International Congress Series 1238 (2002) 11 – 29

Pain modulation triggered by high-intensity

stimulation: implication for acupuncture analgesia?
Daniel Le Bars*, Jean-Claude Willer
INSERM U-161, 2, rue d’Alésia, 75014 Paris, France
C.H.U. Pitié-Salpêtrière Laboratoire de Neurophysiologie, 91 Boulevard de l’Hopital, 75013 Paris, France

Abstract

The spinal transmission of nociceptive signals is modulated by both spinal and supraspinal
systems. Spinal networks underlie segmental inhibitions, which are mediated via myelinated
cutaneous afferent fibres activated by mechanical stimuli (e.g. rubbing, etc.) Diffuse noxious
inhibitory controls (DNIC) are triggered by peripheral Ay- and C-fibres, involve brain structures
confined to the caudal-most part of the medulla including the subnucleus reticularis dorsalis (SRD)
and are mediated by descending pathways in the dorsolateral funiculi. Combined psychophysical
measurements and recordings of nociceptive reflexes (RIII) in both normal volunteers and patients
with lesions in the spinal cord or brain suggest the existence of identical or equivalent inhibitory
processes in man. Both these mechanisms could be triggered to produce hypoalgesia by acupuncture
needles or moxibustion. When applied near a painful focus, the techniques have similarities to high-
frequency, low-intensity transcutaneous nerve stimulation, which brings segmental inhibitory
mechanisms into play. When applied to remote areas, the techniques might be related to ‘‘counter-
irritation’’ or ‘‘counter-stimulation’’ phenomena which, in addition to involving complex autonomic
functions, seem to involve DNIC. Experimental data in both animals and humans support these
conclusions. D 2002 Elsevier Science B.V. All rights reserved.

Keywords: Acupuncture; Pain; Dorsal horn; Nociceptive reflexes; DNIC

Painful stimuli can diminish, or even mask, pain elicited by stimulation of a remote
(extrasegmental) part of the body [1– 3]. This phenomenon has been known of since
ancient times as illustrated by the Hippocrates’ aphorism: ‘‘If a patient be subject to two
pains arising in different parts of the body simultaneously, the stronger blunts the other’’. It

*
Corresponding author. INSERM U-161, 2, rue d’Alésia, 75014, Paris, France. Tel.: +33-1-40-78-93-50; fax:
+33-1-45-88-13-04.
E-mail address: lebars@broca.inserm.fr (D. Le Bars).

0531-5131/02 D 2002 Elsevier Science B.V. All rights reserved.

PII: S 0 5 3 1 - 5 1 3 1 ( 0 2 ) 0 0 4 1 2 - 0
12 D. Le Bars, J.-C. Willer / International Congress Series 1238 (2002) 11–29

has even been used during surgical procedures on both human patients and domestic
animals. In the latter category, two examples are the use of the twitch in horses and of nasal
forceps in cattle for performing caudectomies or castrations, both of which are potentially
painful operations. The working hypothesis was developed that some of the neurones
involved in the transmission of nociceptive signals can be inhibited by nociceptive
stimulation of peripheral territories outside their own excitatory receptive fields. That such
an hypothesis is correct at as early a stage as the spinal cord was revealed by the finding that
some dorsal horn neurones are strongly inhibited when a nociceptive stimulus is applied to
any part of the body, distinct from their excitatory receptive fields. For convenience, this
phenomenon was termed ‘‘diffuse noxious inhibitory controls’’ (DNIC).

