111 Pain.. 3 (1977) 111--119 © Elsevier/North-Hollan d Biomedical Press

PHARMACOLOGICAL MODULATIONS ON THE NOCICEPTIVE FLEXION. REFLEX IN MAN

J.C. W I L L E R and N. BATHIEN

Laboratoire de Physiologie, Facultd de M~decine St-Antoine, 27 rue Chaligny, 75012 Paris (France;

(Accepted October 4~.h, 1976)

SUMMARY

Pharmacological actions on the nociccptive flexion reflexes of the hindlimb were investigated in 14 normal subiects. These reflexes were used as an index of pain and were recorded in the biceps femoris muscle, elicited by electrical stimulation of the ipsflateral sural nerve (RIII,su) and of the skin in t h e distal receptive field of this nerve (RIII,Cu). The ratio of the threshold of RIII,Cu/RIII,Su was calculated since it gives an indication on the mechanism and the efficacy of the drug. During control periods, the mean values of RIII,Su threshold (10 mA) and of RIII,Cu threshold (5 mA) remained stable, 3s RIII,Cu/RIII,Su threshold (50%). Cutaneous application of naphthalene provoked a decrease in the RIII,Cu threshold and relative pain threshold, whereas lignocaine :increased them. No changes in the RIII,Su threshold and relative pain were observed. The ratio RIII,Cu/RIII,Su was lowered to 10% with naphthalene and increased to 110% with lignocaine. Intravenous injection of acetyIsalicylic acid increas~l only the RIII,Cu threshold a n d relative pain threshold. The ratio RIII,Cu/RIII,Su was 90% at the maximal effect o f the drug, In contrast, pethidine provoked a decrease in the RIII,Su threshold and an increase in RIII,Cu threshold, parallel with an increase ia pain threshold sensation. The ratio was found to be 190% at the maximal effect. Practical implications of these results, concerning a method for testing the efficacy and mechanisms of an analgesic, axe then discussed.

INTRODUCTION

Ipsilateral flexion reflexes of the lower limb in man have been studied by others with electrophysiologica! methods [1,3,4,6]. It iis well known that an electrical stimulation of the sural nerve elicits two different reflex responses in a flexor muscle of the hindlimb" the first (RID is of short latency ea~.d cot-

1.~_2 responds ~c a tactile reflex after activation of large diameter cutaneous fibers (AII), the second response (RIII) is of longer latency and higher threshold, and corresponds to a nociceptive reflex after activation of finer cutaneous fibers (AIII) [4,9]. These flexion reflexes were mainly used in man as a tool for the study of spinal motor activity and the effects of supraspinal descending motor systems [4,6,10], but have not been related to sensation, e~pecially ~ t h pain. Such an investigation has been previously undertaken b3. the authors [ 12--15]. It was observed that pain threshold and nociceptive :eflex threshold were well correlated when stimulating either the sural ne~ce or the skin in the distal sensory field of this nerve. Moreover, it was observed that this cutaneous stimulation elicited only a group AIII reflex (RI!I,Cu), the threshold of which was much lower than that of an RIII reflex (RIII,Su) elicited by sural nerve stimulation. The ratio of the threshold RIII,Cu/RIII,Su was noted to be about 50% and remained stable in experienced subjects from one session to the other. This ratio seemed to be a reliable index of pain and can be used as a tool for measuring pain, since its stability contrasted with the marked variations observed in individual pain sensation [J.3], and since it can give some indications on spinal and supraspinal pain mechanisms [12]. In the work presented here, the effects of algogenic chemical agents and analgesic drugs are studied on b~th pain and nociceptive reflex activity, using the method described above. METHODS Experiments were carried out on 15 young (20--30 years) healthy subjects (10 males, 5 females), all volunteers, chosen among medical students or physiologist,~;. All of them had previously participated in similar experimental selies and were carefully briefed before each session.

Stimulation and recordings The ~mral nerve and the skin hi the distal receptive field of this nerve were alternately stimulated, using a constant-current stimulator. Recordings from the biceps femoris muscle (Bi) were made using bipolar surface etectrodes currently used in electromyography. Details of stimulation and recordings are described hi a previous pape': [13]. The intensity of stimulatior~ eliciting 60--70% of reflex responses was :hosen as threshold.

