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Milhaud Claude, Le Bars Daniel. Étude critique de la proposition de loi n°3661 visant à renforcer la lutte contre la maltraitance animale. In: Bulletin de l'Académie Vétérinaire de France tome 173, 2020. pp. 7-8.

Is it relevant to use the english word «sentience» in french ? Since Aristotle animals are considered as sensitive beings, what was recognized at the legislative level in the French rural and civil codes in 1976 and 2017, respectively. The XVIIIth century philosophers introduced the concept of «sentience» – the ability to feel – to differ from the reason – the capacity to think –. This notion was then clarified by the Anglo-Saxon philosophers of mind to express the capacity to feel subjective experiences («qualia», «phenomenal consciousness»), a clear and relatively «simple» concept but only approachable by introspection. In spite of this ontological difficulty, some animal ethics thinkers wish to introduce this concept into the French language, without wondering about its polysemy which, already, blurs its meaning in the English-speaking literature. According to the authors, «sentience» includes sensations, perception, emotions, feelings, affects, feeling, cognition, consciousness, etc. Each of these terms being polysemic and belonging to both the philosophic and scientific fields, the generic name appears as a semantic oldall compromising any reasoned approach. To convince oneself, it is enough to envisage the confusion driven by the replacement of the assertion «the animal is a sensitive being» by «the animal is a sentient being». At the legislative level, it would be the source of regrettable misunderstandings. Let us also underline the semantic trap that hides the grammatical use of the defined article and the singular, so neglecting the extraordinary diversity of the animal kingdom that spread out over space – our planet – and time – 600 millions years –., Depuis Aristote les animaux sont considérés comme des êtres sensibles, ce qui a été reconnu sur le plan juridique dans le code rural en 1976 puis le code civil en 2017. Par ailleurs, les philosophes du XVIIIe siècle ont introduit le concept de «sentience» – la capacité de ressentir – pour l’opposer à la raison – la capacité de penser–. Cette notion s’est précisée ultérieurement entre les mains des philosophes de l’esprit anglo-saxons pour exprimer la capacité d’éprouver des expériences subjectives («qualia», «conscience phénoménale»), un concept clair et relativement «simple» mais que seule l’introspection permet d’approcher. En dépit de cette difficulté ontologique, certains penseurs en éthique animale souhaitent introduire ce concept dans la langue française, sans s’interroger sur sa polysémie qui, déjà, brouille sa signification dans la littérature anglophone. En effet, la «sentience» englobe selon les auteurs les sensations, les perceptions, les émotions, les affects, les sentiments, la cognition, la conscience, etc. Chacun de ces termes étant polysémique et appartenant à la fois aux champs philosophiques et scientifiques, le terme générique apparait comme un fourre-tout sémantique obérant toute approche raisonnée. Pour s’en convaincre, il suffit d’envisager la confusion qu’entraînerait le remplacement de l’affirmation «l’animal est un être sensible» par «l’animal est un être sentient». Sur le plan législatif, il serait source de regrettables malentendus. Soulignons en outre le piège sémantique que dissimule l’utilisation de l’article défini et du singulier, négligeant ainsi l’extraordinaire diversité du monde animal qui s’est épanouie dans l’espace – notre planète – et le temps – 600 millions d’années –., Le Bars Daniel, Milhaud Claude, Rousseau Jean-Paul. L’usage en français du mot anglais « sentience » est-il pertinent ?. In: Bulletin de l'Académie Vétérinaire de France tome 171 n°1, 2018. pp. 30-41.

International audience; 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 similar to 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.

In thermoneutral conditions, rats display cyclic variations of the vasomotion of the tail and paws, the most widely used target organs in current acute or chronic animal models of pain. Systemic morphine elicits their vasoconstriction followed by hyperthermia in a naloxone-reversible and dose-dependent fashion. The dose-response curves were steep with ED50 in the 0.5–1 mg/kg range. Given the pivotal functional role of the rostral ventromedial medulla (RVM) in nociception and the rostral medullary raphe (rMR) in thermoregulation, two largely overlapping brain regions, the RVM/rMR was blocked by muscimol: it suppressed the effects of morphine. “On-” and “off-” neurons recorded in the RVM/rMR are activated and inhibited by thermal nociceptive stimuli, respectively. They are also implicated in regulating the cyclic variations of the vasomotion of the tail and paws seen in thermoneutral conditions. Morphine elicited abrupt inhibition and activation of the firing of on- and off-cells recorded in the RVM/rMR. By using a model that takes into account the power of the radiant heat source, initial skin temperature, core body temperature, and peripheral nerve conduction distance, one can argue that the morphine-induced increase of reaction time is mainly related to the morphine-induced vasoconstriction. This statement was confirmed by analyzing in psychophysical terms the tail-flick response to random variations of noxious radiant heat. Although the increase of a reaction time to radiant heat is generally interpreted in terms of analgesia, the present data question the validity of using such an approach to build a pain index.