1. Diffuse noxious inhibitory controls (DNIC) in animal

In the rat (see references below), the cat [4,5] and, probably, the monkey [6,7], most
wide-dynamic-range and some nociceptive-specific neurones can be strongly inhibited by
noxious inputs applied outside their receptive field. Such effects do not appear to be
somatotopically organised but apply to the whole body. Conversely, they apply to
neurones in the dorsal horn of various segments of the spinal cord [8 – 17] or in either
nucleus caudalis or nucleus oralis of the trigeminal system [18 – 21]. The neurones affected
include some projecting to the thalamus [22]. It should be noted that the inhibitions
triggered by heterotopic noxious stimuli are highly sensitive to the anaesthetic regimen, an
observation that could explain some reports of lesser inhibitory effects [6,9,16,23].
DNIC are triggered by conditioning stimuli applied to any part of the body distant from
the excitatory receptive field of the neurone under study, provided that the stimuli are
clearly noxious. There is a clear relationship between the intensity of the conditioning
stimulus and the strength of the resultant DNIC [24,25]. With strong stimuli, the inhibitory
effects are powerful indeed and are followed by long-lasting post-stimulus effects, which
can persist for several minutes. In some cases, the inhibitory effects can involve a complete
abolition of activity for a long period of time following removal of the conditioning stimuli
(‘‘switch-off’’) and the activity can be restored to preconditioning levels by further
manipulations of the excitatory receptive field (‘‘switch-on’’) [26].
With regard to the viscera, some differences should be noted: visceral stimuli, e.g.
distension of the colon or urinary bladder, generally produce inhibitions with slower rates of
onset and recovery but starting with intensities below a painful level [15]. It was proposed
that these differences may have reflected different amounts and patterns of activity in the
relevant primary afferent fibres rather than being due to different central neural mechanisms.
In any case, these data suggest that DNIC are triggered specifically by the activation of
peripheral nociceptors whose signals are carried by D- and C-fibres. In order to further
investigate the types of peripheral fibres involved in DNIC, we took advantage of the
facts: (1) that trigeminal and spinal dorsal horn neurones respond with relatively steady
discharges to the electrophoretic application of excitatory amino-acids, and (2) that DNIC
act by a final postsynaptic inhibitory mechanism involving hyperpolarisation of the
neuronal membrane [27,28]. It was found that when spinal or trigeminal wide-dynamic-
range neurones were directly excited by the electrophoretic application of glutamate, the
 D. Le Bars, J.-C. Willer / International Congress Series 1238 (2002) 11–29 13

percutaneous application of single square-wave, electrical stimuli to the tail always

induced a biphasic depression of the resultant activity [29,30]. Both the early and late
components of this inhibition occurred with shorter latencies when the base rather than the
tip of the tail was stimulated. Such differences in latency were used to estimate the mean
conduction velocities of the peripheral fibres triggering the inhibitions: the means were
found to be 7.3 and 0.7 m/s, which fall into the D- and C-fibre ranges, respectively. Such
biphasic inhibitions could be elicited from any part of the body and recorded from any
wide-dynamic-range neurones. Fig. 1 shows a recording from a lumbar wide-dynamic-
range neurone with an excitatory receptive field located on the extremity of the ipsilateral
hind paw: two components of inhibition were induced by the activation of D- and C-fibres,
respectively, when a single 2-ms duration shock of 10 mA was applied to the muzzle, the
base or the tip of the tail.
DNIC are not observed in anaesthetised or decerebrated animals in which the spinal
cord has been sectioned [5,10,31]. It is therefore obvious that the mechanisms underlying
DNIC are not confined to the spinal cord and that supraspinal structures must be involved.
Such a system is therefore completely different from segmental inhibitory systems, which
work both in intact and in spinal animals, and can be triggered by the activation of low
threshold afferents [32,33]. DNIC are also very different from the propriospinal inhibitory
processes which can be triggered by noxious inputs [6,10,34,35].
The ascending and descending limbs of this loop travel through the ventrolateral and
dorsolateral funiculi, respectively [36,37]. Since thalamic lesions do not affect DNIC [37],
it has been proposed that they result from a physiological activation of some of the
brainstem structures which produce descending inhibition [38]. Surprisingly, DNIC were
not modified by lesions of the following structures: the PAG, cuneiform nucleus, para-
brachial area, locus coeruleus/subcoeruleus, RVM [39 – 41]. By contrast, lesions of
subnucleus reticularis dorsalis (SRD) in the caudal medulla strongly reduced DNIC [42].
The SRD is located ventral to the cuneate nucleus, between trigeminal nucleus caudalis and
the nucleus of the solitary tract and contains neurones with characteristics which suggest
that they have a key role in processing specifically nociceptive information [43]. Indeed,
they are preferentially or exclusively activated by nociceptive stimuli from a ‘‘whole-body’’
receptive field, they encode the intensity of cutaneous and visceral stimulation within
noxious ranges and are activated exclusively by activity in cutaneous D- or D- and C-fibres.
In addition, they send descending projections through the dorsolateral funiculus that
terminate in the dorsal horn at all levels of the spinal cord. The fact that the supraspinal
loop sustaining DNIC is confined within the most caudal part of the medulla was confirmed
in a series of experiments where the potency of DNIC was tested in animals with complete
transections at different levels of the brainstem [44] (Fig. 2).
Interestingly, a C-fibre reflex elicited by electrical stimulation of the sural nerve and
recorded from the biceps femoris muscle was reported to be strongly inhibited in intact
anaesthetised rats by both mechanical and thermal noxious heterotopic stimuli whether to
the muzzle, a paw or the tail, and by colorectal distension [46]. These inhibitory effects
disappeared when the C-fibre reflex was recorded in spinal animals, or ipsilateral to a
rostral unilateral lesion of the dorsolateral funiculus (DLF). These observations are in
keeping with several earlier reports: the reflex discharge in the common peroneal nerve
following electrical stimulation of the sural nerve in the rat was inhibited by pinching the
14 D. Le Bars, J.-C. Willer / International Congress Series 1238 (2002) 11–29