Pharmacological preparation In 10 subjects (7 males, 3 ferrules). *~he skin was rubbed with ar abrasive paste h~ the distal receptive field of the .~ural nerve, so as to expose the d~rmis over an area of approximately i ~q. cm. This maneuver could allow the study of drugs acting locally ol per:pherally: 2--3 ml of an algogenic chemical agent (naphthalene), o~."a loca! ~a~esthetic (iignocaine 2%) and of a peripheral analgesic (acetylsalicySc acid ~00 mg/ml: ASA)were successively dropped on this exposed area. In the interval of each of these drugs, the

113 dermis was copiously washed with physiological serum, so as to obtain again the control v~ues of the reflex thresholds. In all subjects, the effects of an intravenous (i.v.) injec~mn of ASA (1 g) and of physiological serum (5 ml) were studied. In 4 subjects, a well-known morphine-like central analgesic (pethidine: Peth.} was also studied, given as an intramuscular (i.m.) injection of 200 mg solution. In all cases of injection, solutions were heated to body temperature (37°C) before administration. Each experimental session lasted between 30 and 40 min, and each subject was tested at least 3 times. The numerical data obtained were statistically analyzed and the significance of the variations was studied using the Student t-test. RESULTS

(1) Control recordings As was mentioned in the Introduction, stimulation of the sural nerve elicits two types of reflex: activity in the Bi which corresponds to two different sensatiGns: the first response (BID has a short latency (40--70 msec) and a low threshold (6 mA). It corresponds to a tactile sensation similar to that provoked by a superficia! artery pulsation. The second response (RIII,Su) is of longer latency (80--150 msec) and of higher threshold (10 mA). It corresponds, at threshold, to a light pricking pain well localized at the stimulation point. In contrast, when a 10 mA stimulation is applied on the skin in the distal receptive field of the sural nerve, an obvious supra:iminal nociceptive reflex response (RIII,Cu) can be observed. At the same time, the subjects experience a very strong, short duration burning pain, poorly localized in the area of the'stimulating electrodes. In this experimental condition, the threshold of l~III,Cu is found to be 5 mA, and corresponds to a light pricking pai'.~_ well localized at the stimulating electrode point. No tactile response (BII) is ever observed when the skin is stimulated according to these conditions (Fig.

1). (2) Effects of drugs In this part, the effects o[ chemical and pharmacological agents are studied on both RIII,Cu and RIII,Su thresholds. Local application of 2 ml naphthalene on the exposed dermis or on the undamaged skin immediately provokes a warm pruriitic sensation which quickly becomes {after a S0--69 sec delay} a painful burning sensation which lasts for 5--6 min. Simultaneously, the threshold of RIII,Cu is very significantly lowered ~o 3 mA {t = 3.12, N = 120, P < 0.001), while the RIII,Su threshold is not significantly modified (t = 1.29, N = 120, N.S.). When the action of the dn~g is maximal, about 80--100 sec after application, the ratio RIII,Cu/ttIII,Su threshold is decreased from 50 to 10%; it returns progressively to its control values by the sixth minute following naphthalene app}ication {Fig. 2). By this time, the spontaneous burning :pain described by ~he subjects has completely disappeared.

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v Fig. 1. Reflex responses (RII, RIII) recorded in the ipsilateral biceps femoris muscle, elicited by a 10 mA stimuiation applied on the sural nerve (A) and on the skin in the distal receptive field of this nerve (B). Note that RII is absent in B whereas RIII is of shorter latency, larger amplitude and longer duration than in A, indicating clearly a supra-liminal activation of the AIII afferent fibers.

Local application of 2--3 ml of lignocaine on the dermis provokes after a 2 rain d31ay slight local anesthesia which increases with time. Simultaneously, there is a very significant increase in the RIII,Cu threshold (10 mA, N = 120, t = 4.25, P < 0.001). In contrast, no significant variation in the RIII,Su threshold is noted ( t = 0.9, N = 120, N.S.). At the time of maximal effect of lignocaine, the ratio o f RIII,Cu/RIII,Su threshold is notably increased from 50 to 110% and returns progressively to its control value

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Fig. 3. Effects of application of lidocaine (Lid.) on the dermis of the distal receptive field of the sural nerve on the threshold of RIII,Cu (o) and of RIII,Su (o). Note an increase in the RIII,Cu threshold, beginning 3 rain after application of lid. This effect is reversible by washing {Wash.) copiously the dermis.

about 5 min after washing the exposed dermis (Fig. 3). Identical variations are noted when ASA is applied to the exposed dermis area, whereas no change is observed in the reflex thresholds when lignocaine or ASA are applied on undamaged skin. When ASA is gh'en i.v., it provokes a progressive and very significant increase in the 1R,III,Cu threshold (8.5--9 mA, t = 3.22, N = 120, P < 0.001) after a 6--7 min delay. This increase remains constant and stable during the 20 min examination following the injection. In contrast, no significant variation in the RIII,Su threshold can be observed at the same time (t = 1.47, N =

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120. N.S.). The ratio ttIII,Cu/RIII,Su threshold is progressively increased to 85% by the ~'th min following ASA injection and remains stable during the 20 min examination (Fig. 4). An i.v. injection of physiological serum given a~ a placebo does not induce amy significant variation either in the RIII,Cu threshold (t = 0.91, N = 120, N.S.) or in the RIII,Su threshold ( t = 1.12, N = 120, N.S.). The ratio RIII,Cu/RIII,Su threshold remains constant to its control value (50%) during

