daniel le bars

The tail and paws in
rodents are heat exchangers involved in the maintenance of core body
temperature (Tcore). They are also the most widely used target organs
to study acute or chronic “models” of pain. We describe the fluctuations
of vasomotor tone in the tail and paws in conditions of thermal
neutrality and the constraints of these physiological processes on the
responses to thermal nociceptive stimuli, commonly used as an index
of pain. Skin temperatures were recorded with a calibrated thermal
camera to monitor changes of vasomotor tone in the tail and paws of
awake and anesthetized rats. In thermoneutral conditions, the sympathetic
tone fluctuated at a rate of two to seven cycles/h. Increased
mean arterial blood pressure (MAP; 46 mmHg) was followed by
increased heart rate (HR; 45 beats/min) within 30 s, vasoconstriction
of extremities (3.5–7°C range) within 3–5 min, and increased
Tcore (0.7°C) within 6 min. Decreased MAP was followed by
opposite events. There was a high correlation between HR and Tcore
recorded 5–6 min later. The reaction time of the animal’s response to
a radiant thermal stimulus—heat ramp (6°C/s, 20 mm2 spot) generated
by a CO2 laser—directed to the tail depends on these variations.
Consequently, the fluctuations in tail and paw temperature thus
represent a serious confound for thermal nociceptive tests, particularly
when they are conducted at thermal neutrality.

In thermal neutral
condition, rats display cyclic variations of the vasomotion of the tail
and paws, synchronized with fluctuations of blood pressure, heart rate,
and core body temperature. “On-” and “off-” cells located in the
rostral ventromedial medulla, a cerebral structure implicated in somatic
sympathetic drive, 1) exhibit similar spontaneous cyclic activities
in antiphase and 2) are activated and inhibited by thermal
nociceptive stimuli, respectively. We aimed at evaluating the implication
of such neurons in autonomic regulation by establishing correlations
between their firing and blood pressure, heart rate, and skin
and core body temperature variations. When, during a cycle, a relative
high core body temperature was reached, the on-cells were activated
and within half a minute, the off-cells and blood pressure were
depressed, followed by heart rate depression within a further minute;
vasodilatation of the tail followed invariably within 3 min, often
completed with vasodilatation of hind paws. The outcome was an
increased heat loss that lessened the core body temperature. When the
decrease of core body temperature achieved a few tenths of degrees,
sympathetic activation switches off and converse variations occurred,
providing cycles of three to seven periods/h. On- and off-cell activities
were correlated with inhibition and activation of the sympathetic
system, respectively. The temporal sequence of events was as follows:
core body temperature ¡ on-cell ¡ off-cell  blood pressure ¡
heart rate¡skin temperature¡core body temperature. The function
of on- and off-cells in nociception should be reexamined, taking into
account their correlation with autonomic regulations.

Cette revue examine la sensibilité, la fiabilité
et la validité de tests et modèles animaux pour l’étude de la
douleur. Une attention particulière est portée à la validité
conceptuelle (sous ses différentes formes), c’est-à-dire le
degré avec lequel un test mesure effectivement ce qu’il est
censé mesurer dans un modèle dont la validité a été établie
par ailleurs. Après l’étude des principaux facteurs qui influencent
la validité, nous estimons qu’elle reste un problème
majeur, bien que sous-estimé voire parfois nié, particulièrement
en matière de recherches précliniques sur la douleur.

Background: The mouse is increasingly used in biomedical research, notably in behavioral neurosciences for the
development of tests or models of pain. Our goal was to provide the scientific community with an outstanding tool that
allows the determination of psychophysical descriptors of a nociceptive reaction, which are inaccessible with conventional
methods: namely the true threshold, true latency, conduction velocity of the peripheral fibers that trigger the response and
latency of the central decision-making process.
Methodology/Principal Findings: Basically, the procedures involved heating of the tail with a CO2 laser, recording of tail
temperature with an infrared camera and stopping the heating when the animal reacted. The method is based mainly on
the measurement of three observable variables, namely the initial temperature, the heating rate and the temperature
reached at the actual moment of the reaction following random variations in noxious radiant heat. The initial temperature
of the tail, which itself depends on the ambient temperature, very markedly influenced the behavioral threshold, the
behavioral latency and the conduction velocity of the peripheral fibers but not the latency of the central decision-making.
Conclusions/Significance: We have validated a psychophysical approach to nociceptive reactions for the mouse, which has
already been described for rats and Humans. It enables the determination of four variables, which contribute to the overall
latency of the response. The usefulness of such an approach was demonstrated by providing new fundamental findings
regarding the influence of ambient temperature on nociceptive processes. We conclude by challenging the validity of using
as ‘‘pain index’’ the reaction time of a behavioral response to an increasing heat stimulus and emphasize the need for a very
careful control of the ambient temperature, as a prevailing environmental source of variation, during any behavioral testing
of mice.

Sur le plan psychophysique, l’analyse de la douleur
expérimentale évoquée par la chaleur est difficile pour deux
raisons principales : 1) un stimulus thermique est toujours
progressif ; 2) un stimulus douloureux peut activer deux
types de nocicepteurs, connectés à des fibres périphériques
Aδ et C dont les vitesses de conduction sont différentes.
Pourtant, dans beaucoup de tests comportementaux de nociception
chez l’animal, on mesure le temps de réaction, c’està-
dire la durée séparant la réponse évoquée du début de
l’application de chaleur. Puisqu’il est techniquement impossible
de chauffer la peau instantanément par des moyens
conventionnels, on doit s’interroger sur la signification
d’un temps de réaction obtenu dans ces conditions. Nous
avons développé un corpus théorique, un paradigme expérimental
et un modèle pour analyser en termes psychophysiques
chez le rat les réponses évoquées par l’application de
chaleur radiante nociceptive de puissance aléatoire. Nous
avons étendu cette approche, fondée sur l’analyse conjointe
du stimulus et de la réponse du sujet, à l’homme pour mesurer
les seuils thermiques et les latences de la douleur déclenchées
par les fibres Aδ et C.

