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1Pain modulation triggered by high-intensity

2stimulation: implication for acupuncture analgesia?

3Daniel Le Bars *, Jean-Claude Willer

4INSERM U-161, 2, rue d’Alesia, 75014 Paris, France

5C.H.U. Pitie-Salpetriere Laboratoire de Neurophysiologie, 91 Boulevard de l’Hopital, 75013 Paris, France6

7Abstract

8The spinal transmission of nociceptive signals is modulated by both spinal and supraspinal

9systems. Spinal networks underlie segmental inhibitions, which are mediated via myelinated

10cutaneous afferent fibres activated by mechanical stimuli (e.g. rubbing, etc.) Diffuse noxious

11inhibitory controls (DNIC) are triggered by peripheral Ay- and C-fibres, involve brain structures

12confined to the caudal-most part of the medulla including the subnucleus reticularis dorsalis (SRD)

13and are mediated by descending pathways in the dorsolateral funiculi. Combined psychophysical

14measurements and recordings of nociceptive reflexes (RIII) in both normal volunteers and patients

15with lesions in the spinal cord or brain suggest the existence of identical or equivalent inhibitory

16processes in man. Both these mechanisms could be triggered to produce hypoalgesia by acupuncture

17needles or moxibustion. When applied near a painful focus, the techniques have similarities to high-

18frequency, low-intensity transcutaneous nerve stimulation, which brings segmental inhibitory

19mechanisms into play. When applied to remote areas, the techniques might be related to ‘‘counter-

20irritation’’ or ‘‘counter-stimulation’’ phenomena which, in addition to involving complex autonomic

21functions, seem to involve DNIC. Experimental data in both animals and humans support these

22conclusions. D 2002 Elsevier Science B.V. All rights reserved.23

24Keywords: Acupuncture; Pain; Dorsal horn; Nociceptive reflexes; DNIC

25262728Painful stimuli can diminish, or even mask, pain elicited by stimulation of a remote

29(extrasegmental) part of the body [1–3]. This phenomenon has been known of since

30ancient times as illustrated by the Hippocrates’ aphorism: ‘‘If a patient be subject to two

31pains arising in different parts of the body simultaneously, the stronger blunts the other’’. It

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

PII: S0531 -5131 (02 )00412 -0

* Corresponding author. INSERM U-161, 2, rue d’Alesia, 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).

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32has even been used during surgical procedures on both human patients and domestic

33animals. In the latter category, two examples are the use of the twitch in horses and of

34nasal forceps in cattle for performing caudectomies or castrations, both of which are

35potentially painful operations. The working hypothesis was developed that some of the

36neurones involved in the transmission of nociceptive signals can be inhibited by

37nociceptive stimulation of peripheral territories outside their own excitatory receptive

38fields. That such an hypothesis is correct at as early a stage as the spinal cord was revealed

39by the finding that some dorsal horn neurones are strongly inhibited when a nociceptive

40stimulus is applied to any part of the body, distinct from their excitatory receptive fields.

41For convenience, this phenomenon was termed ‘‘diffuse noxious inhibitory controls’’

42(DNIC).

431. Diffuse noxious inhibitory controls (DNIC) in animal

44In the rat (see references below), the cat [4,5] and, probably, the monkey [6,7], most

45wide-dynamic-range and some nociceptive-specific neurones can be strongly inhibited by

46noxious inputs applied outside their receptive field. Such effects do not appear to be

47somatotopically organised but apply to the whole body. Conversely, they apply to

48neurones in the dorsal horn of various segments of the spinal cord [8–17] or in either

49nucleus caudalis or nucleus oralis of the trigeminal system [18–21]. The neurones affected

50include some projecting to the thalamus [22]. It should be noted that the inhibitions

51triggered by heterotopic noxious stimuli are highly sensitive to the anaesthetic regimen, an

52observation that could explain some reports of lesser inhibitory effects [6,9,16,23].

53DNIC are triggered by conditioning stimuli applied to any part of the body distant from

54the excitatory receptive field of the neurone under study, provided that the stimuli are

55clearly noxious. There is a clear relationship between the intensity of the conditioning

56stimulus and the strength of the resultant DNIC [24,25]. With strong stimuli, the inhibitory

57effects are powerful indeed and are followed by long-lasting post-stimulus effects, which

58can persist for several minutes. In some cases, the inhibitory effects can involve a complete

59abolition of activity for a long period of time following removal of the conditioning stimuli

60(‘‘switch-off’’) and the activity can be restored to preconditioning levels by further

61manipulations of the excitatory receptive field (‘‘switch-on’’) [26].