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 stimulus–response recruitment curve. The C-fibre reflex was not modified following intravenous gabapentin. Gabapentin pre-treatment at lower doses (0.01–7.5 mg/kg) not only antagonized the depressive effect of morphine, but caused facilitation of the reflex. At higher doses (10–50 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.

Exposure to mid range ultrat violet radiations (UVBs) has been shown to produce systemic inflammation and hyperalgesia in mice [Saade, N.E., Nasr, I.W., Massaad, C.A., Safieh-Garabedian, B., Jabbur, S.J., Kanaan, S.A., 2000. Modulation of ultraviolet-induced hyperalgesia and cytokine upregulation by interleukins 10 and 13. Br. J. Pharmacol. 131, 1317–1324]. Our aim was to characterize a new rat model of localized exposure to UVB and to determine the role of skin innervation in the observed hyperalgesia and cytokine upregulation. In several groups of rats one hindpaw was exposed to UVB (250–350 mJ/cm 2 ) and this was followed by the application, to the plantar area of the paw, of either Von Frey hairs or a few acetone drops to measure tactile and cold allodynia, respectively. Thermal hyperalgesia was assessed by the paw withdrawal latency and duration. Cytokine levels were determined, by ELISA, in processed samples of skin tissue isolated from the exposed and non-exposed paws. UVB induced a biphasic thermal hyperalgesia and cold and tactile allodynia with an early phase that peaked at 3–6 h and disappeared at 24 h and a late phase with a peak at 48 h and recovery at 72-h post-exposure. Tumor necrosis factor, interleukins 1β, 6, 8, 10 and NGF levels were significantly increased following the same biphasic temporal pattern. Chemical ablation of capsaicin sensitive afferents and guanethidine injection produced significant alteration of the hyperalgesia and allodynia. The increase in cytokine levels by UVB was also altered by both treatments. The present study describes a new animal model for localized UVB-induced inflammatory hyperalgesia and provides evidence about the involvement of neurogenic mechanisms in the observed hyperalgesia and upregulation of proinflammatory mediators.

Thermal neutrality in rodents is achieved by large cyclic variations of the sympathetic drive of the vasomotion of the tail and paws, the most widely used target organs in current acute or chronic animal models of pain. Given the pivotal functional role of rostral ventromedial medulla (RVM) in nociception and rostral medullary raphe (rMR) in thermoregulation, two largely overlapping brain regions, we aimed at circumscribing the brainstem regions that are the source of premotor afferents to sympathetic preganglionic neurons that control the vasomotor tone of the tail and hind paws. A thermometric infrared camera recorded indirectly the vasomotor tone of the tail and hind paws. During the control period, the rat was maintained in vasoconstriction by preserving a stable, homogeneous, and constant surrounding temperature, slightly below the core temperature. The functional blockade of the RVM/rMR by the GABAA receptor agonist muscimol (0.5 nmol, 50 nl) elicited an extensive increase of the temperature of the paws and tail, associated with a slight decrease of blood pressure and heart rate. Both the increased heat loss through vasodilatation and the decrease heart-induced heat production elicited a remarkable reduction of the central temperature. The effective zones were circumscribed to the parts of the RVM/rMR facing the facial nucleus. They match very exactly the brain regions often described as specifically devoted to the control of nociception. Our data support and urge on the highest cautiousness regarding the interpretation of results aimed at studying the effects of any pharmacological manipulations of RVM/rMR with the usual tests of pain.

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.