Fig. 1. Example of heterotopic activation of D- and C-fibres triggering inhibitions in a spinal wide-dynamic-range
neurone. (A) Schematic representation of the experimental design. Recordings were made in the lumbar dorsal
horn from a wide-dynamic-range neurone with a receptive field located on the ipsilateral hindpaw. The
continuous electrophoretic application of the excitatory amino acid, DL-homocysteic acid (DLH) induced a steady
discharge from the neurone under study. The repetitive application of individual percutaneous electrical stimuli of
adequate intensities to the contralateral muzzle (a), the base (b) or the tip (c) of the tail-induced biphasic
depressions of the neuronal activity. (B) Peri-stimulus histograms (bin width: 5 ms) prepared during the
continuous electrophoretic application (15 nA) of DLH onto the membrane of the neurone. The broken white
lines show the timing of percutaneous electrical stimulation (10 mA; 2-ms duration; 0.66 Hz; 200-ms delay; 100
sweeps) of the contralateral muzzle (a), the base (b) or the tip (c) of the tail. The broken black line represents the
mean firing calculated during the prestimulation control period ( 200 to 0 ms). Two waves of inhibition can be
seen. They occurred earlier when the base of the tail (b) was stimulated instead of the tip (c). The time gaps are
shown as grey areas between the histograms, for both inhibitory components. The gap was 7 and 25 ms for the
beginning and the end of the first component; it was 210 and 330 ms for the beginning and the end of the second
component. Knowing that the distance between b and c was 100 mm, one can easily calculate the conduction
velocities of fibres that elicited the first and second components: 4 – 14 and 0.3 – 0.5 m/s, respectively. These
fibres therefore belong to the D- and C-groups, respectively (adapted from Ref. [30]).

muzzle or tail [12]; the gastrocnemious medialis reflex evoked by sural nerve stimulation
in the decerebrated rabbit was inhibited by electrical stimulation of the contralateral
common peroneal or either ipsi- or contralateral median nerves [47]; the digastric reflex
evoked by tooth pulp stimulation in the cat was inhibited by toe pinch, percutaneous
electrical stimulation of a limb or electrical stimulation of the saphenous nerve [48 – 50].
These results also fit with the observations in animals of an increase in nociceptive
thresholds triggered by heterotopic noxious conditioning [1].
 D. Le Bars, J.-C. Willer / International Congress Series 1238 (2002) 11–29 15

Fig. 2. Triggering of descending inhibitory controls by nociceptive stimulation. When a painful focus appears in a
region of the body, dorsal horn neurones are activated and send an excitatory signal through the ventrolateral
quadrant towards higher centres, including the lower brainstem. This signal activates DNIC, which will inhibit
spinal and trigeminal convergent neurones through the dorsolateral funiculi. The levels of transection that did not
modify DNIC are shown as shaded areas in the upper drawing of a sagittal section of the brainstem. By contrast,
transection caudal to this area blocked DNIC completely, suggesting that the open areas of the drawing
correspond to the parts of the brainstem involved in the upper part of the DNIC circuitry. Abbreviations: 4V,
fourth ventricle; 12, hypoglossal nucleus; AP, area postrema; C, cerebellum; Gi, gigantocellular nucleus; GiA,
gigantocellular nucleus pars alpha; GiV, gigantocellular nucleus ventral; IO, inferior olive; pyx, pyramidal
decussation; RMg, nucleus raphe magnus; RPa, nucleus raphe palidus; ROb, nucleus raphe obscurus (from Ref.
[45], with permission).
16 D. Le Bars, J.-C. Willer / International Congress Series 1238 (2002) 11–29