Gabapentin is a structural analogue of gamma-amino-butyric acid with anticonvulsant activity. Recently,
indications for its use were extended to the management of acute pain in the postoperative period. The
effects of pre-administration of gabapentin on the depressive action of intravenous morphine were
studied on the C-fibre reflex elicited by a wide range of stimulus intensities.
The reflex was elicited by electrical stimulation of the sural nerve and recorded from the ipsilateral
biceps femoris muscle in halothane anaesthetized rats with either an intact neuraxis or a brainstem
previously transected at the level of the obex.
As previously reported, 6 mg/kg intravenous morphine both increased the threshold and decreased
the slope of the stimuluseresponse recruitment curve. The C-fibre reflex was not modified following
intravenous gabapentin. Gabapentin pre-treatment at lower doses (0.01e7.5 mg/kg) not only antagonized
the depressive effect of morphine, but caused facilitation of the reflex. At higher doses (10e50 mg/
kg), gabapentin pre-treatment potentiated the depressive effect of morphine. In obex-transected rats, the
facilitation of the C-fibre reflex, seen following 1 mg/kg gabapentin and 6 mg/kg morphine, disappeared
and was replaced by a strong reinforcement of the depressive effect of morphine.
It is concluded that a strong synergy between the effects of gabapentin and morphine can be seen at
the spinal level. However, radically opposite effects with supraspinal origins thwart this mechanism.
From the clinical standpoint, these results incite cautiousness in the use of combinations of gabapentin
and opioids.

An increased tail-flick latency to noxious heat during or after stress in the rodent is usually interpreted as
a stress-induced reduction in pain sensitivity and often described as a form of stress-induced ‘‘analgesia.’’
However, this measure is an indirect and flawed measure of the change in nociceptive threshold to noxious
heat. A major confound of the latency measure is the initial temperature of the tail, which can drop
down to room temperature during stress, the consequence of a marked sympathetically mediated vasoconstriction
in the skin of the extremities. We addressed this issue with tail-flick tests during contextual
fear using infrared thermography to monitor temperature changes and a CO2 laser to deliver the heat
stimulus. The experiment revealed a 4.2C increase of the nociceptive threshold, confirming a true antinociceptive
effect. However, its contribution to the increased withdrawal latency was less than two-thirds
(63.2%). Nearly one-third (32.2%) was due to the drop in tail temperature (4.4C), which also slowed conduction
along sensory fibers (2.2%, included in the 32.2%). The remaining 4.6% was due to an increase in
decisional/motor latency. This new unbiased method establishes beyond doubt that a conditioned stress
response is associated with true antinociception to noxious heat. It also confirms that stress-induced
changes in skin temperature can be a major confound in tail-flick tests. The present study shows, for
the first time, the exact contribution of these two components of the tail-flick latency for a stress
response.

La nociception et son expression la plus élaborée sur le plan cognitif, la douleur, constituent un signal
d’alarme qui protège l’organisme: elles déclenchent des réactions dont la finalité est de diminuer la
cause qui les a provoquées et d’en limiter ainsi les conséquences. Un stimulus nociceptif active un
ensemble discret d’organes sensoriels, les nocicepteurs, terminaisons libres de fibres amyéliniques qui
tapissent l’ensemble des tissus. Ces nocicepteurs sont polymodaux, c’est-à-dire qu’ils répondent à des
stimulus de différentes natures physiques (thermique, mécanique, chimique). Le message nociceptif
est relayé dans la corne dorsale de la moelle épinière pour être distribué vers les cornes ventrale et
latérale (réflexes somatiques et végétatifs) et dans de nombreuses structures cérébrales, notamment
la formation réticulée, le thalamus et plusieurs aires corticales. Ces dernières incluent chez l’homme
les cortex somesthésiques primaire et secondaire et surtout les cortex cingulaire et insulaire qui appartiennent
au système limbique, essentiel dans la genèse des émotions. Les systèmes nociceptifs sont
très anciens dans la phylogenèse. Ce n’est qu’avec l’apparition du cerveau émotionnel (limbique), que
l’on peut parler de douleur au sens d’une expérience sensorielle et émotionnelle. Comme l’absence
de communication verbale sera toujours un obstacle pour évaluer la douleur de l’animal, il est suggéré
que, pour mieux la comprendre, l’incontournable anthropomorphisme se nourrisse des données
neuropsychologiques.

Using the C-fibre reflex as a nociceptive response elicited by a wide range of stimulus intensities in the rat, we recently reported that a single
treatment with (þ)-HA966, a glycine site-specific NMDA receptor antagonist: (1) potentiates morphine antinociception; and (2) reverses an
established morphine tolerance. We presently aimed at determining whether our observation was likely to result from a direct effect on the spinal
cord or an indirect effect of supraspinal origin. In a 2  2  2 experimental design, we compared the effects of 5 mg/kg morphine in: (1) shamoperated
rats or animals whose brainstems had been transected at the level of the obex; (2) rats that were implanted with pellets, either 150 mg
morphine or placebo; and (3) animals injected either with saline or 10 mg/kg (þ)-HA966. The control C-fibre reflexes were similar in all groups
of animals. As compared to ‘‘non-tolerant’’ rats, the depressive effect of morphine was weaker in ‘‘morphine-tolerant’’ animals where the threshold
did not change following morphine but the gain of the stimulus-response curve decreased, albeit to a significantly lesser extent than in the
‘‘non-tolerant’’ group. Whether in ‘‘non-tolerant’’ or ‘‘tolerant’’ groups, the effects of morphine were stronger in ‘‘obex-transected’’ than in
‘‘sham-operated’’ animals. In all groups, the effects of morphine were potentiated by the preliminary administration of (þ)-HA966. However,
in the ‘‘morphine-tolerant’’ group, the preliminary administration of (þ)-HA966 was more potent in the ‘‘sham-operated’’ than in the ‘‘obextransected’’
groups. Since overall effects were very similar in ‘‘sham-operated’’ and ‘‘obex-transected’’ animals, we concluded for our model
that the critical site for the expression of the neuronal plastic changes associated with morphine tolerance lies in the spinal cord.