62With regard to the viscera, some differences should be noted: visceral stimuli, e.g.

63distension of the colon or urinary bladder, generally produce inhibitions with slower rates

64of onset and recovery but starting with intensities below a painful level [15]. It was

65proposed that these differences may have reflected different amounts and patterns of

66activity in the relevant primary afferent fibres rather than being due to different central

67neural mechanisms.

68In any case, these data suggest that DNIC are triggered specifically by the activation of

69peripheral nociceptors whose signals are carried by A- and C-fibres. In order to further

70investigate the types of peripheral fibres involved in DNIC, we took advantage of the

71facts: (1) that trigeminal and spinal dorsal horn neurones respond with relatively steady

72discharges to the electrophoretic application of excitatory amino-acids, and (2) that DNIC

73act by a final postsynaptic inhibitory mechanism involving hyperpolarisation of the

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74neuronal membrane [27,28]. It was found that when spinal or trigeminal wide-dynamic-

75range neurones were directly excited by the electrophoretic application of glutamate, the

76percutaneous application of single square-wave, electrical stimuli to the tail always

77induced a biphasic depression of the resultant activity [29,30]. Both the early and late

78components of this inhibition occurred with shorter latencies when the base rather than the

79tip of the tail was stimulated. Such differences in latency were used to estimate the mean

80conduction velocities of the peripheral fibres triggering the inhibitions: the means were

81found to be 7.3 and 0.7 m/s, which fall into the A- and C-fibre ranges, respectively. Such

82biphasic inhibitions could be elicited from any part of the body and recorded from any

83wide-dynamic-range neurones. Fig. 1 shows a recording from a lumbar wide-dynamic-

84range neurone with an excitatory receptive field located on the extremity of the ipsilateral

85hind paw: two components of inhibition were induced by the activation of A- and C-fibres,

86respectively, when a single 2-ms duration shock of 10 mA was applied to the muzzle, the

87base or the tip of the tail.

88DNIC are not observed in anaesthetised or decerebrated animals in which the spinal

89cord has been sectioned [5,10,31]. It is therefore obvious that the mechanisms underlying

90DNIC are not confined to the spinal cord and that supraspinal structures must be involved.

91Such a system is therefore completely different from segmental inhibitory systems, which

92work both in intact and in spinal animals, and can be triggered by the activation of low

93threshold afferents [32,33]. DNIC are also very different from the propriospinal inhibitory

94processes which can be triggered by noxious inputs [6,10,34,35].

95The ascending and descending limbs of this loop travel through the ventrolateral and

96dorsolateral funiculi, respectively [36,37]. Since thalamic lesions do not affect DNIC [37],

97it has been proposed that they result from a physiological activation of some of the

98brainstem structures which produce descending inhibition [38]. Surprisingly, DNIC were

99not modified by lesions of the following structures: the PAG, cuneiform nucleus, para-

100brachial area, locus coeruleus/subcoeruleus, RVM [39–41]. By contrast, lesions of

101subnucleus reticularis dorsalis (SRD) in the caudal medulla strongly reduced DNIC

102[42]. The SRD is located ventral to the cuneate nucleus, between trigeminal nucleus

103caudalis and the nucleus of the solitary tract and contains neurones with characteristics

104which suggest that they have a key role in processing specifically nociceptive information

105[43]. Indeed, they are preferentially or exclusively activated by nociceptive stimuli from a

106‘‘whole-body’’ receptive field, they encode the intensity of cutaneous and visceral

107stimulation within noxious ranges and are activated exclusively by activity in cutaneous

108A- or A- and C-fibres. In addition, they send descending projections through the

109dorsolateral funiculus that terminate in the dorsal horn at all levels of the spinal cord.

110The fact that the supraspinal loop sustaining DNIC is confined within the most caudal part

111of the medulla was confirmed in a series of experiments where the potency of DNIC was

112tested in animals with complete transections at different levels of the brainstem [44] (Fig.

1132).