2. Comparison with effects triggered by acupuncture manipulation in animal

The effects of manual acupuncture performed by a traditional Chinese acupuncturist at

the ‘‘Zusanli’’ point on the right hind limb were compared with the effects elicited by
acupuncture applied at a non-acupoint, next to ‘‘Zusanli’’, on responses of trigeminal
wide-dynamic-range neurones [51]. Similar strong inhibitory effects on the C-fibre-evoked
responses of these neurones were obtained regardless of whether the acupuncture was
applied at ‘‘Zusanli’’ or the non-acupoint; indeed, such effects were also produced by
noxious thermal stimulation (Fig. 3). These results were confirmed and extended to
moxibustion [52,53]. Interestingly, both the acupuncture- and noxious-evoked inhibitions
were significantly reduced by systemic naloxone.
The effects on SRD neurones of manual acupuncture at the ‘‘Renzhong’’, ‘‘Sousanli’’,
‘‘Changqiang’’ and ‘‘Zusanli’’ acupoints, and at a non-acupoint next to ‘‘Zusanli’’ were

Fig. 3. Comparison of noxious- and acupuncture-induced inhibitions of wide-dynamic-range neurones. (A)

Schematic representation of the experimental design. Recordings were made in the left trigeminal nucleus
caudalis, from a wide-dynamic-range neurone with a receptive field located ipsilaterally on the muzzle. The
responses following percutaneous electrical stimulation of their receptive fields were conditioned by manual
acupuncture applied at the ‘‘Zusanli’’ point (a), at a close, non-acupoint on the right hindpaw (b) or by immersion
of the extremity of the left hindpaw in 48 jC water (c). (B) The histograms represent the temporal evolution
(abscissa: time) of the C-fibre responses (ordinate: number of spikes computed within 60 – 100 ms following each
stimulus) of the neurone to percutaneous electrical stimulation (2 ms; 0.67 Hz). During the period arrowed in the
upper parts of the figures, manual acupuncture was applied either at ‘‘Zusanli’’ (a) or at a non-acupoint (b) on the
right hindpaw or the left hindpaw was immersed in a 48 jC water bath (c). Note that both noxious heat and
acupuncture induced a depression of neuronal activity followed by after-effects of variable duration (adapted from
Ref. [51]).
 D. Le Bars, J.-C. Willer / International Congress Series 1238 (2002) 11–29 17

Fig. 4. Manual acupuncture activates nociceptive neurones. Individual example of responses of a SRD neurone
elicited by 30 s of acupuncture stimulation at points located in different parts of the body (circled). Note that
needle stimulation at all points, including the non-acupoint, induced strong neuronal activity followed by long-
lasting post-stimulus discharges (adapted from Ref. [54]).

also studied [54]. Acupuncture stimulation at the acupoints or the non-acupoint strongly
excited all the neurones tested (Fig. 4). These neurones responded with a discharge of
rapid onset, which was often followed by post-stimulus discharges. The levels of induced
activity were of similar magnitude to those evoked by noxious mechanical stimuli applied
under identical experimental conditions. No differences were found between the capacities
to activate the neurones from the ‘‘Zusanli’’ point and the adjacent non-acupoint, no matter
whether these were stimulated ipsi- or contralaterally; this suggests a lack of topographical
specificity in the activation of these neurones.