La douleur s’élabore au sein d’un cerveau imprégné par son passé. En particulier, les événements
somesthésiques antérieurs, qu’ils soient ou non douloureux, sont intégrés dans l’élaboration de la douleur
présente. C’est l’ensemble de ces événements qui, de concert avec la proprioception et l’équilibration,
permet à chacun de construire progressivement et inconsciemment son schéma corporel, étape
essentielle de l’édification biologique du soi. Sa consolidation progressive et son incessante
restructuration peuvent cependant être remises en cause par de nombreux facteurs biologiques et
psychologiques. On peut faire l’expérience de la distorsion de ce schéma dans certaines situations
particulières. Ainsi, les viscères peuvent, du moins pour certains d’entre eux, prendre le pouvoir au sein du
schéma corporel. Le besoin pressant d’uriner ou de déféquer, que l’on qualifiera « d’impérieux » lorsque
l’on ne peut le satisfaire, distord notre schéma corporel au point que notre être entier se résume à ce
besoin physiologique. Le schéma corporel se situe dans un « interland » lâche entre l’inconscient et le
conscient. Tapi dans la monotonie du « normal », il se dilue dans l’inconscient, mais il ne demande qu’à
se « réveiller » à la moindre occasion, soit vers le plaisir, soit vers la douleur. Les douleurs intenses, les
douleurs qui durent, les douleurs qui évoluent vers la chronicité figurent probablement parmi les causes
physiques les plus courantes de perturbation du schéma corporel : elles focalisent l’attention sur une
partie du corps au détriment des autres, le schéma se déformant par une « sur-représentation » du foyer
douloureux. Les neurones à convergence de la corne postérieure de la moelle sont capables de saisir la
globalité des informations issues à la fois de l’interface avec le milieu extérieur (la peau) et du milieu
intérieur (les viscères, les muscles). Sur la base d’expériences électrophysiologiques effectuées chez
l’animal et chez l’homme, nous défendons la thèse suivante : « l’activité somesthésique de base »
constituée par l’ensemble de ces informations joue un rôle important dans l’élaboration du schéma
corporel, du moins dans sa composante qui complète le schéma postural. Un foyer douloureux, qui active
un sous-ensemble segmentaire de neurones à convergence et inhibe le reste de la population, perturbe
profondément cette activité. Il en résulte une déformation du schéma corporel au profit du foyer
douloureux qui s’extrait de l’activité de fond et devient surdimensionné.

Background: The quantitative end-point for many behavioral tests of nociception is the reaction time, i.e. the time lapse
between the beginning of the application of a stimulus, e.g. heat, and the evoked response. Since it is technically impossible
to heat the skin instantaneously by conventional means, the question of the significance of the reaction time to radiant heat
remains open. We developed a theoretical framework, a related experimental paradigm and a model to analyze in
psychophysical terms the ‘‘tail-flick’’ responses of rats to random variations of noxious radiant heat.
Methodology/Principal Findings: A CO2 laser was used to avoid the drawbacks associated with standard methods of
thermal stimulation. Heating of the skin was recorded with an infrared camera and was stopped by the reaction of the
animal. For the first time, we define and determine two key descriptors of the behavioral response, namely the behavioral
threshold (Tb) and the behavioral latency (Lb). By employing more than one site of stimulation, the paradigm allows
determination of the conduction velocity of the peripheral fibers that trigger the response (V) and an estimation of the
latency (Ld) of the central decision-making process. Ld (,130 ms) is unaffected by ambient or skin temperature changes
that affect the behavioral threshold (,42.2–44.9uC in the 20–30uC range), behavioral latency (,500 ms), and the
conduction velocity of the peripheral fibers that trigger the response (,0.35–0.76 m/s in the 20–30uC range). We propose a
simple model that is verified experimentally and that computes the variations in the so-called ‘‘tail-flick latency’’ (TFL)
caused by changes in either the power of the radiant heat source, the initial temperature of the skin, or the site of
stimulation along the tail.
Conclusions/Significance: This approach enables the behavioral determinations of latent psychophysical (Tb, Lb, Ld) and
neurophysiological (V) variables that have been previously inaccessible with conventional methods. Such an approach
satisfies the repeated requests for improving nociceptive tests and offers a potentially heuristic progress for studying
nociceptive behavior on more firm physiological and psychophysical grounds. The validity of using a reaction time of a
behavioral response to an increasing heat stimulus as a ‘‘pain index’’ is challenged. This is illustrated by the predicted
temperature-dependent variations of the behavioral TFL elicited by spontaneous variations of the temperature of the tail for
thermoregulation.

N-methyl-D-aspartate (NMDA) receptors are widely involved in opioid tolerance. However, it is less clear whether NMDA receptor antagonists reverse already-established tolerance and whether the intensity of the nociceptive stimulus influences morphine tolerance. Three days after implantation of morphine or control pellets the effects of i.v. morphine and pre-administration of saline or (+)-HA966 (a glycine site-specific NMDA receptor antagonist), were studied on the C-fibre reflex elicited by a wide range of stimulus intensities. Morphine both increased the threshold and decreased the slope of the recruitment curve in the "non-tolerant" group of animals. In the "morphine-tolerant" group, the threshold did not change but the gain of the stimulus-response curve decreased. The expression of tolerance to morphine depended on the intensity of the stimulus, being maximal when threshold stimulus intensities were used but considerably less with supra-threshold stimulation. As expected, a single treatment with (+)-HA966, potentiated morphine antinociception in "non-tolerant" rats. However, in "morphine-tolerant" rats (+)-HA966 reversed established morphine tolerance and increased the antinociceptive effects of morphine. These results suggest that (+)-HA966 interfered with expression of morphine tolerance, and offered an encouraging therapeutic approach for pain management in opioid abusers.

Les influx nociceptifs sont générés en périphérie par les terminaisons libres de fibres nerveuses de petit diamètre appelées nocicepteurs
dont la réaction dépend de l’environnement tissulaire. De nombreux médiateurs chimiques activent, sensibilisent ou « réveillent » les nocicepteurs
: les kinines, les cytokines pro-inflammatoires ou anti-inflammatoires, les prostanoïdes, les lipo-oxygénases, le «médiateur central de
la réponse immunitaire » (NF-jB), les facteurs de croissance tels les neurotrophines, les neuropeptides, l’oxyde nitrique, l’histamine, la
sérotonine, les protéases, les acides aminés excitateurs, les amines adrénergiques et les opioïdes. Que ce soit de concert ou à un moment ou un
autre des processus inflammatoires, ces médiateurs interviennent pour engendrer de façon subtile les phénomènes d’hyperalgésie et d’allodynie.
Les mécanismes moléculaires et cellulaires les plus connus qui sous-tendent ces manifestations cliniques seront présentés. Le rôle du
système nerveux périphérique dans le passage des rhumatismes inflammatoires à la chronicité sera soulevé.
© 2005 Elsevier SAS. Tous droits réservés.