Resume Les influx nociceptifs sont generes en peripherie par les terminaisons libres de fibres nerveuses de petit diametre appelees nocicepteurs dont la reaction depend de l'environnement tissulaire. De nombreux mediateurs chimiques activent, sensibilisent ou « reveillent » les nocicepteurs : les kinines, les cytokines pro-inflammatoires ou anti-inflammatoires, les prostanoides, les lipo-oxygenases, le « mediateur central de la reponse immunitaire » (NF-κB), les facteurs de croissance tels les neurotrophines, les neuropeptides, l'oxyde nitrique, l'histamine, la serotonine, les proteases, les acides amines excitateurs, les amines adrenergiques et les opioides. Que ce soit de concert ou a un moment ou un autre des processus inflammatoires, ces mediateurs interviennent pour engendrer de facon subtile les phenomenes d'hyperalgesie et d'allodynie. Les mecanismes moleculaires et cellulaires les plus connus qui sous-tendent ces manifestations cliniques seront presentes. Le role du systeme nerveux peripherique dans le passage des rhumatismes inflammatoires a la chronicite sera souleve.

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.

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

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-fiber-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 significantly 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 fibers and/or sprouting of nerve terminals may thus be the main causes of DNIC increase in this model of neuropathic pain.

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 ED(50) from 0.58 (0.40-0.86) to 2.40 (1.87-3.31) microgram/kg for i.v. sufentanil and from 0.64 (0.46-0.79) to 1.63 (1.29-3.31) microgram/kg 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 ED(50)s 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 and/or on the descending control of nociceptive transmission.

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.

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 Aδ- and C-fiber activities with mean conduction velocities of 12.9 ± 0.9 and 1 ± 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 VMlneurons 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 VMlneurons were antidromically activated by stimulation in layer I of the dorsolateral frontal cortex. These findings suggest that the rat VMlconveys and encodes cutaneous nociceptive inputs from any part of the body surface to layer I of the dorsolateral neocortex. This reticulo-thalamo-cortical 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.

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.

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.

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.

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.

Gozariu, Manuela, Dominique Bragard, Jean-Claude Willer, and Daniel Le Bars. Temporal summation of C-fiber afferent inputs: competition between facilitatory and inhibitory effects on C-fiber reflex in the rat. J. Neurophysiol. 78: 3165–3179, 1997. Long-lasting facilitations of spinal nociceptive reflexes resulting from temporal summation of nociceptive inputs have been described on many occasions in spinal, nonanesthetized rats. Because noxious inputs also trigger powerful descending inhibitory controls, we investigated this phenomenon in intact, halothane-anesthetized rats and compared our results with those obtained in other preparations. The effects of temporal summation of nociceptive inputs were found to be very much dependent on the type of preparation. Electromyographic responses elicited by single square-wave electrical shocks (2 ms, 0.16 Hz) applied within the territory of the sural nerve were recorded in the rat from the ipsilateral biceps femoris. The excitability of the C-fiber reflex recorded at 1.5 times the threshold ( T) was tested after 20 s of electrical conditioning stimuli (2 ms, 1 Hz) within the sural nerve territory. During the conditioning procedure, the C-fiber reflex was facilitated (wind-up) in a stimulus-dependent fashion in intact, anesthetized animals during the application of the first seven conditioning stimuli; thereafter, the magnitude of the responses reached a plateau and then decreased. Such a wind-up phenomenon was seen only when the frequency of stimulation was 0.5 Hz or higher. In spinal, unanesthetized rats, the wind-up phenomenon occurred as a monotonic accelerating function that was obvious during the whole conditioning period. An intermediate picture was observed in the nonanesthetized rat whose brain was transected at the level of the obex, but the effects of conditioning were profoundly attenuated when such a preparation was anesthetized. In intact, anesthetized animals the reflex was inhibited in a stimulus-dependent manner during the postconditioning period. These effects were not dependent on the frequency of the conditioning stimulus. Such inhibitions were blocked completely by transection at the level of the obex, and in nonanesthetized rats were then replaced by a facilitation. A similar long-lasting facilitation was seen in nonanesthetized, spinal rats. It is concluded that, in intact rats, an inhibitory mechanism counteracts the long-lasting increase of excitability of the flexor reflex seen in spinal animals after high-intensity, repetitive stimulation of C-fibers. It is suggested that supraspinally mediated inhibitions also participate in long term changes in spinal cord excitability after noxious stimulation.

A C-fibre reflex elicited by electrical stimulation within the territory of the sural nerve, was recorded from the ipsilateral biceps femoris muscle in anaesthetized rats. The temporal evolution of the response was studied using a constant stimulus intensity (3 x threshold) and recruitment curves were built by varying stimulus intensity from 0 to 7 x threshold. The intravenous administration of 0.02-0.2 mg/kg clonidine resulted in a dose-dependent depression of the C-fibre reflex. The alpha 2-adrenoceptor antagonist idazoxan completely prevented this depressive effect of clonidine. The effects of clonidine on the C-fibre reflex elicited by a wide range of stimulus intensities were investigated using recruitment curves: following 0.16 mg/kg clonidine, a dramatic shift of the recruitment curve to the right was seen with both an increase in the threshold and a decrease in the slope. Clonidine also produced a dose-dependent increase in blood pressure, but this was not correlated with the depression of the nociceptive reflex.