3. Control of spinal nociceptive reflexes in man

3.1. ‘‘TENS-like acupuncture’’ and ‘‘acupuncture-like TENS’’

It appears to us to be very meaningful that Sarlandière [55], one of the first European
acupuncturists in the early 19th century, had the idea of connecting needles to a galvanic
18 D. Le Bars, J.-C. Willer / International Congress Series 1238 (2002) 11–29

current source to treat rheumatism and gout. Electrical stimulation was then, and has been
since, widely used in clinical practice to relieve acute or chronic pain [56]. Schematically,
two types of current are effective in producing significant relief of experimental or clinical
pain [57 – 62]. The first, usually termed transcutaneous electrical nerve stimulation
(TENS), constitutes high-frequency, low-intensity and short-duration pulses applied to
the skin or cutaneous nerves supplying the painful focus. This nonpainful stimulus
activates large diameter cutaneous afferents (A-fibres) which convey nonpainful signals.
The second, often termed ‘‘acupuncture-like’’ TENS, constitutes lower frequency, higher
intensity and longer duration pulses to the skin or cutaneous nerves supplying the painful
focus or remote (heterotopic) regions. These currents activate nociceptive (D- and C-)
fibres and produce unpleasant sensations.
The effects of these two different types of stimulation applied either segmentally (Fig.
5A: a) or heterotopically (Fig. 5A: b) to an experimental painful focus were studied on the
nociceptive flexion RIII reflex, elicited in the lower limb by electrical stimulation of the
sural nerve [63]. Sural nerve stimulation at 1.2 times threshold elicited a slightly
supraliminal RIII reflex response, which was found to be affected in various ways by
TENS, depending on the type and location of the conditioning stimulus.
TENS produced an inhibitory effect only when applied segmentally to the sural nerve.
This inhibition was maximal within the first minute of stimulation, remained stable
throughout the 2-min conditioning period and was followed by significant post-stimulus
effects lasting 2 –3 min (Fig. 5B, left). The heterotopic application of TENS remained
without effect on the RIII (Fig. 5B, right). TENS elicited pleasant tickling and vibrating
sensations locally at the stimulation site and did not produce any noticeable modifications
of the skin under the stimulating electrodes.
By contrast (Fig. 5C), ‘‘acupuncture-like’’ TENS resulted in biphasic facilitatory–
inhibitory effects when applied segmentally and only in an inhibition when applied
heterotopically. ‘‘Acupuncture-like’’ TENS applied for 2 min to the sural nerve produced a
facilitation of the RIII reflex, which was maximal by the second minute of conditioning.
This facilitatory effect decreased rapidly when the conditioning stimulation was removed
and inhibitory post-stimulus effects were clear for a period of 14– 15 min (Fig. 5C, left).
By contrast, heterotopic application of ‘‘acupuncture-like’’ TENS induced a clear-cut
inhibition of the RIII reflex both during and following the 2-min period of application (Fig.
5C, right). ‘‘Acupuncture-like’’ TENS was associated with (1) unambiguous, albeit

Fig. 5. Depressive effects of segmental and heterotopic application of transcutaneous electrical nerve stimulation
on a lower limb nociceptive flexion reflex in man. (A) A nociceptive flexion reflex (RIII reflex) elicited in the lower
limb by electrical stimulation of the sural nerve at the ankle was studied before, during and after a 2-min application
of conventional or acupuncture-like transcutaneous electrical nerve stimulation (TENS). Conventional TENS
consisted of low-intensity (2 mA), short-duration (0.1 ms) and high-frequency (100 Hz) rectangular pulses.
Acupuncture-like TENS consisted of high-intensity (20 mA), long-duration (2 ms) and low-frequency (3 Hz)
rectangular pulses. Each conditioning stimulus was applied either homotopically to the sural nerve itself (a) or
heterotopically on the skin overlying the first interosseous space of the contralateral hand (b). (B) Non-noxious
conventional TENS applied segmentally produced inhibitions of the RIII reflex only during the 2-minute
conditioning period (a). Heterotopic TENS had no effect (b). (C) When given segmentally, the acupuncture-like
TENS produced a facilitatory effect during the 2-min application, followed by significant inhibitory post-stimulus
effects (a). The administration of acupuncture-like TENS heterotopically resulted in inhibitions of the RIII reflex
both during and after the 2-min conditioning period (b) (adapted from Ref. [63]).
D. Le Bars, J.-C. Willer / International Congress Series 1238 (2002) 11–29 19
20 D. Le Bars, J.-C. Willer / International Congress Series 1238 (2002) 11–29

bearable, painful sensations (muscular cramp, pinprick and burning) at the stimulation site
and radiating into the receptive field of the stimulated nerve, and (2) the appearance of a
slight cutaneous erythema, localised in the area surrounding the stimulating electrodes.
None of the conditioning stimuli elicited any significant fluctuations in heart rate or
respiration—two very sensitive parameters of emotional reactions.