The spinal transmission of nociceptive signals is modulated by both spinal and supraspinal 8
systems. Spinal networks underlie segmental inhibitions, which are mediated via myelinated 9
cutaneous afferent fibres activated by mechanical stimuli (e.g. rubbing, etc.) Diffuse noxious 10
inhibitory controls (DNIC) are triggered by peripheral Ay- and C-fibres, involve brain structures 11
confined to the caudal-most part of the medulla including the subnucleus reticularis dorsalis (SRD) 12
and are mediated by descending pathways in the dorsolateral funiculi. Combined psychophysical 13
measurements and recordings of nociceptive reflexes (RIII) in both normal volunteers and patients 14
with lesions in the spinal cord or brain suggest the existence of identical or equivalent inhibitory 15
processes in man. Both these mechanisms could be triggered to produce hypoalgesia by acupuncture 16
needles or moxibustion. When applied near a painful focus, the techniques have similarities to high- 17
frequency, low-intensity transcutaneous nerve stimulation, which brings segmental inhibitory 18
mechanisms into play. When applied to remote areas, the techniques might be related to ‘‘counter- 19
irritation’’ or ‘‘counter-stimulation’’ phenomena which, in addition to involving complex autonomic 20
functions, seem to involve DNIC. Experimental data in both animals and humans support these 21
conclusions. D 2002 Elsevier Science B.V. All rights reserved.

Multireceptive neurones are found in the spinal dorsal horn and may be projection neurones and/or interneurones for polysynaptic
reflexes. The cutaneous receptive field of a multireceptive neurone exhibits a gradient of sensitivity with the centre responding to any
mechanical stimulus, including hair movements and light touch, while the periphery responds only to noxious stimuli. These neurones
also receive signals from viscera, muscles and joints. This convergence of inputs means that multireceptive neurones are continuously
capturing all the information from both the interface with the external environment (the skin) and the internal milieu (the viscera, muscles,
etc.). This information constitutes a ‘basic somaesthetic activity’ that could help the somatosensory system build a ‘global representation
of the body’. In addition to be seen as a global entity, the output of multireceptive neurones should be understood in dynamic terms since
the size of the peripheral fields of the individual neurones may change, as a result of the plasticity of both excitatory and inhibitory
segmental processes. Furthermore, the activity of these neurones can be inhibited from most of the remaining parts of the body via
supraspinal mechanisms. These diffuse noxious inhibitory controls (DNIC) are triggered by peripheral Ad- 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. A painful focus that both activates a segmental subset of neurones and inhibits the
remaining population can seriously disrupt this basic activity, resulting in the distortion of the body representation in favour of the painful
focus, which becomes pre-eminent and (relatively) oversized.

The effect of N-[(R,S)-2-benzyl-3[(S)-(2-amino-4-methylthio)butyldithiol]-1-oxopropyl]-L-phenylalanine benzyl ester (RB101), a dual
inhibitor of the enkephalin-degrading enzymes, neutral endopeptidase and aminopeptidase N, was assessed in anaesthetised rats on the Cfibre
reflex elicited by electrical stimulation within the sural nerve territory and recorded from the ipsilateral biceps femoris muscle. The
temporal evolution of the pharmacological response was monitored by the repeated application of a constant stimulus intensity, namely three
times threshold (3 T). In addition, recruitment curves were built by varying the stimulus intensity from 0 to 7 T. RB101 (7.5, 15 and 30 mg
kg
1, i.v.) induced a dose-dependent, naloxone-reversible depression of the reflex, which lasted around 60 min with the highest dose. The
ED50 was calculated as 16.9 mg kg
1. Analyses of the recruitment curves revealed: (1) a significant increase of threshold; (2) a significant
depression of the reflex in the ascending part of the curve; and (3) a lack of major depressive effects on the responses elicited by the strongest
stimuli (corresponding to the plateau of the curve). The increase in the nociceptive threshold by enkephalin-degrading enzyme inhibitors,
confirms previous data obtained from behavioural tests. In addition, the present study revealed an efficacy of these compounds over a wide
range of stimulus intensities, albeit excluding the highest.

The study of pain in awake animals
raises ethical, philosophical, and technical problems.
We review the ethical standards for studying pain in
animals and emphasize that there are scientific as well
as moral reasons for keeping to them. Philosophically,
there is the problem that pain cannot be monitored
directly in animals but can only be estimated by examining
their responses to nociceptive stimuli; however,
such responses do not necessarily mean that there is a
concomitant sensation. The types of nociceptive stimuli
(electrical, thermal, mechanical, or chemical) that
have been used in different pain models are reviewed
with the conclusion that none is ideal, although chemical
stimuli probably most closely mimic acute clinical
pain. The monitored reactions are almost always motor
responses ranging from spinal reflexes to complex
behaviors. Most have the weakness that they may be
associated with, or modulated by, other physiological
functions. The main tests are critically reviewed in
terms of their sensitivity, specificity, and predictiveness.
Weaknesses are highlighted, including 1) that in
most tests responses are monitored around a nociceptive
threshold, whereas clinical pain is almost always
more severe; 2) differences in the fashion whereby
responses are evoked from healthy and inflamed tissues;
and 3) problems in assessing threshold responses
to stimuli, which continue to increase in intensity. It is
concluded that although the neural basis of the most
used tests is poorly understood, their use will be more
profitable if pain is considered within, rather than
apart from, the body’s homeostatic mechanisms.

The effects of intravenous sufentanil and pre-administration of N-methyl-D-aspartate (NMDA) receptor antagonists were tested on a reflex triggered by C-fibre activation. The reflex was elicited by electrical stimulation of the sural nerve and recorded from the ipsilateral biceps femoris muscle in halothane anaesthetized rats either (1) with an intact neuraxis or (2) in which the brain had previously been transected at the level of the obex.All four doses of sufentanil (0.33, 0.6, 1 and 2 μg kg−1) elicited a depression of the reflex in a dose-dependent manner. However, following the expected depression, all doses of sufentanil elicited both facilitation of the reflex and tonic inter-stimulus discharges.The C-fibre reflex was not modified following intravenous ketamine (1 mg kg−1) or (+)-HA966 (5 or 10 mg kg−1) but, when administered 5 min before sufentanil, these drugs enhanced both the extent and the duration of the depression and strongly reduced the facilitations.In the obex-transected rats, the depressive effect of 1 μg kg−1 sufentanil increased, while the facilitation of the C-fibre reflex and the tonic inter-stimulus discharges disappeared. Pre-administration of 10 mg kg−1 (+)-HA966 reinforced and prolonged the depressive effect of sufentanil.These results extend previous studies suggesting the involvement of NMDA receptors in the spinal transmission of nociceptive signals. They illustrate the potential of spinal NMDA receptor blockade to both enhance the analgesic, and prevent the pro-nociceptive, effects of sufentanil.The effects of intravenous sufentanil and pre-administration of N-methyl-D-aspartate (NMDA) receptor antagonists were tested on a reflex triggered by C-fibre activation. The reflex was elicited by electrical stimulation of the sural nerve and recorded from the ipsilateral biceps femoris muscle in halothane anaesthetized rats either (1) with an intact neuraxis or (2) in which the brain had previously been transected at the level of the obex.All four doses of sufentanil (0.33, 0.6, 1 and 2 μg kg−1) elicited a depression of the reflex in a dose-dependent manner. However, following the expected depression, all doses of sufentanil elicited both facilitation of the reflex and tonic inter-stimulus discharges.The C-fibre reflex was not modified following intravenous ketamine (1 mg kg−1) or (+)-HA966 (5 or 10 mg kg−1) but, when administered 5 min before sufentanil, these drugs enhanced both the extent and the duration of the depression and strongly reduced the facilitations.In the obex-transected rats, the depressive effect of 1 μg kg−1 sufentanil increased, while the facilitation of the C-fibre reflex and the tonic inter-stimulus discharges disappeared. Pre-administration of 10 mg kg−1 (+)-HA966 reinforced and prolonged the depressive effect of sufentanil.These results extend previous studies suggesting the involvement of NMDA receptors in the spinal transmission of nociceptive signals. They illustrate the potential of spinal NMDA receptor blockade to both enhance the analgesic, and prevent the pro-nociceptive, effects of sufentanil.British Journal of Pharmacology (2001) 133, 1013–1022; doi:10.1038/sj.bjp.0704148