The involvement of bulbospinal pathways in the antinociceptive effect of clomipramine in experimental pain was studied. The antinociceptive effect of the antidepressant (0.5 mg/kg), intravenously injected, was evaluated after a unilateral lesion of the dorsolateral funiculus. The results showed that this effect was suppressed only in the hindpaw ipsilateral to the dorsolateral funiculus lesion, and suggest that the antinociceptive effect of antidepressants needs intact descending inhibitory bulbospinal pathways.

The distribution and organization of descending spinal projections from the dorsal part of the caudal medulla were studied in the rat following injections of Phaseolus vulgaris leucoagglutinin into small areas of the subnucleus reticularis dorsalis (SRD) and the adjacent cuneate nucleus (Cu). The caudal aspect of the Cu projected only to the dorsal horn of the ipsilateral cervical cord via the dorsal funiculus. These projections were mainly to laminae I, IV, and V. More ventrally located reticular structures projected to the full length of the cord. Fibers originating from the SRD travelled through the ipsilateral dorsolateral funiculus and terminated within the deep dorsal horn and upper layers of the ventral horn, mainly in laminae V–VII. Fibers originating from subnucleus reticularis ventralis (SRV) travelled ipsilaterally through the lateral and ventrolateral funiculi and bilaterally through the ventromedial funiculus. These fibers terminated within the ventral horn. The density of labeling within the gray matter varied at different levels of the cord was as follows: cervical > sacral > thoracic > lumbar. The reciprocal connections between the caudal medulla and the spinal cord suggest that the former is an important link in feedback loops that regulate spinal outflow. © 1995 Wiley-Liss, Inc.

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 4.2°C 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 (4.4°C), 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. Less than two-thirds of the increase in tail-flick latency to noxious heat, evoked by conditioned fear, reflects true antinociception. The remaining is due to skin vasoconstriction.

Two distinctive features characterize the way in which sensations including pain, are evoked by heat: (1) a thermal stimulus is always progressive; (2) a painful stimulus activates two different types of nociceptors, connected to peripheral afferent fibers with medium and slow conduction velocities, namely Adelta- and C-fibers. In the light of a recent study in the rat, our objective was to develop an experimental paradigm in humans, based on the joint analysis of the stimulus and the response of the subject, to measure the thermal thresholds and latencies of pain elicited by Adelta- and C-fibers. For comparison, the same approach was applied to the sensation of warmth elicited by thermoreceptors. A CO(2) laser beam raised the temperature of the skin filmed by an infrared camera. The subject stopped the beam when he/she perceived pain. The thermal images were analyzed to provide four variables: true thresholds and latencies of pain triggered by heat via Adelta- and C-fibers. The psychophysical threshold of pain triggered by Adelta-fibers was always higher (2.5-3 degrees C) than that triggered by C-fibers. The initial skin temperature did not influence these thresholds. The mean conduction velocities of the corresponding fibers were 13 and 0.8 m/s, respectively. The triggering of pain either by C- or by Adelta-fibers was piloted by several factors including the low/high rate of stimulation, the low/high base temperature of the skin, the short/long peripheral nerve path and some pharmacological manipulations (e.g. Capsaicin). Warming a large skin area increased the pain thresholds. Considering the warmth detection gave a different picture: the threshold was strongly influenced by the initial skin temperature and the subjects detected an average variation of 2.7 degrees C, whatever the initial temperature. This is the first time that thresholds and latencies for pain elicited by both Adelta- and C-fibers from a given body region have been measured in the same experimental run. Such an approach illustrates the role of nociception as a "double level" and "double release" alarm system based on level detectors. By contrast, warmth detection was found to be based on difference detectors. It is hypothesized that pain results from a CNS build-up process resulting from population coding and strongly influenced by the background temperatures surrounding at large the stimulation site. We propose an alternative solution to the conventional methods that only measure a single "threshold of pain", without knowing which of the two systems is involved.