3.2. Diffuse noxious inhibitory controls in man

Results reminiscent of what had been found in animals were obtained in man during
studies which combined psychophysical measurements with the recording of nociceptive
reflexes [64 – 68]. Electrical stimulation of the sural nerve at the ankle simultaneously
induces a nociceptive reflex in a flexor muscle of the thigh (the RIII reflex) and a painful
sensation in the territory of the nerve [69]. Painful heterotopic cutaneous conditioning
stimuli, no matter whether it is thermal, mechanical or chemical in nature, increase the
thresholds of both the reflex and the associated painful sensations, with stronger effects
being observed with more intense conditioning stimuli. These inhibitory phenomena are
exerted selectively on nociceptive responses and do not affect monosynaptic reflexes of
proprioceptive origin. These results demonstrate that in man, a painful conditioning
stimulus can depress both a preexisting pain and its associated nociceptive reflex at as
early a stage as the first spinal relays for the transmission of nociceptive information.
Interestingly, the RII-component of the blink reflex is also inhibited by remote painful heat
[70,71].
This prompts the following question: Are the inhibitory mechanisms purely spinal or do
they involve supraspinal structures? To answer this question, the effects on the RIII reflex
in the right leg of nociceptive conditioning stimuli applied to the fourth and fifth fingers of
the left hand were compared in normal subjects and tetraplegic patients with lesions of
traumatic origin at the C5 –C7 level [72]. In the normal subjects, as previously, the painful
conditioning stimuli caused a strong depression of both the RIII reflex and the associated