A C-fibre reflex elicited by electrical stimulation within the territory of the sural nerve was recorded from the ipsilateral biceps
femoris muscle in anaesthetised, intact rats, and in anaesthetised rats whose brains had been transected at the level of the obex. The
temporal evolution of the response was studied by recording recruitment curves built with stimulus intensities from 0 to 10 times
threshold. Both i.v. and i.t. sufentanil resulted in dose-dependent depressions of the reflex. Increasing the stimulus intensity from 1.5 to 10
times threshold resulted in an increase in the ED50 from 0.580.40–0.86.to 2.401.87–3.31.mgrkg for i.v. sufentanil and from 0.64
0.46–0.79.to 1.631.29–3.31.mgrkg for i.t. sufentanil. With increasing stimulus intensity, the dose–response curves showed a
progressive shift to the right, but this shift was only slight with the highest intensity stimuli. The ratios for the ED50s for i.v. to i.t.
sufentanil were near 1. Following i.v. administration, sufentanil also facilitated the C-fibre reflex and produced tonic inter-stimulus
discharges. They disappeared after the i.v. injection of naloxone. In the obex-transected rats, the depressive effect of sufentanil increased,
while the facilitations and tonic inter-stimulus discharges disappeared. These findings suggest that the analgesic effects of i.v. ant i.t.
sufentanil are similar, probably because sufentanil is highly soluble in lipids. Sufentanil-induced facilitations relate to supraspinal actions
on motor controls andror on the descending control of nociceptive transmission.

Diffuse noxious inhibitory controls (DNIC), which involve supraspinal structures and modulate the transmission of nociceptive signals,
were investigated in rats with chronic constriction injury of the sciatic nerve. Nerve-injured rats with increased sensitivity to mechanical and
thermal stimulation on the operated side were anesthetized and recordings were made from trigeminal convergent neurons. Inhibitions of
C-®ber-evoked neuronal responses during and after the application of nociceptive conditioning stimuli to the hindpaw, were measured to
evaluate DNIC. The conditioning stimuli consisted of graded natural (pressure and heat) and electrical stimuli and were applied alternately to
non-operated and operated hindpaws. Compared with the non-operated paw, inhibitions elicited by pressure on the operated hindpaw were
increased signi®cantly at all stimulus intensities. Albeit to a lesser extent, inhibitions elicited by thermal stimulation of the operated paw were
also increased in the nerve-injured animals. Such exacerbation of DNIC-induced inhibitions produced by mechanical and thermal stimulation
of the operated paw can be explained by an increase in the afferent input to the spinal cord. In contrast to the results obtained with natural
stimulations, inhibitions evoked from the operated and non-operated paws were similar when graded electrical stimulation was used as the
conditioning stimulus. This was true regardless of the intensity and frequency of stimulation and regardless of whether the stimuli were
applied transcutaneously or directly to the sciatic nerve. The clear-cut difference between the results obtained with natural and electrical
conditioning stimuli suggests that the nociceptive neurons involved in the triggering of DNIC may not be sensitized at the central level.
Peripheral mechanisms such as the sensitization of nerve injured ®bers and/or sprouting of nerve terminals may thus be the main causes of
DNIC increase in this model of neuropathic pain. q 2001 International Association for the Study of Pain. Published by Elsevier Science B.V.
All rights reserved.

Spinal and supraspinal controls can tonically or phasically modulate the output of spinal nociceptive neurons. Alterations of these modulatory systems have been described during the acute stage of inflammation. In the present study in the rat, tonic descending controls were assessed during acute (24–48 h) and chronic (3–4 weeks) stages of monoarthritis of the ankle. The electrophysiological properties of spinal convergent neurons with ankle input were compared before and after spinalization. In a parallel series of experiments, spinal convergent neurons were recorded from the normal side in order to assess the propriospinal and supraspinal inhibitory controls triggered by nociceptive stimulation of the inflamed ankle. Tonic descending inhibition of convergent neurons with input from the inflamed ankle was enhanced during the acute stage and then decreased during the chronic stage of monoarthritis. Contralateral-induced inhibitions exhibited a similar temporal evolution. Time-dependent changes in the spinal transmission of nociceptive signals were shown by removing descending modulation in animals with monoarthritis; sensitization of spinal neurons with input from the inflamed ankle was demonstrated during the acute stage of monoarthritis, whereas a crossed transmission between inflamed and normal sides was observed during the chronic stage of the disease. These results show that dynamic and stage-dependent modifications of descending controls tend to dampen the central changes associated with inflammation.

The effect of spatial summation, produced by noxious thermal stimuli, was investigated on medullary Subnucleus Reticularis Dorsalis (SRD) neurons of anaesthetized rats. Neurons with 'whole body' receptive fields were excited by a random sequence of thermal stimuli involving four different surface areas of a hindpaw (1.9, 4.8, 7.5 and 18 cm(2)). The responses of SRD neurons progressively decrease when the area of noxious stimulation exceeded 4.8 cm(2). The shape of the stimulus-response curve closely match the shape of dorsal horn convergent neurons, previously recorded under similar experimental conditions. These results suggest that, with respect to spatial encoding properties, SRD neurons are driven by the same supraspinally-mediated inhibitory mechanisms as dorsal horn convergent neurons.