114Interestingly, a C-fibre reflex elicited by electrical stimulation of the sural nerve and

115recorded from the biceps femoris muscle was reported to be strongly inhibited in intact

116anaesthetised rats by both mechanical and thermal noxious heterotopic stimuli whether to

117the muzzle, a paw or the tail, and by colorectal distension [46]. These inhibitory effects

118disappeared when the C-fibre reflex was recorded in spinal animals, or ipsilateral to a

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119rostral unilateral lesion of the dorsolateral funiculus (DLF). These observations are in

120keeping with several earlier reports: the reflex discharge in the common peroneal nerve

121following electrical stimulation of the sural nerve in the rat was inhibited by pinching the

122muzzle or tail [12]; the gastrocnemious medialis reflex evoked by sural nerve stimulation

123in the decerebrated rabbit was inhibited by electrical stimulation of the contralateral

124common peroneal or either ipsi- or contralateral median nerves [47]; the digastric reflex

Fig. 1. Example of heterotopic activation of A- 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 A- and C-groups, respectively (adapted from Ref. [30]).

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125evoked by tooth pulp stimulation in the cat was inhibited by toe pinch, percutaneous

126electrical stimulation of a limb or electrical stimulation of the saphenous nerve [48–50].

127These results also fit with the observations in animals of an increase in nociceptive

128thresholds triggered by heterotopic noxious conditioning [1].

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).

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1292. Comparison with effects triggered by acupuncture manipulation in animal

130The effects of manual acupuncture performed by a traditional Chinese acupuncturist at

131the ‘‘Zusanli’’ point on the right hind limb were compared with the effects elicited by

132acupuncture applied at a non-acupoint, next to ‘‘Zusanli’’, on responses of trigeminal

133wide-dynamic-range neurones [51]. Similar strong inhibitory effects on the C-fibre-evoked

134responses of these neurones were obtained regardless of whether the acupuncture was

135applied at ‘‘Zusanli’’ or the non-acupoint; indeed, such effects were also produced by

136noxious thermal stimulation (Fig. 3). These results were confirmed and extended to

137moxibustion [52,53]. Interestingly, both the acupuncture- and noxious-evoked inhibitions

138were significantly reduced by systemic naloxone.

139The effects on SRD neurones of manual acupuncture at the ‘‘Renzhong’’, ‘‘Sousanli’’,

140‘‘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. (A) 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]).

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141also studied [54]. Acupuncture stimulation at the acupoints or the non-acupoint strongly

142excited all the neurones tested (Fig. 4). These neurones responded with a discharge of

143rapid onset, which was often followed by post-stimulus discharges. The levels of induced

144activity were of similar magnitude to those evoked by noxious mechanical stimuli applied

145under identical experimental conditions. No differences were found between the capacities

146to activate the neurones from the ‘‘Zusanli’’ point and the adjacent non-acupoint, no matter

147whether these were stimulated ipsi- or contralaterally; this suggests a lack of topographical

148specificity in the activation of these neurones.

1493. Control of spinal nociceptive reflexes in man

150

1513.1. ‘‘TENS-like acupuncture’’ and ‘‘acupuncture-like TENS’’

152It appears to us to be very meaningful that Sarlandiere [55], one of the first European

153acupuncturists in the early 19th century, had the idea of connecting needles to a galvanic

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]).

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154current source to treat rheumatism and gout. Electrical stimulation was then, and has been

155since, widely used in clinical practice to relieve acute or chronic pain [56]. Schematically,

156two types of current are effective in producing significant relief of experimental or clinical

157pain [57–62]. The first, usually termed transcutaneous electrical nerve stimulation

158(TENS), constitutes high-frequency, low-intensity and short-duration pulses applied to

159the skin or cutaneous nerves supplying the painful focus. This nonpainful stimulus

160activates large diameter cutaneous afferents (A-fibres) which convey nonpainful signals.

161The second, often termed ‘‘acupuncture-like’’ TENS, constitutes lower frequency, higher

162intensity and longer duration pulses to the skin or cutaneous nerves supplying the painful

163focus or remote (heterotopic) regions. These currents activate nociceptive (A- and C-)

164fibres and produce unpleasant sensations.

165The effects of these two different types of stimulation applied either segmentally (Fig.