Fig. 6. Triggering of DNIC in a patient with a Brown – Séquard syndrome. A patient with Brown – Séquard
syndrome due to a 4-year-old spinal cord hemisection produced by a knife-wound in the back was carefully
investigated. The neurological observations and drawing of the lesion from MRI (left side, T6 level) are
summarised on the left. RIII reflexes elicited by stimulation of cutaneous afferents in the ulnar or sural nerves were
studied in the upper and lower limbs by recording from the biceps brachialis and biceps femoris muscles,
respectively. For each limb, the RIII reflex was elicited regularly by stimuli of 1.2 times threshold, before, during
and after periods of nociceptive electrical conditioning stimulation (15 mA; 4 Hz; 1 min) applied successively to
the other three limbs. The experimental set-up is represented in the centre of each insert, while the results are
shown in three histograms, each of which is adjacent to where the appropriate conditioning stimulus was applied.
In the histograms, each bar represents a single reflex response expressed as a percentage of the mean control (0 – 2
min) values; reflex responses observed during the conditioning period are shown as grey bars. (A) RIII reflex in
the upper right limb (URL). (B) RIII reflex in the upper left limb (ULL). (C) RIII reflex in the lower right limb
(LRL). (D) RIII reflex in the lower left limb (LLL). Strong inhibitions followed by post-conditioning effects were
observed in all situations except that (1) no inhibition could be obtained when the conditioning stimuli were
applied to the lower right limb (contralateral to the spinal lesion) and (2) the RIII reflex in the lower left limb was
completely insensitive to any of the conditioning stimuli. These results suggest that (1) the ascending part of the
loop subserving DNIC is completely crossed at the spinal level and (2) the descending part is confined to the
white matter ipsilateral to the limb being tested (adapted from Ref. [74]).
D. Le Bars, J.-C. Willer / International Congress Series 1238 (2002) 11–29 21
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pain. By contrast, in the tetraplegic patients, nociceptive stimulation of the same cutaneous
territories, which, being in the C8 and T1 dermatomes, were clinically unaffected by the
spinal lesion, did not produce any depression of the RIII reflex recorded in the contralateral
leg. These results demonstrate that in man, as in animals, the inhibitory effects triggered by
heterotopic nociceptive stimuli are most likely sustained by a loop which includes
supraspinal structures.
These results also lead to a subsidiary question: Is it possible to identify, or at least
localise, these supraspinal structures? Tentative answers were obtained by observations
made on patients with cerebral lesions causing contralateral hemianalgesia [73]. These
were patients with either a unilateral thalamic lesion (identified and delineated by a CT
scan) or a lesion of the retro-olivary part of the medulla (Wallenberg’s syndrome). In the
former group, the RIII reflex on the normal side was strongly depressed, as in normal
subjects, by nociceptive conditioning stimuli applied to the affected side which were not
felt as painful. By contrast, in the patients with Wallenberg’s syndrome, no inhibitions
were observed when the nociceptive conditioning stimuli were applied to the affected side,
whereas if these stimuli were applied to the normal side, they triggered inhibitory effects
and after-effects very similar to those seen in normal subjects. These results show that in
humans, thalamic structures and, consequently, spinothalamic pathways are not involved
in DNIC, whereas brainstem—probably reticular—structures seem to play a key role in
these phenomena.
We also reported an exceptional case of a patient with (Fig. 6) Brown – Séquard
syndrome due to a 4-year-old spinal cord hemisection (left side, T6 level) produced by a
knife-wound in the back [74]. The RIII reflexes elicited by stimulation of cutaneous
afferents in the ulnar and sural nerves were studied in the upper and lower limbs by
recording from the biceps brachialis and biceps femoris muscles, respectively. For each
limb, the RIII reflex was elicited regularly by stimuli of 1.2 times threshold before, during
and after periods of nociceptive electrical conditioning stimulation applied successively to
the other three limbs. Inhibitions of around 90% followed by after-effects were observed in
all situations except that: (1) no inhibition could be obtained when the conditioning stimuli
were applied to the lower right limb (contralateral to the spinal lesion), and (2) the RIII
reflex in the lower left limb was completely insensitive to any of the conditioning stimuli.
These results suggest that in humans: (1) the ascending part of the loop subserving DNIC
is completely crossed at the spinal level, and (2) the descending part is confined to the
white matter, ipsilateral to the limb being tested.
Thus, the following features are shared by the RIII reflex and associated painful
sensations in humans and by dorsal horn wide-dynamic-range neurones in the rat spinal
cord. (1) The RIII reflex and the responses of wide-dynamic-range neurones to electrical
stimulation of their cutaneous receptive fields are similarly inhibited by various hetero-
topic nociceptive stimuli. (2) The extent of the inhibitions is directly related to the
intensity of the conditioning stimulus. (3) The inhibitions are followed by after-effects,
which can last for several minutes. (4) The inhibitions are mediated by a spino – bulbo –
spinal loop, the ascending part of which is composed of the spinoreticular tract and
synaptic relays in the brainstem. (5) The ascending pathways of the loop are mainly
crossed while the descending pathways run ipsilaterally to the recording site. (6) There is
at least one opioidergic link in this loop both in the rat and in man [75,76]. Such simi-
 D. Le Bars, J.-C. Willer / International Congress Series 1238 (2002) 11–29 23

larities allow one to conclude that the inhibitory processes observed in man, and DNIC in
the rat, share common mechanisms; the existence of DNIC in humans is therefore more
than likely.

