaction, the flare and the direct response, by exam-a fig 2b. The ining 45 male and 54 female healthy subjects, aged,n is usually 20-72 years. The sole of the foot was examined since.icating that this site is most commonly affected in patients withby this pro- peripheral neuropathy. In each case the probe was sit-

uated on the supple skin immediately posterior to theintradermal first metatarsal head.histamine- The size of the flare can be expressed either as the

tilar in mae- absolute magnitude of the flux recorded or as anled from aname subject

for the flareXsaline. Theie comparedctrophoresis

ex flare wasnaesthetiseddeeply intocal trauma,est was car-had become'. There wastrophoresedchemically-pilocarpineic nature of

Ir

E

4 ,

L-o

a

a

10 v

5

OL ACh(lmA)0 . .

0Hist.

4t-

0 2 4 6 8 10 120 2Time (min)

4 6 8 10

Fig 3 Laser Dopplerflux (m V): (a) and (b) recordedfromforearm ofP.L. (a) during electrophoresis of (ACh) fromouter ring; (b) intradermal histamine was then injected at anadjacent site and the probe placed over theflare whichdeveloped.

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Quantitative objective assessment ofperipheral nociceptive Cfibre function

20r o151-

10

ACh (1mA)

01 I I I I 110 112 11L 16 18 20 22%A15

Prior s.c.10 - 1% Lignocaine

5 -

_ACh(1mA) Pilo.1mA) lmA 2mAOuter ring Centre

O 2 4 6 8 10 12 14 0 2 41 6 8 10Time (min)

Fig 4 Laser Dopplerflux (m V): (a) recordedfrom the soleoffoot ofP.L. during electrophoresis ofsalinefollowed byacetylcholine (ACh), bothfrom outer ring; (b) and (c) fromforearm ofP.L. (b) during electrophoresis ofAChfromouter ringfollowed by pilocarpine from central well 5 minafter sc. injection of1% lignocaine; (c) duringelectrophoresis ofAChfrom outer ring with I mA currentfollowed by 2mA current.

increase from the resting value. It was shown that thehigher the resting flux, the higher the figure afterinduction of the flare (R = 0-225, p < 0 02), but the

Males

Table Flux values for various vascular reactions recordedfrom the sole of thefoot of90 healthy subjects

Resting Flare Stroke Pilocarpine Index

Mean 32 117 159 219 705%SD 1-8 3-7 41 66 28-6%p NS

32index was 70 5% and like the absolute size of theflare, it decreased significantly with age (p < 0 001)(table). The direct red reaction, although not maximalvasodilatation, has been used for this index, becauseof the slight reduction in pilocarpine or ACh-vasodilatation in totally denervated skin.

Discussion

We have used the electrophoresis of ACh as a stan-dard, reproducible, atraumatic stimulus which willproduce a maximal flare within a few minutes.Douglas and Ritchie"4 demonstrated that ACh has adirect excitatory action on non-myelinated C fibres inthe saphenous nerve of the cat, this being abolishedby hexamethonium but not by atropine. Pilocarpineproduces direct vasodilation identical to that pro-duced by ACh but no flare; these two observationsboth suggest that stimulation of the flare depends onthe nicotinic action of ACh. Other substances whichproduce a flare are less convenient for clinical use andfor producing a quantifiable response. Histaminemust be injected intracutaneously. A singleapplication of capsaicin produces a flare, but it isabolished by repeated applications probably due todepletion of substance P.'5 The flare produced bymustard oil is so variable that it is only possible todetermine whether a flare is present or absent. 16

Previous attempts at quantification of the flarehave depended on measurement of the area of visiblevasodilatation. This can be difficult, not only becauseof variability due to lack of standardisation of thestimulus, but also because the flare has an irregularoutline and crenated edge9 due to anatomical vari-ations in the distribution of the responsible nerves.We have overcome these problems by measuring thechange in superficial cutaneous blood flow at onefixed point at the centre of a ring stimulus. LaserDoppler measurement has the additional advantagethat an objective measurement may be made whenerythema is not visible to the naked eye, such as wherethe skin is thickened, as on the sole of the foot, and onpigmented skin.