Human pains and animal pains. Nociception and pain, its most elaborate cognitive expression, are an alarm system designed to protect the body : they elicit reactions that aim to decrease their initial cause and therefore limit its consequences. A nociceptive stimulus activates a series of sensory organs called “nociceptors”, which are free endings of non-myelinated fibres spread throughout the tissues. These nociceptors are polymodal in the sense that they are activated by stimuli of various physical natures (thermal, mechanical, chemical). Nociceptive signals travel to the dorsal horn of the spinal cord before being distributed to the ventral and lateral horns (for somatic and vegetative reflexes) and to numerous brain structures, including the reticular formation, the thalamus and several cortical areas. In man, this latter category includes the primary and secondary somaesthetic cortices, and especially the cingular and insular cortices belonging to the limbic system, which plays an essential role in the genesis of emotions. Nociceptive systems are very old phylogenetically. Only in species that acquired an emotional brain (limbic system) can pain be defined as a sensory and emotional experience. As the evaluation of pain in animals will always be hindered by the absence of verbal communication, the anthropomorphic approach is our only option, but our understanding may be improved by the additional use of neuropsychological data., 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., Le Bars Daniel. Douleurs de l’homme, douleurs des animaux. In: Bulletin de l'Académie Vétérinaire de France tome 163 n°4-5, 2010. pp. 315-332.

Several lines of evidence have suggested the participation of the caudal medulla, including the subnucleus reticularis dorsalis (SRD), in the supraspinally mediated diffuse noxious inhibitory controls (DNICs). To test this hypothesis directly, DNICs acting on spinal convergent neurones were compared in sham-operated rats and rats with unilateral quinolinic acid-induced lesions of the SRD. Inhibitions produced by heterotopic noxious stimuli (i.e. DNIC), of the C-fibre-evoked responses of the convergent neurones were significantly reduced in the lesioned animals. This depression of DNIC, by 40–45%, was similar no matter where the conditioning stimuli were applied and was not significantly different for neurones recorded ipsilaterally to the lesion from those recorded contralaterally. These results suggest that the SRD is one of the supraspinal relay(s) in the circuitry underlying DNIC in the rat.

Diffuse noxious inhibitory controls (DNIC) acting on trigeminal convergent neurons were compared in sham-operated animals and rats with quinolinic acid induced lesions of the locus coeruleus/subcoeruleus (LC/SC). No significant differences were observed between control animals and those with ipsilateral, contralateral or bilateral lesions of the LC/SC, in respect of: (1) the general properties of the recorded units; and (2) the magnitude of the depressions of C-fiber-evoked responses of convergent neurons produced by immersing each paw in a 50°C water bath (i.e. DNIC). It is concluded that the LC/SC is not involved, at least directly, in the supraspinal part of the loop which subserves DNIC in the rat.

In man, heterotopic painful thermal conditioning stimuli induce parallel decreases in the spinal nociceptive flexion (RIII) reflex and the concurrent sensation of pain elicited by electrical stimulation of the sural nerve at the ankle. Such phenomena may be related to the diffuse noxious inhibitory controls (DNIC) which were initially described in the rat and subsequently documented in humans. In 9 subjects in the present study, a 2 min application of a moderately noxious temperature (46 degrees C) to the contralateral hand strongly depressed the RIII reflex elicited in the biceps femoris muscle by electrical stimulation of the sural nerve at 1.2 times the reflex threshold. These depressive effects were maximal during the second min of the conditioning period, showing a 80% inhibition of the RIII reflex which gradually recovered to its baseline value 7 min after the end of the conditioning period. Such inhibitory effects were completely blocked 15-26 min after administration of a low dose of morphine hydrochloride (0.05 mg/kg, i.v.). The lifting of the inhibitions was compatible with an action at the opioid receptors since the inhibitions were re-observed 5-16 min after naloxone injection (0.006 mg/kg, i.v.). During all the experimental sessions, heart and respiratory rates remained stable at their control levels. Since it has been shown previously that such a dose of morphine could not have a direct effect within the spinal cord (Willer 1985), it is concluded that this opiate blocks, in a naloxone-reversible fashion, those bulbo-spinal controls which are triggered by heterotopic nociceptive events. Possible implications for hypoalgesia based on the principles of counter-irritation are discussed.