1665A: a) or heterotopically (Fig. 5A: b) to an experimental painful focus were studied on the

167nociceptive flexion RIII reflex, elicited in the lower limb by electrical stimulation of the

168sural nerve [63]. Sural nerve stimulation at 1.2 times threshold elicited a slightly

169supraliminal RIII reflex response, which was found to be affected in various ways by

170TENS, depending on the type and location of the conditioning stimulus.

171TENS produced an inhibitory effect only when applied segmentally to the sural nerve.

172This inhibition was maximal within the first minute of stimulation, remained stable

173throughout the 2-min conditioning period and was followed by significant post-stimulus

174effects lasting 2–3 min (Fig. 5B, left). The heterotopic application of TENS remained

175without effect on the RIII (Fig. 5B, right). TENS elicited pleasant tickling and vibrating

176sensations locally at the stimulation site and did not produce any noticeable modifications

177of the skin under the stimulating electrodes.

178By contrast (Fig. 5C), ‘‘acupuncture-like’’ TENS resulted in biphasic facilitatory–

179inhibitory effects when applied segmentally and only in an inhibition when applied

180heterotopically. ‘‘Acupuncture-like’’ TENS applied for 2 min to the sural nerve produced a

181facilitation of the RIII reflex, which was maximal by the second minute of conditioning.

182This facilitatory effect decreased rapidly when the conditioning stimulation was removed

183and inhibitory post-stimulus effects were clear for a period of 14–15 min (Fig. 5C, left).

184By contrast, heterotopic application of ‘‘acupuncture-like’’ TENS induced a clear-cut

185inhibition of the RIII reflex both during and following the 2-min period of application (Fig.

1865C, 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]).

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187bearable, painful sensations (muscular cramp, pinprick and burning) at the stimulation site

188and radiating into the receptive field of the stimulated nerve, and (2) the appearance of a

189slight cutaneous erythema, localised in the area surrounding the stimulating electrodes.

190None of the conditioning stimuli elicited any significant fluctuations in heart rate or

191respiration—two very sensitive parameters of emotional reactions.

192

1933.2. Diffuse noxious inhibitory controls in man

194Results reminiscent of what had been found in animals were obtained in man during

195studies which combined psychophysical measurements with the recording of nociceptive

196reflexes [64–68]. Electrical stimulation of the sural nerve at the ankle simultaneously

197induces a nociceptive reflex in a flexor muscle of the thigh (the RIII reflex) and a painful

198sensation in the territory of the nerve [69]. Painful heterotopic cutaneous conditioning

199stimuli, no matter whether it is thermal, mechanical or chemical in nature, increase the

200thresholds of both the reflex and the associated painful sensations, with stronger effects

201being observed with more intense conditioning stimuli. These inhibitory phenomena are

202exerted selectively on nociceptive responses and do not affect monosynaptic reflexes of

203proprioceptive origin. These results demonstrate that in man, a painful conditioning

204stimulus can depress both a preexisting pain and its associated nociceptive reflex at as

205early a stage as the first spinal relays for the transmission of nociceptive information.

206Interestingly, the R2-component of the blink reflex is also inhibited by remote painful heat

207[70,71].

208This prompts the following question: Are the inhibitory mechanisms purely spinal or do

209they involve supraspinal structures? To answer this question, the effects on the RIII reflex

210in the right leg of nociceptive conditioning stimuli applied to the fourth and fifth fingers of

211the left hand were compared in normal subjects and tetraplegic patients with lesions of

212traumatic origin at the C5–C7 level [72]. In the normal subjects, as previously, the painful

213conditioning stimuli caused a strong depression of both the RIII reflex and the associated

Fig. 6. Triggering of DNIC in a patient with a Brown–Sequard syndrome. A patient with Brown–Sequard

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]).

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214pain. By contrast, in the tetraplegic patients, nociceptive stimulation of the same cutaneous

215territories, which, being in the C8 and T1 dermatomes, were clinically unaffected by the

216spinal lesion, did not produce any depression of the RIII reflex recorded in the contralateral

217leg. These results demonstrate that in man, as in animals, the inhibitory effects triggered by

218heterotopic nociceptive stimuli are most likely sustained by a loop which includes

219supraspinal structures.