Electrophoresis of ACh over the area of the ring ofthe capsule produces, in most people, a "prickling"sensation, which is not actually painful. Prickling hasin the past been ascribed to the small cutaneous nervefibres responsible for pain sensation.'7 Pain is pro-duced by the simultaneous stimulation of many neu-rons, the pattern of impulse discharge probably beingof importance. Microneurographic studies haveshown that low frequency firing of nociceptive fibresdoes not produce pain, whereas pain does occur at ahigher firing frequency of the same fibres.'8 It istherefore quite understandable that maximum reflexvasodilation is evoked by a stimulus which is not per-

Parkhouse, Le Quesneceived as painful. We have shown that increasing thestrength of the electrophoresis current to a level whichproduces pain does not increase the vasodilatation.Chronic ischaemia impairs non-neurogenic vaso-

dilatation, so that little significance can be attached toan absent flare in an ischaemic limb. It is thereforeimportant that the flare should always be comparedwith directly stimulated vasodilatation. Intradermalnitroprusside is probably the best agent for producingmaximal vasodilatation. '" We did not use this stimu-lus because we sought to make the whole techniquenon-invasive. It was hoped that pilocarpine or AChwould provide an adequate direct stimulus but it wasfound that in totally denervated skin this reaction wasslightly reduced. In keeping with this finding, recentexperimental observations have suggested that ACh-vasodilatation is less in totally denervated vessels inthe rabbit's ear.20 For these reasons we have useddirect mechanical stimulation with the dermograph asa stimulus totally independent of neural influence,even though this dilatation is not maximal.Many neurological functions decrease with age.

For example, in the lower limb threshold forvibration perception21 - 23 and for cooling andwarming24 25 have been found to increase with age.Sensory nerve action potential amplitude26 and thedensity of nerve fibres in peripheral nerve trunks27both decrease with age in the lower limb. In a pre-vious study of the flare produced by topical capsaicinthe area of the flare over the trapezoid ridge wasfound to decrease with age, as was the substance Pcontent of skin from the cubital fossae and ankle.28When sensory thresholds have been estimated sepa-rately for males and females the decrease in age hasbeen more marked in males, for example forvibration29 30 and for temperature.3' Thus, thepresent findings of an age decrease in the flare, whichis more marked in males, is similar to the findings forother peripheral nerve functions. To be able to detectthis effect gives an indication of the quantitativesensitivity of the technique.

This technique provides an indirect method ofmeasuring the integrity of peripheral pain pathways,providing an objective, atraumatic alternativeto psychophysical techniques for measuring pain.Quantification of pain pathways will be valuable inassessment of peripheral neuropathies; for example,in analysing the multiple defects contributing to theformation of diabetic neuropathic foot compli-cations. The presence or absence of an axon reflex hasbeen diagnostically useful in the past, but a quan-titative test is more valuable. The flare may be absentin diabetics,32 - 3 and we have now been able to studyit quantitatively in diabetics with neuropathic ulcer-ation and Charcot arthropathy.35 Following tractioninjuries to the brachial plexus, the presence of a flare

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Quantitative objective assessment ofperipheral nociceptive Cfibre functionin an area of sensory loss indicates a pre-ganglioniclesion.3637 We have found its quantification to beuseful in the diagnosis of mixed pre- and post-ganglionic lesions. A histamine flare test is valuable inthe diagnosis of familial dysautonomia (theRiley-Day syndrome),38 since non-myelinated noci-ceptive fibres are lost as well as autonomic nerves. It ispossible that a quantitative deficit might be found inobligate heterozygotes which would permit accurategenetic counselling in affected families.

It is increasingly apparent that neurogenicinflammation plays an essential part in the body'sdefence mechanisms. The quantitative test nowdescribed allows us to explore the importance of adeficit in this mechanism. In diseases such as con-genital insensitivity to pain, where the flare isabsent,39 and in diabetes, loss of the neurogenicinflammatory response may be as important as loss ofpain sensation in the manifestations of the disease.

In conclusion, the dual role of the nociceptive sys-tem allows the flare to be used to study deficits both ofpain and of neurogenic inflammation. It has beenadded to our battery of other quantitative tests toproduce a profile of abnormalities of the differenttypes of fibre making up a peripheral nerve.

NP was supported by the William Scholl Foundationadministered through the London Foot Hospital towhom he is most grateful. We are also grateful toMr Tarlock Gajree for assistance, to Dr Bruce Lynn,Dr J C Foreman and Mr J H Scurr for their adviceand to Mr N M Breach, Mr M D Brough, Mr D MEvans and Mr R Sanders for allowing us to studytheir patients with free flaps.

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