Background The functional significance of proenkephalin systems in processing pain remains an open question and indeed is puzzling. For example, a noxious mechanical stimulus does not alter the release of Met-enkephalin-like material (MELM) from segments of the spinal cord related to the stimulated area of the body, but does increase its release from other segments. Methodology/Principal Findings Here we show that, in the rat, a noxious mechanical stimulus applied to either the right or the left hind paw elicits a marked increase of MELM release during perifusion of either the whole spinal cord or the cervico-trigeminal area. However, these stimulatory effects were not additive and indeed, disappeared completely when the right and left paws were stimulated simultaneously. Conclusion/Significance We have concluded that in addition to the concept of a diffuse control of the transmission of nociceptive signals through the dorsal horn, there is a diffuse control of the modulation of this transmission. The “freezing” of Met-enkephalinergic functions represents a potential source of central sensitization in the spinal cord, notably in clinical situations involving multiple painful foci, e.g. cancer with metastases, poly-traumatism or rheumatoid arthritis.

Some neurones in the dorsal horn of the spinal cord are strongly inhibited when a nociceptive stimulus is applied to any part of the body, distinct from their excitatory receptive fields. This phenomenon was termed "Diffuse Noxious Inhibitory Controls" (DNIC). DNIC influence only convergent neurones: the other cell types which are found in the dorsal horn, including specific nociceptive neurones, are not affected by this type of control. In normal conditions, these inhibitions can be triggered only by conditioning stimuli which are nociceptive. The inhibitions are then extremely potent, affect all the activities of the convergent neurones and persist, sometimes for several minutes, after the removal of the conditioning stimulus. In fact, only activity of A delta- or A delta- and C-peripheral fibres can trigger DNIC. DNIC are sustained by a complex loop which involves supraspinal structures since, unlike segmental inhibitions, they can not be observed in animals in which the cord has previously been transsected at the cervical level. The ascending and descending limbs of this loop travel respectively through the ventro-lateral and dorso-lateral funiculi respectively. We proposed that DNIC result from the physiological activation of some brain structures putatively involved in descending inhibition. However, lesions of the following structures did not modify DNIC: Periaqueductal grey (PAG), Cuneiform nucleus, Parabrachial area, locus coeruleus/subcoeruleus, rostral ventromedial medulla (RVM) including Raphe Magnus, Gigantocellularis and Paragigantocellularis nuclei. By contrast, lesions of Subnucleus Reticularis Dorsalis (SPD) in the caudal medulla strongly reduced DNIC. Both electrophysiological and anatomical data support the involvement of SRD neurones in spin-bulbo-spinal loop(s). Indeed, they are unresponsive to visual, auditory or proprioceptive stimulation but are preferentially or exclusively activated by nociceptive stimuli with a "whole-body receptive field"; they encode precisely the intensity of cutaneous and visceral stimulation within the noxious range and are exclusively activated by cutaneous A delta- or A delta- and C-fibre peripheral volleys; they send descending projections through the dorsolateral funiculus that terminate in the dorsal horn at all levels of the spinal cord. In man, exactly analogous results have been obtained by means of combined psychophysical measurements and recordings of nociceptive reflexes. Electrical stimulation of the sural nerve at the ankle simultaneously induces a nociceptive reflex in a flexor muscle of the knee (the RIII reflex) and a painful sensation from the territory of the nerve. Painful heterotopic conditioning stimuli, no matter whether thermal, mechanical or chemical in nature, depress both the reflex and the associated painful sensation, with stronger effects being observed with more intense conditioning stimuli.(ABSTRACT TRUNCATED AT 400 WORDS)

In man, heterotopic painful thermal conditioning stimuli induce parallel decreases in the spinal nociceptive flexion (RIII) reflex and the concurrent sensation of pain elicited by electrical stimulation of the sural nerve at the ankle. Such phenomena may be related to the diffuse noxious inhibitory controls (DNIC) which were initially described in the rat and subsequently documented in humans. In nine subjects in the present study, a 2-min application of a moderately noxious temperature (46 degrees C) to the contralateral hand strongly depressed the RIII reflex elicited in the biceps femoris muscle by electrical stimulation of the sural nerve at 1.2 times the reflex threshold. These depressive effects were maximal during the 2nd min of the conditioning period, showing an almost complete inhibition of the RIII reflex which gradually recovered its baseline value 6-9 min after the end of the conditioning period. Using a double-blind, cross-over design, it was found that these inhibitory effects were completely blocked 5 min after naloxone hydrochloride administration (0.4 mg i.v.) whereas the administration of saline was totally ineffective. The lifting of the inhibitions was compatible with the short duration of the pharmacological effects of naloxone in that the inhibitions were observed again 50 min after the naloxone injection. During all the experimental sessions, heart and respiratory rates remained stable at their control levels. It is concluded that the loop subserving DNIC which ascends from--and redescends to--the spinal cord involves an opioidergic link in man as in experimental animals. Possible implications for hypoalgesia based on the principles of counter-irritation or elicited by naloxone are discussed.