220These results also lead to a subsidiary question: Is it possible to identify, or at least

221localise, these supraspinal structures? Tentative answers were obtained by observations

222made on patients with cerebral lesions causing contralateral hemianalgesia [73]. These

223were patients with either a unilateral thalamic lesion (identified and delineated by a CT

224scan) or a lesion of the retro-olivary part of the medulla (Wallenberg’s syndrome). In the

225former group, the RIII reflex on the normal side was strongly depressed, as in normal

226subjects, by nociceptive conditioning stimuli applied to the affected side which were not

227felt as painful. By contrast, in the patients with Wallenberg’s syndrome, no inhibitions

228were observed when the nociceptive conditioning stimuli were applied to the affected side,

229whereas if these stimuli were applied to the normal side, they triggered inhibitory effects

230and after-effects very similar to those seen in normal subjects. These results show that in

231humans, thalamic structures and, consequently, spinothalamic pathways are not involved

232in DNIC, whereas brainstem—probably reticular—structures seem to play a key role in

233these phenomena.

234We also reported an exceptional case of a patient with (Fig. 6) Brown–Sequard

235syndrome due to a 4-year-old spinal cord hemisection (left side, T6 level) produced by a

236knife-wound in the back [74]. The RIII reflexes elicited by stimulation of cutaneous

237afferents in the ulnar and sural nerves were studied in the upper and lower limbs by

238recording from the biceps brachialis and biceps femoris muscles, respectively. For each

239limb, the RIII reflex was elicited regularly by stimuli of 1.2 times threshold before, during

240and after periods of nociceptive electrical conditioning stimulation applied successively to

241the other three limbs. Inhibitions of around 90% followed by after-effects were observed in

242all situations except that: (1) no inhibition could be obtained when the conditioning stimuli

243were applied to the lower right limb (contralateral to the spinal lesion), and (2) the RIII

244reflex in the lower left limb was completely insensitive to any of the conditioning stimuli.

245These results suggest that in humans: (1) the ascending part of the loop subserving DNIC

246is completely crossed at the spinal level, and (2) the descending part is confined to the

247white matter, ipsilateral to the limb being tested.

248Thus, the following features are shared by the RIII reflex and associated painful

249sensations in humans and by dorsal horn wide-dynamic-range neurones in the rat spinal

250cord. (1) The RIII reflex and the responses of wide-dynamic-range neurones to electrical

251stimulation of their cutaneous receptive fields are similarly inhibited by various hetero-

252topic nociceptive stimuli. (2) The extent of the inhibitions is directly related to the intensity

253of the conditioning stimulus. (3) The inhibitions are followed by after-effects, which can

254last for several minutes. (4) The inhibitions are mediated by a spino–bulbo–spinal loop,

255the ascending part of which is composed of the spinoreticular tract and synaptic relays in

256the brainstem. (5) The ascending pathways of the loop are mainly crossed while the

257descending pathways run ipsilaterally to the recording site. (6) There is at least one

258opioidergic link in this loop both in the rat and in man [75,76]. Such similarities allow one

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259to conclude that the inhibitory processes observed in man, and DNIC in the rat, share

260common mechanisms; the existence of DNIC in humans is therefore more than likely.

2614. Summary and conclusions

262The question arises as to what mechanisms underlie the hypoalgesic effects of

263acupuncture, electroacupuncture and moxibustion, and whether they might share common

264neuronal substrates with other means of relieving pain. As stated above, it seems possible

265to distinguish at least two means of producing hypoalgesia by somatic stimulation. In

266some cases, acupuncture probably activates such processes, especially when the needles

267are applied in the vicinity of the painful focus. The participation of large A-afferent fibres

268is then very likely [32,33,57,77]. However, the mechanisms underlying TENS and

269acupuncture at sites either close or remote to the source of pain cannot be explained on

270the basis of a single mechanism [78–81]. It has been shown that stronger analgesic effects

271can be elicited by using a critical level of stimulation which produces an unpleasant

272sensation [82,83], suggesting that A-fibre activation is important in the production of

273analgesia by somatic stimulation. Indeed, numerous studies have demonstrated that the

274activation of A-fibres: (1) produces the most powerful segmental inhibitions and (2)

275induces extrasegmental inhibitions [84–88]. We have also already mentioned the existence

276of propriospinal inhibitory processes triggered by noxious inputs [6,10,34,35].