We previously
showed that slow-ramp rectal distensions induce graded inhibitions
of the somatic nociceptive RIII reflex recorded from
the lower limb, which correlated with both distension volume
and visceral sensation. In contrast, rapid phasic rectal distensions
induced facilitatory or biphasic effects (i.e., facilitations
followed by inhibitions) depending on the level of distension.
To examine the role of mucosal and serosal rectal
mechanoreceptors in these viscerosomatic interactions, we
analyzed, in six healthy volunteers, the effects of both types
of rectal distension on the RIII reflex after topical application
of lidocaine or placebo administered in a double-blind and
crossover fashion. Inhibitions of the RIII reflex induced by
both slow-ramp and rapid distensions were strongly reduced
after administration of lidocaine but not after placebo. In
contrast, facilitations of the RIII reflex observed during the
initial phase of rapid distensions were not modified after
lidocaine or placebo applications. These results suggest that
inhibitions, but not facilitations, of the nociceptive RIII reflex
triggered by rectal distensions depend preferentially on the
activation of superficial mucosal receptors. This reflexologic
technique might thus represent an interesting tool for studying
the role of the different rectal mechanoreceptors involved
in visceral sensations.

In intact rats, an inhibitory mechanism counteracts the increase in excitability of a flexor reflex, which is seen in spinal animals
following temporal summation of C-fibre inputs; the Rostral Ventromedial Medulla is involved in this inhibitory mechanism.
Electromyographic responses elicited by electrical stimulation of the sural nerve were recorded from the biceps femoris in four types of
preparations, namely intact, sham-operated, Rostral Ventromedial Medulla-lesioned and decerebrate-spinal rats. The excitability of the
C-fibre reflex was tested during and following high intensity homotopic electrical conditioning stimuli. Morphine2 mgrkg.did not
significantly change the basal test response but increased the excitability of the spinal cord during conditioning. This effect was triggered
by the strength of inputs, involved the Rostral Ventromedial Medulla and was probably related to some forms of motor stimulation
through dopaminergic transmission. While wind-up was not reduced, the inhibition related to Diffuse Noxious Inhibitory Controls, which
occurred following the conditioning period, did. In spinal animals where inhibitory mechanisms disappear, the depressive effects of
morphine were unmasked for both wind-up and post-conditioning facilitations. All effects of morphine were completely reversed by
naloxone.

BACKGROUND:
Stimulus intensity is a major determinant of the antinociceptive activity of opiates. This study focused on the influence of the spatial characteristics of nociceptive stimuli, on opiate-induced depressions of nociceptive transmission at the level of the spinal cord.
METHODS:
Anesthetized rats were prepared to allow extracellular recordings to be made from convergent neurons in the lumbar dorsal horn. The effects of systemic morphine (1 and 10 mg/kg) were compared with those of saline for thermal stimuli of constant intensity, applied to the area of skin surrounding the excitatory receptive field (1.9 cm2) or to a much larger adjacent area (18 cm2).
RESULTS:
The responses (mean +/- SD) elicited by the 1.9-cm2 stimulus were not modified by 1 mg/kg intravenous morphine, although they were decreased by the 10-mg/kg dose (to 11+/-4% of control values compared with saline; P < 0.05). In contrast, when the 18-cm2 stimulus was applied, 1 mg/kg intravenous morphine produced a paradoxical facilitation of the neuronal responses (159+/-36% of control values; P < 0.05) and 10 mg/kg intravenous morphine resulted in a weaker depression of the responses (to 42+/-24% of control values; P < 0.05) than was observed with the smaller stimulus.
CONCLUSIONS:
Doses of systemic morphine in the analgesic range for rats had dual effects on nociceptive transmission at the level of the spinal cord, depending on the surface area that was stimulated. Such effects are difficult to explain in terms of accepted pharmacodynamic concepts and may reflect an opioid-induced depression of descending inhibitory influences triggered by spatial summation.

Diffuse noxious inhibitory controls (DNIC), which involve su-
praspinal structures and modulate the transmission of nocicep-
tive signals, were investigated at different stages during the
development of adjuvant-induced monoarthritis in the rat. After
behavioral evaluation, recordings of trigeminal convergent neu-
rons were performed in anesthetized animals with acute (24–48
hr) or chronic (3–4 weeks) monoarthritis of the ankle. Inhibitions
of C-fiber-evoked neuronal responses during and after the
application of noxious conditioning stimuli to the ankle were
measured to evaluate DNIC. The conditioning stimuli consisted
of mechanical (maximal flexion and graded pressures) and
graded thermal stimuli and were applied alternately to normal
and arthritic ankles. Behaviorally, the two groups of animals
exhibited a similar increased sensitivity to mechanical stimuli
applied to the arthritic joint (i.e., an increased ankle-bend score
and a decreased vocalization threshold to pressure stimuli).
However, they showed different electrophysiological profiles. In
the animals with acute monoarthritis, the DNIC-induced inhibi-
tions produced by mechanical or thermal stimulation of the
arthritic joint were significantly increased at all intensities com-
pared with the normal joint. In contrast, in the chronic stage of
monoarthritis, the DNIC-induced inhibitions triggered by ther-
mal or pressure stimuli were similar for both ankles, except with
the most intense mechanical stimuli. This discrepancy between
the behavioral and electrophysiological findings suggests that
inputs activated during chronic monoarthritis may fail to recruit
DNIC and may thus be functionally different from those acti-
vated in the acute stage of inflammation.

The distribution and organization of cortical projections to the subnucleus reticularis
dorsalis (SRD), the neighboring cuneate nucleus (Cu), and trigeminal nucleus caudalis (Sp5C)
were studied in the rat using microinjections of wheat germ agglutinin-apo horseradish
peroxidase-gold and Biotin-Dextran. Cortical cells projecting to the caudal medulla were
confined to the contralateral layer V with their descending axons crossing the midline at the
level of pyramidal decussation. Cortical afferents to Sp5C originated from cells located mainly
in the primary somatosensory cortex (S1) and the insular cortex, whereas cortical projections
to the Cu originated mainly from the primary motor cortex (M1), the primary and secondary
somatosensory cortex (S1 and S2). The SRD received dense cortical afferents from larger,
widespread cortical areas: M1, M2, S1, S2, and the insular cortex. The existence of dense
cortico-SRD connections supports the possibility of a pyramidal influence over SRD neurons,
which might modify nociceptive information ascending to the cortex itself. This proposal is
consistent with the fact that SRD efferents terminate densely in thalamic areas that influence
sensorimotor cortical regions which in turn project to the SRD. Moreover, these corticofugal
mechanisms could allow the cortex to select its own input by suppressing or augmenting
transmission of signals through SRD-hindbrain/forebrain pathways or by coordinating
activities in spino-SRD-spinal circuits and thus selecting the relevant information produced
by the noxious stimulus.