This chapter discusses the modeling of human pain in rats. Topics covered include models of chronic pain, behavioral reactions, stimulus and response, requirements for models of nociception, tests based on the measurement of reaction time for escape behavior, test based on the measurement of threshold for escape behavior, and tests based on the observation of behavior.

Nociceptive signals are generated by peripheral sensory organs called nociceptors, which are endings of small-diameter nerve fibers responsive to the tissue environment. The myriad chemical mediators capable of activating, sensitizing, or arousing nociceptors include kinins, proinflammatory and anti-inflammatory cytokines, prostanoids, lipooxygenases, the "central immune response mediator" NF-kappaB, neurotrophins and other growth factors, neuropeptides, nitric oxide, histamine, serotonin, proteases, excitatory amino acids, adrenergic amines, and opioids. These mediators may act in combination or at a given time in the inflammatory process, producing subtle changes that result in hyperalgesia or allodynia. We will review the most extensively studied molecular and cellular mechanisms underlying these two clinical abnormalities. The role of the peripheral nervous system in progression of inflammatory joint disease to chronicity is discussed.

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 A delta- 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 C-fibre 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 ED 50 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.

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.

Diffuse Noxious Inhibitory Controls (DNIC) - which involve supraspinal structures and modulate the transmission of nociceptive signals - were investigated during the development of joint inflammation in rats with acute or chronic monoarthritis and in rats with chronic polyarthritis. During both acute monoarthritis and chronic polyarthritis, DNIC triggered by nociceptive stimulations of the inflamed joint(s) were clearly exacerbated, parallel with the increased sensitivity of inflamed joints to mechanical stimulations. In contrast, in the chronic stage of monoarthritis, DNIC triggered by thermal or pressure stimuli were almost similar for both normal and inflamed ankles. The discrepancy between behavioral and electrophysiological data during chronic monoarthritis indicates that inputs activated at this stage of the disease fail to recruit DNIC. This suggests that chronic inflammatory processes can induce a re-organisation of the spinal transmission of nociceptive signals, which modifies the recruitment of DNIC.

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 medulla (RVM) 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 groups (the 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.

The distribution and organization of projections from the spinal cervical enlargement to subnucleus reticularis dorsalis (SRD) and the neighbouring Cuneate nucleus (Cu) area was studied in the rat by using microinjections of Phaseolus vulgaris leucoagglutinin (PHA-L) into different laminae around the C7 level. The Cu received very dense projections from the dorsal horn, with the highest density being observed following injections into the medial part of laminae III-IV. The SRD received dense projections from laminae V-VII of the cervical enlargement, particularly from the reticular and medial aspects of lamina V, lamina VI, and the dorsal part of lamina VII. By contrast, the superficial part of the dorsal horn (laminae I to IV) and the dorsal part of lamina X provided only sparse projections to the SRD. Clusters of labelled terminals and boutons were observed mainly in the SRD areas subjacent to the Cu. In the caudorostral axis, labelled terminals were spread along the whole SRD from the cervicomedullary junction up to the caudal-most part of the area postrema. Contralateral projections to the SRD were scarce and were observed mainly after injections into the medial part of laminae VI-VII. These data give further support to the proposal that there are two parallel systems in neighbouring structures of the caudal medulla, viz. the Cu and the SRD, which, respectively, relay lemniscal and nociceptive information from the spinal cord to the thalamus.