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117

t h e 3 0 min examination. In the same way, the pain threshold is not si~-lificantly medified(Fig. 5). In contrasL, upon an i.m. injection of pethidine, there is a modification in t h e pain threshold as well as in both RIII,Cu and RIII,Su thresholds. Towards the 20th rain following the injection, a very significant increase is n o t e d in the RIH,Cu threshold ( 1 0 m A , t = 4 . 1 7 , N = 120, P < 0.001), paradoxally with a very significant decrease in the RIII,Su threshold (6 mA, t = 3.75, N - 120, P < 0.001). The ratio RIII,Cu/RIII,Su threshold increases progressively to reach a steady value of about 170--19,0% by the 20th min after injection and during the 45 min of examination (Fig. 6). At the same time, the subjects describe a feeling of lightness accompanied with a certain degree of s~eepiness. The pain threshold is then increased but is associated with an apparent indifference from the subjects towards the nociceptive electrical stimulation. DISCUSSION

These results show that ~m appropriate cutaneous stimulus, giving rise only to a late nociceptive reflex (RIII,Cu), can activate only receptors from which small caliber fibers originate, including the free ending paravascular sensory nerves [7], a n d may be the superficial small caliber fibers themselves [13]. Moreover, the threshold of this nociceptive response, corresponding to a sensation of pricking pain, was found to be much lower than that of the nociceptive reflex (RIIi,Su) elicited by sural nerve stimulation, which elicits also a tactile RII reflex. This confirms that activation of large diameter fibers inhibits both nociceptive reflex acti~'ity [4,8] and pain sensation. On the other hand, these results show the possibility to modify the pain sensation and the nociceptive reflexes either by m~ogemc '~ " chemical agents, by local anesthe~i:cs or by analgesic drugs. It ha~ been observed that an algogenic~chemical agent (naphthalene) dropped on the skin, provokes a decrease:in both RIII,Cu and relative pain thresholds, whereas RIII,Su and corresponding pain were not altered. These findings are consistent with those of Van Hees and Gybels [11], who showed an increase in the non-myelinated fiber disc':n:gge, well correlated with a burning pain described by the subjects, w h e n naphthalene was rubbed to the skin. This suggest3 that the flexor motoneurons are facilitated by the inpW~s conveyed in these non.myelinated fibers, and could explain the facilitation of the cutaneous nociceptive reflex (RIILCu). In contr.ast, the sural nociceptive reflex (RilI,Su) remains unchanged, since the stimulation of this nelve trunk is demonstrated to activa~e also the large diame~,;er cutaneous fibers (AID which are supposed to inhibi~ the inputs conveyed via the finer caliber fibers [ 13]. The corollary experiment is realized hy the action of a local ane,'~thetic. In this case, when lignocame is dropped directly on the dermis, it provokes an ~ncrease in the cutaneous response thresholds (pain and reflex) whereas the ~urat response thresholds remain constant. This suggests tha~: tignocaine, blocking tl~e smaL ~"~a ~~e s the cut~ let superficial cutaneous fibers and recep~;ors,. i" n ~ , ~.... - ~ ~u. s

response thresholds but h~,-' ::~ effects on fibers a,+. the level of the ~runk of the sur~ ne>ve. Id..ntic.A~ #, results are obtained when ASA is studmd, dropped directly on the dermis or administered parenterally (i.v.). These findings are in ~greemen~ with those of Lira [7], who has shown thac ASA acts peripherally, by b~oc~Sng splanchnic potentials evoked by intra-arterial injections of bradykinin i:,~to ~he spleen of cats and dogs. These data give some evidence for a pefipher~ mechanism of the analgesia induced by ASA in man, but one cannot exclude an associated central effect, since ASA reduces the discharge of the lamina V cells of the spinal cord: evoked by intraarterial injection of bradykinin in spinal cats (J.M. Besson, personal communication). In contrast, there is a paradoxal effect on pain sensation and nociceptive reflexes, when pethidine is studied: pain thresholds (cutaneous and sural) are increased, as well as RIII,Cu threshold, while the RIII,Su threshold is notably =lecreased. At the same time, the subjects seem to be slightly sleepy and show a kind of indifference to the painful stimulation. Depression of nociceptive

Pharmacological modulations on the nociceptive flexion reflex in man.

111 Pain.. 3 (1977) 111--119 © Elsevier/North-Hollan d Biomedical Press PHARMACOLOGICAL MODULATIONS ON THE NOCICEPTIVE FLEXION. REFLEX IN MAN J.C. W...
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