Pour detinir le phenomene de contre-irritation, on pourrait se referer au be1 aphorisme d’Hippocrate
: << Deux souffrances survenant en meme temps, mais sur des points differents, la plus forte fait taire la
plus faible >). C’est en effet sur la base de cette observation clinique assez commune et bien souvent mise
spontanement a profit par les patients, qu’ont Cte developpees de nombreuses methodes therapeutiques a visee
antalgique, regroupees sous les termes de contre-irritation ou contre-stimulation.
Bien que ce phenomene soit connu des medecins depuis l’Antiquit6, il n’est analyse sur le plan scientifique que
depuis peu. Neanmoins, des resultats experimentaux reunis au tours des dernieres annees ont permis de montrer
qu’il possede un substrat neurologique bien defini tant chez l’animal que chez l’homme. Ces rtsuhats suggerent
en outre que l’etude de la contre-irritation est essentielle pour aborder la physiologie des systemes de controle
de la nociception et de la douleur, dont l’importance a et.6 largement soulignee au tours des dernieres an&es.
De ce fait, l’existence mime du phenomene de contre-irritation constitue probablement l’indice le plus
facilement observable temoignant de la presence d’un systbme specifique de modulation de la douleur chez
l’homme. Outre son interet scientifique, l’elucidation des bases neurophysiologiques sous-tendant la contreirritation
rev&t done une importance clinique, car elle pourrait permettre d’ameliorer notre comprehension de
certains syndromes douloureux, et contribuer au developpement de nouveaux moyens d’investigations des
patients, voire de nouveaux moyens therapeutiques.

In intact rats, an inhibitory mechanism counteracts the increase in excitability of a flexor reflex seen in spinal animals following
high-intensity, repetitive stimulation of C-fibres. We tested the hypothesis that the rostral ventromedial medullaRVM.is involved in
these processes. Electromyographic responses elicited by electrical stimulation of the sural nerve, were recorded from the ipsilateral
biceps femoris in halothane-anaesthetised, sham-operated or RVM-lesioned rats. There were no significant differences between the
C-fibre reflexes in the two groups in terms of their thresholds, latencies, durations or mean recruitment curves. The excitability of the
C-fibre reflex was tested following 20 s of high-intensity homotopic electrical conditioning stimuli at 1 Hz. During the conditioning
period, the EMG responses first increased in both groupsthe wind-up phenomenon., but then decreased in the sham-operated rats and
plateaued in the RVM-lesioned rats. These effects were followed by inhibitions that were very much smaller in the RVM-lesioned rats,
both in terms of their magnitudes and their durations. It is concluded that the RVM is involved in inhibitory feedback mechanisms elicited
by temporal summation of C-fibre afferents that both counteract the wind-up phenomenon and trigger long periods of inhibition.

In order to set up a non-invasive, reliable and reproducible model for investigating a-motoneuronal activity, we studied the electrophysiological features of a monosynaptic H-reflex in anaesthetised intact rats, anaesthetised and non-anaesthetised rats transected at
the level of the obex. Electrical stimulation of the tibial nerve at the ankle elicited an H-reflex, an F-wave and a direct motorM.response
in the plantaris muscles of all preparations. The H-reflex and F-wave exhibited very similar latencies. The H-reflex had a low threshold
and a constant latency. Its amplitude increased as a function of stimulus intensity to reach a maximum value but then decreased when the
stimulus intensity was further increased. It could follow high rates of stimulation without any change in shape or latency. The F-wave had
a lower amplitude which together with its latency varied from one stimulus to the next. It appeared with intensities of stimulation that
elicited an almost maximal M-response and did not decrease when the stimulation was increased. It did not appear systematically from
one stimulus to the next. The H-reflex, but neither the F-wave nor the direct motor M-response, was depressed both by vibratory stimuli
applied on the Achilles’ tendon and following nociceptive stimulation of the flexor reflex afferents. This model could be used for
assessing any potential direct effect on motoneurones of a physiological or pharmacological conditioning procedure.

The distribution and organization of diencephalic projections from the subnucleus
reticularis dorsalis (SRD) and the neighbouring cuneate nucleus (Cu) were studied in the rat
by using microinjections of Phaseolus vulgaris leucoagglutinin in SRD and Cu and wheat
germ agglutinin-apo horseradish peroxidase-gold in some selected thalamic areas. As
previously reported, the efferent projections from the Cu were essentially contralateral and
terminated mainly in the ventroposterolateral thalamic nucleus. Less dense terminals from
the Cu were also observed in the posterior thalamic group, the ventral aspect of the zona
incerta and the caudal and dorsal portion of the reuniens area. Retrograde tracer injections in
the medial ventroposterolateral thalamic nucleus labeled numerous cells in the contralateral
Cu, with a smaller number in the gracile nucleus. From the SRD, terminals were observed in
the lateral aspect of the ventromedial thalamic nucleus, the lateral parafascicular area and, to
a lesser extent, in the ventral aspect of the zona incerta and the core of the reuniens area.
Retrograde tracer injections in the lateral part of the ventromedial thalamic nucleus labeled
cells in the caudal medulla, many of which were located in the dorsal-most aspect of the SRD
throughout its caudo-rostral extent. The existence of SRD-thalamic connections reinforces the
idea that the caudal reticular formation is an important nociceptive relay to the thalamus.
Our data shed new light on old hypotheses suggesting that, in addition to spino-thalamic
pathways, spino-reticulo-thalamic pathways may play an important role in distributing pain
signals to the forebrain.