4. Summary and conclusions

The question arises as to what mechanisms underlie the hypoalgesic effects of

acupuncture, electroacupuncture and moxibustion, and whether they might share common
neuronal substrates with other means of relieving pain. As stated above, it seems possible
to distinguish at least two means of producing hypoalgesia by somatic stimulation. In
some cases, acupuncture probably activates such processes, especially when the needles
are applied in the vicinity of the painful focus. The participation of large A-afferent fibres
is then very likely [32,33,57,77]. However, the mechanisms underlying TENS and
acupuncture at sites either close or remote to the source of pain cannot be explained on
the basis of a single mechanism [78 – 81]. It has been shown that stronger analgesic effects
can be elicited by using a critical level of stimulation which produces an unpleasant
sensation [82,83], suggesting that D-fibre activation is important in the production of
analgesia by somatic stimulation. Indeed, numerous studies have demonstrated that the
activation of D-fibres: (1) produces the most powerful segmental inhibitions and (2)
induces extrasegmental inhibitions [84 –88]. We have also already mentioned the existence
of propriospinal inhibitory processes triggered by noxious inputs [6,10,34,35].
The pain relief produced by acupuncture can have a widespread distribution when the
stimulation is strong enough to induce the feeling of ‘‘Teh-Chi’’ (or ‘‘de qi’’, ‘‘needling
sensation’’), which is an unpleasant ‘‘heavy-dull’’ sensation that is probably related to
activity in thin peripheral fibres [89]. Mann [90] concluded that for effective analgesia, the
sensation resulting from the stimulation point should be the maximum that the patient can
support. As stated by MacDonald [91], ‘‘over the two millennia that acupuncture has been
practised in China, a variety of vigorous needling methods have been codified in
descriptive traditional terms such as ‘mountain-burning fire’, ‘penetrating heaven cool-
ness’, ‘dragon and tiger joined in battle’ and ‘green dragon wags its tail’’’ [92].
Furthermore, it has been shown that antinociceptive effects elicited by acupuncture are
stronger when the stimulation intensities are sufficient to recruit D- and C-fibres [85,93],
including Capsaicine-sensitive polymodal nociceptors [94,95].
A role for endogenous opioid systems in the analgesic effects of acupuncture is very
likely [96 – 98]. Naloxone reversed acupuncture analgesia [99,100] and the effects
triggered by low-frequency but not high-frequency electroacupuncture [101 –103]. Enke-
phalins might be involved in these effects since: (1) manual acupuncture stimulation of the
‘‘Zusanli’’ point (or an adjacent non-acupoint) induces a heterosegmental release of Met-
enkephalin-like material in the rat spinal cord [104] and (2) low-frequency electro-
acupuncture elicits a rise of Met-enkephalin-like material in the cerebrospinal fluid of
patients [105]. One can emphasise the close relationship between the neural systems
involved in pain modulation and those involved with autonomic functions [106,107].
Acupuncture and electroacupuncture produce complex changes in autonomic functions in
both animals and man [108 – 110]. This is probably achieved through spinal and supra-
24 D. Le Bars, J.-C. Willer / International Congress Series 1238 (2002) 11–29

spinal somato-vegetative reflexes—the latter including spino– bulbo –spinal pathways

which travel in the dorsolateral funiculi [111]. Such functional connections might play a
key role in acupuncture analgesia (see Sato, this volume).
We have also proposed that DNIC may well form a neural basis for the pain-relieving
effects of procedures related to ‘‘counter-stimulation’’ or ‘‘counter-stimulation’’ phenom-
ena in which fine afferent fibres play an important role [1,2]. Interestingly, DNIC—
whether tested on wide-dynamic-range neurones in animals or the nociceptive reflex RIII
in man—are blocked by naloxone [75,76]. In addition, regardless of whether inhibitions of
trigeminal wide-dynamic-range neurones are triggered by noxious heat or by manual
stimulation of the ‘‘Zusanli’’ point, they are reduced to a similar extent by naloxone [51].
In brief, the inhibitory effects elicited by acupuncture on wide-dynamic-range neurones:
(1) had a similar magnitude and time-course to those evoked by noxious stimulation, (2)
exhibited a lack of topographical specificity and (3) involved an opioidergic link. This
suggests that acupuncture manoeuvres trigger the neuronal mechanisms involved in
diffuse noxious inhibitory controls, at least under our experimental conditions. Since
SRD neurones, which are activated exclusively or preferentially by noxious inputs, are
also activated by manipulation of needles, the conclusion is reached that the signals
elicited by manual acupuncture travel through pathways responsible for the transmission
of nociceptive information.
It is possible that the activation of D-fibres produces a more synchronised input to the
central nervous system than does the activation of C-fibres, and thus produces a more
efficacious drive of DNIC for a given stimulus intensity. During electroacupuncture, the
practitioner generally progressively increases the current intensity applied through the
needles. This makes the stimulus itself bearable by the patient. The unpleasantness of
vigorous needling is less in patients complaining of pain that one would expect on the
basis of corresponding sensations elicited in normal subjects, probably because DNIC is
already triggered by the preexisting painful focus [91].
The diffuse nature of the effects of acupuncture has been underlined on several
occasions. We will not address here the questions of the specificity and size of acupoints
and their relationship with tender and trigger points (‘‘Ah-Shi points’’). These topics were
summarised in splendid reviews [91,112 –114]. ‘‘One only has a look at modern charts to
realise there is hardly a site on the body that is not an acupuncture point’’ [91].

Acknowledgements

The authors are very grateful to Dr. Cadden for advice in the preparation of the
manuscript.

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