277The pain relief produced by acupuncture can have a widespread distribution when the

278stimulation is strong enough to induce the feeling of ‘‘Teh-Chi’’ (or ‘‘de qi’’, ‘‘needling

279sensation’’), which is an unpleasant ‘‘heavy-dull’’ sensation that is probably related to

280activity in thin peripheral fibres [89]. Mann [90] concluded that for effective analgesia, the

281sensation resulting from the stimulation point should be the maximum that the patient can

282support. As stated by MacDonald [91], ‘‘over the two millennia that acupuncture has been

283practised in China, a variety of vigorous needling methods have been codified in

284descriptive traditional terms such as ‘mountain-burning fire’, ‘penetrating heaven cool-

285ness’, ‘dragon and tiger joined in battle’ and ‘green dragon wags its tail’’’ [92].

286Furthermore, it has been shown that antinociceptive effects elicited by acupuncture are

287stronger when the stimulation intensities are sufficient to recruit A- and C-fibres [85,93],

288including Capsaicine-sensitive polymodal nociceptors [94,95].

289A role for endogenous opioid systems in the analgesic effects of acupuncture is very

290likely [96–98]. Naloxone reversed acupuncture analgesia [99,100] and the effects

291triggered by low-frequency but not high-frequency electroacupuncture [101–103]. Enke-

292phalins might be involved in these effects since: (1) manual acupuncture stimulation of the

293‘‘Zusanli’’ point (or an adjacent non-acupoint) induces a heterosegmental release of Met-

294enkephalin-like material in the rat spinal cord [104] and (2) low-frequency electro-

295acupuncture elicits a rise of Met-enkephalin-like material in the cerebrospinal fluid of

296patients [105]. One can emphasise the close relationship between the neural systems

297involved in pain modulation and those involved with autonomic functions [106,107].

298Acupuncture and electroacupuncture produce complex changes in autonomic functions in

299both animals and man [108–110]. This is probably achieved through spinal and supra-

300spinal somato-vegetative reflexes—the latter including spino–bulbo–spinal pathways

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301which travel in the dorsolateral funiculi [111]. Such functional connections might play a

302key role in acupuncture analgesia (see Sato, this volume).

303We have also proposed that DNIC may well form a neural basis for the pain-relieving

304effects of procedures related to ‘‘counter-stimulation’’ or ‘‘counter-stimulation’’ phenom-

305ena in which fine afferent fibres play an important role [1,2]. Interestingly, DNIC—

306whether tested on wide-dynamic-range neurones in animals or the nociceptive reflex RIII

307in man—are blocked by naloxone [75,76]. In addition, regardless of whether inhibitions of

308trigeminal wide-dynamic-range neurones are triggered by noxious heat or by manual

309stimulation of the ‘‘Zusanli’’ point, they are reduced to a similar extent by naloxone [51].

310In brief, the inhibitory effects elicited by acupuncture on wide-dynamic-range neurones:

311(1) had a similar magnitude and time-course to those evoked by noxious stimulation, (2)

312exhibited a lack of topographical specificity and (3) involved an opioidergic link. This

313suggests that acupuncture manoeuvres trigger the neuronal mechanisms involved in

314diffuse noxious inhibitory controls, at least under our experimental conditions. Since

315SRD neurones, which are activated exclusively or preferentially by noxious inputs, are

316also activated by manipulation of needles, the conclusion is reached that the signals

317elicited by manual acupuncture travel through pathways responsible for the transmission

318of nociceptive information.

319It is possible that the activation of A-fibres produces a more synchronised input to the

320central nervous system than does the activation of C-fibres, and thus produces a more

321efficacious drive of DNIC for a given stimulus intensity. During electroacupuncture, the

322practitioner generally progressively increases the current intensity applied through the

323needles. This makes the stimulus itself bearable by the patient. The unpleasantness of

324vigorous needling is less in patients complaining of pain that one would expect on the

325basis of corresponding sensations elicited in normal subjects, probably because DNIC is

326already triggered by the preexisting painful focus [91].

327The diffuse nature of the effects of acupuncture has been underlined on several

328occasions. We will not address here the questions of the specificity and size of acupoints

329and their relationship with tender and trigger points (‘‘Ah-Shi points’’). These topics were

330summarised in splendid reviews [91,112–114]. ‘‘One only has a look at modern charts to

331realise there is hardly a site on the body that is not an acupuncture point’’ [91].

332Acknowledgements

333The authors are very grateful to Dr. Cadden for advice in the preparation of the

334manuscript.

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