Electromyographic recordings were made in healthy volunteers from the knee-flexor biceps femoris muscle of the nociceptive RIII reflex elicited by electrical stimulation of the cutaneous sural nerve. The stimulus intensity was adjusted to produce a moderate pricking-pain sensation. The test responses were conditioned by a nonnoxious thermal (</=40 degrees C) stimulus applied to the receptive field of the sural nerve. This stimulus was delivered by a CO2 laser stimulator and consisted of a 100-ms pulse of heat with a beam diameter of 20 mm. Its power was 22.7 +/- 4.2 W (7.2 mJ/mm2), and it produced a sensation of warmth. The maximum surface temperature reached at the end of the period of stimulation was calculated to be 7 degrees C above the actual reference temperature of the skin (32 degrees C). The interval between the laser (conditioning) and electrical (test) stimuli was varied from 50 to 3, 000 ms in steps of 50 ms. It was found that the nociceptive flexion reflex was facilitated by the thermal stimulus; this modulation occurred with particular conditioning-test intervals, which peaked at 500 and 1,100 ms with an additional late, long-lasting phase between 1,600 and 2,300 ms. It was calculated that the conduction velocities of the cutaneous afferent fibers responsible for facilitating the RIII reflex, fell into three ranges: one corresponding to A delta fibers (3.2 m/s) and two in the C fiber range (1.3 and 0.7 m/s). It is concluded that information emanating from warm receptors and nociceptors converges. In this respect, the present data show, for the first time, that in man, conditioning nonnociceptive warm thermoreceptive A delta and C fibers results in an interaction at the spinal level with a nociceptive reflex. This interaction may constitute a useful means whereby signals add together to trigger flexion reflexes in defensive reactions and other basic motor behaviors. It also may contribute to hyperalgesia in inflammatory processes. The methodology used in this study appears to be a useful noninvasive tool for exploring the thermoalgesic mechanisms in both experimental and clinical situations.

We previously showed that gastric distension inhibits the somatic nociceptive flexion RIII reflex. To explore further the viscerosomatic interactions, we tested in the present study the effects of rectal distensions on RIII reflexes. Rapid and slow-ramp rectal distensions were performed in 10 healthy volunteers with an electronic barostat. The RIII reflex was continuously recorded from the lower limb during both types of distension and from the upper limb during rapid distensions. The visceral sensations were scored on a graded questionnaire. Rapid distensions facilitated the RIII reflex recorded from the lower limb, but at the highest distension level, facilitation was followed by inhibition. Slow-ramp distension induced gradual inhibition of the RIII reflex, which correlated with both distension volume and visceral sensation. RIII reflex recorded from the upper limb was also inhibited by rapid rectal distensions. Reflex inhibitions were probably related to the activation of pain modulation systems. One plausible explanation for the facilitatory effects, observed only at the lower limb, is the convergence of rectal and reflex afferents at the same levels of the spinal cord. The differential effects of rapid and slow-ramp distensions suggest the activation of two distinct populations of mechanoreceptors by these two modes of distension.

In the rat, applying noxious heat stimuli to the excitatory receptive fields and simultaneously to adjacent, much larger, areas of the body results in a surface-related reduction in the responses of lumbar dorsal horn convergent neurons. These inhibitory effects induced by spatial summation of nociceptive inputs have been shown to involve a supraspinally mediated negative feedback loop. The aim of the present study was to determine the anatomic level of integration of these controls and hence to ascertain what relationships they might share with other descending controls modulating the transmission of nociceptive signals. The responses of lumbar convergent neurons to noxious stimulation (15-s immersion in a 48 degrees C water bath) applied to increasing areas of the ipsilateral hindlimb were examined in several anesthetized preparations: sham-operated rats, rats with acute transections performed at various levels of the brain stem, and spinal rats. The effects of heterotopic noxious heat stimulation (tail immersion in a 52 degrees C water bath) on the C-fiber responses of these neurons also were analyzed. The electrophysiological properties of dorsal horn convergent neurons, including their responses to increasing stimulus surface areas, were not different in sham-operated animals and in animals the brain stems of which had been transected completely rostral to a plane -2. 8 mm remote from interaural line (200 micron caudal to the caudal end of the rostral ventromedial medulla). In these animals, increasing the stimulated area size from 4.8 to 18 cm2 resulted in a 35-45% reduction in the responses. In contrast, relative to responses elicited by 4.8 cm2 stimuli, responses to 18 cm2 were unchanged or even increased in animals with transections at more caudal level and in spinal animals. Inhibitions of the C-fiber responses elicited by heterotopic noxious heat stimulation were in the 70-80% range during conditioning in sham-operated animals and in animals with rostral brain stem transections. Such effects were reduced significantly (residual inhibitions in the 10-20% range) in animals with transections >500 micron caudal to the caudal end of the rostral ventromedial medulla and in spinal animals. It is concluded that the caudal medulla constitutes a key region for the expression of negative feed-back mechanisms triggered by both spatial summation of noxious inputs and heterotopic noxious inputs.

The somatosensory properties of ventromedial (VM) thalamic
neurons were investigated in anesthetized rats by examining
their responses to calibrated cutaneous stimuli. A population of
neurons within the lateral part of the ventromedial thalamus
(VMl) showed two peaks of activation after percutaneous electrical
stimuli, regardless of which part of the body was stimulated.
The early and late peaks were elicited by Ad- and C-fiber
activities with mean conduction velocities of 12.9 6 0.9 and 1 6
0.2 m/sec, respectively. These responses were strongly depressed
or blocked after microinjections within the medullary
subnucleus reticularis dorsalis of xylocaine or the NMDA antagonist
MK-801. None of the VMl neurons responded to innocuous
cutaneous or proprioceptive stimuli. In contrast, all
these neurons responded to noxious mechanical and thermal
stimulation of the limbs and showed monotonic increases in
their discharges to increasingly strong noxious cutaneous stimuli.
In addition, some VMl neurons were antidromically activated
by stimulation in layer I of the dorsolateral frontal cortex. These
findings suggest that the rat VMl conveys and encodes cutaneous
nociceptive inputs from any part of the body surface to
layer I of the dorsolateral neocortex. This reticulo-thalamocortical
network may allow any signal of pain to gain access to
widespread areas of the neocortex and thus help prime the
cortex for attentional reactions and/or the coordination of motor
responses.

In order to investigate the effects of spatial summation on the spinal transmission of nociceptive
information, we compared in intact and spinal anaesthetized rats, responses of lumbar convergent neurones elicited
by noxious heat stimuli applied to areas of the body much greater in size than their individual excitatory receptive
fields, located distally on the hindpaw. Twenty-four neurones were recorded in each group of animals. For each
neurone, 4 successive immersions of increasing areas (1.9-18 cm 2) of the ipsilateral hindpaw in a 48°C water bath
(15-sec duration) were performed with 10-min intervals in a randomized and balanced order. In intact animals, the
responses of convergent neurones progressively decreased when the area of noxious thermal stimulation reached
and then exceeded approximately twice the area of their individual excitatory receptive fields. This decrease was
highly significant for 18 cm 2 which represents approximately 10-fold the mean of the receptive field areas. Such a
phenomenon was not observed for neurones recorded in spinal animals although their excitatory receptive field
areas were not significantly different. These results suggest that the activation of a large population of nociceptive
afferents triggers supraspinally mediated negative feed-back loop modulating the responses of convergent neurones.