The organization of efferent projections from the spinal cervical enlargement to the parabrachial (PB) area and the periaqueductal gray (PAG) was studied in the rat by using microinjections of Phaseolus vulgaris-leucoagglutinin (PHA-L) into different laminae around the C7 level. The results demonstrated two areas of cervical enlargement which project in different ways to the PB area and PAG. First, the superficial laminae (I, II) showed a very dense projection, with a clear contralateral dominance at the coronal level where the inferior colliculus merges with the pons, to a restricted "superficial" portion of the PB area, namely the lateral crescent area, the dorsal lateral, the superior lateral (PBsl), and the outer portion of the external lateral PB subnuclei. Less dense projections were observed in the Kolliker-Fuse nucleus (KF) and in the ventrolateral/lateral quadrant of the caudal and mid PAG. By contrast, the labeling was weak or absent in the other PB subnuclei and the outer adjacent regions; in particular, no, or very little, labeling was found in the cuneiform nucleus. The PB area appeared to be the supraspinal target that received the densest projection from laminae I and II. Projections were less dense in the PAG and the thalamus and markedly less in other sites such as the ventrolateral medulla, the subnucleus reticularis dorsalis, and the nucleus of the solitary tract. Second, the reticular portion of lamina V, the medial portion of laminae IV-VI up to X and lamina VIII, showed bilateral projections with a weak ipsilateral dominance and a high to medium density on a very restricted portion of the PB area, namely the internal lateral PB subnucleus. A lesser projection was also observed in the adjacent portion of the PBsl, the KF, and the lateral quadrant of the PAG. These results suggest that signals carried by neurons from lamina I-II converge on a restricted superficial portion of the PB area and the ventral part of the lateral quadrant of the PAG. These results are discussed in the context of the role of the spino-PB and spino-PAG pathways in nociception.

The spinal nociceptive RIII reflex, an exteroceptive cutaneous-muscular flexion reflex, is powerfully and specifically inhibited by painful heterotopic somatic stimuli. The aim of the present study was to evaluate the effects of nonpainful and painful visceral stimuli on this reflex.In nine healthy volunteers, the effects of five levels of gastric distention were tested on the RIII reflex, recorded from the biceps femoris, and elicited by electrical stimulation of the ipsilateral sural nerve. Distentions were performed by means of a balloon that was placed in the proximal part of the stomach and connected to an electronic barostat. The sensations evoked by gastric distention were scored using a graded (0-6) questionnaire.The 200- and 400-mL distention levels elicited no significant modifications of the RIII reflex; the 600-, 800-, and 1000-mL levels inhibited the RIII reflex by 25%, 35%, and 55%, respectively. The magnitude of this inhibition correlated significantly (P0.0001) with both the level of distention and the intensity of visceral perception.Gastric distention produces volume-dependent inhibition of the somatic RIII reflex in humans. This model may provide an interesting tool for objective and quantitative evaluation of normal and disturbed visceral sensations in humans.

Face à l'expérience individuelle qu'est la douleur, c'est l'ensemble des sociétés, et pour chacune d'entre elles toutes leurs composantes, qui s'efforcent de donner une signification aux douleurs. Celles-ci prennent alors une valeur culturelle, dont émergent croyances et pratiques sociales.Personne : la symbolique qui s'attache à la douleur inscrit les êtres dans un vécu, une corporéïté et une crainte de la souffrance. C'est une expérience du corps et de l'esprit. La douleur paraîtrait sans doute plus acceptable sans son propre souvenir ...Expressions : comment parler de la douleur, comment l'exprimer ? Tant en ce qui concerne le langage que les arts, les expressions des douleurs apparaissent dans les productions humaines comme des repères conventionnels ou sublimés.Chacun y fait référence avec sa culture, sa sensibilité, mais aussi son langage et les mots qu'y consacre sa langue.

Sensation et expérience du corps mais aussi souffrance de l'âme, génératrice d'angoisse, de peur et souvent de malheurs, la douleur reste pour l'homme une source perpétuelle d'interrogation. Pourquoi souffrir ? Comment justifier cette expérience si difficilement communicable ? Des douleurs biologiques au vécu de la douleur, comment comprendre, agir, soigner, maîtriser et peut-être guérir ? Le nourrisson, le jeune enfant,, l'animal perçoivent-ils la douleur au même titre que l'homme adulte ? La douleur de l'autre est-elle comparable à la nôtre ? Qu'il s'agisse d'individus ou de sociétés, la douleur, son rôle et sa signification suscitent de multiples questions. Si nous tentons de répondre ici à quelques-unes d'entre elles, c'est, dans un esprit de défi,, afin de confronter des domaines traditionnellement dissociés et de susciter le dialogue entre des spécialistes généralement peu enclins à le nouer.

)werful inhibitions of dorsal horn neurons are triggered in animals by noxious stimulation of large cutaneous areas. This tenomenon described as “Diffuse Noxious Inhibitory Controls” (DNIC) involves supraspinal structures and can be observed, beit indirectly, in man. The question arises as to whether cortical network can be modified by the involvement of DNIC. The asent study was designed to examine the central effects of noxious heat applied to large areas, namely 560 (one hand) or 1120 n2 (two hands) using WRI.