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ABSTRACTThis study presents an event-based storyline framework to assess the influence of future climatic and socioeconomic conditions on coastal flood impacts to critical infrastructure. The framework combines well-established quantitative methods of sea level rise, coastal inundation, and critical infrastructure (CI) physical damage assessments into an integrated modelling approach. We apply our approach to re-imagine three historic events: storm Xaver, storm Xynthia , and a storm surge event along the coast of Emilia Romagna (Italy). Our results indicate that northern Germany would benefit mostly from coordinated adaptation action to reduce the flood impact, whereas the southwestern coast of France would find the highest damage reduction through asset-level ‘autonomous’ adaptation action. Our approach helps to improve the scientific understanding of how coastal flood risk are assessed and best managed, and forces a distillation of the science into an accessible narrative to support policymakers and asset owners to make progress towards more climate-resilient coastal communities.

Since the inner workings of the human brain and spinal cord cannot be observed directly, they must be inferred from the accumulation of experimental results and clinical observations. It has been observed that the electrical stimulation of the sural nerve in the ankle results in pain and a pain-avoidance reflex. The reflex, called RIII, and the painful sensation can be depressed by the application of painful stimuli to another remote region of the body, such as the fingers. The application of a non-painful stimulus to a remote region of the body is ineffective in depressing the painful results of the ankle stimulation. To determine if this effect requires the brain, or if only the spinal cord is necessary, this test was performed on quadriplegic patients with spinal cord damage. The depression was ineffective in these patients, indicating that the part of the nervous system responsible for the effect lies above the neck. To further identify the part of the nervous system responsible for this pain suppression, the test was repeated on three patients with damage to the thalamus and three patients with Wallenberg's syndrome, which involves unilateral damage to the brainstem. The patients with the lesions in the thalamus, who could feel the sensation on the hand as noxious but not as painful, displayed an inhibition of the reflex similar to that seen in normal controls. However, the patients with Wallenberg's syndrome showed no such inhibition. The authors feel that the inhibition of the pain and the pain-avoidance reflex cannot be explained simply by the diversion of attention. The researchers believe that these findings suggest that the lemniscal and spinothalamic nerve pathways cannot be involved in the pain inhibition, and suggest that the brainstem and the spinoreticular nerve tract are likely to be involved. (Consumer Summary produced by Reliance Medical Information, Inc.)

Desde 2003, fecha de la última revisión de los autores de este artículo sobre la fisiología del dolor, se ha logrado un progreso fenomenal, en particular en las áreas de biología molecular y neuroimagen funcional (electroencefalograma, tomografía por emisión de positrones y resonancia magnética). Los autores de este artículo han tratado de sintetizar estas nuevas adquisiciones sin olvidar los fundamentos de la fisiología, para extraer la información más sólida. En efecto, esta riqueza se acompaña de una paradoja: la traducción en medios terapéuticos de este nuevo conocimiento, a menudo adquirida con modelos animales, sigue siendo decepcionante. En la primera parte se analizarán los medios de exploración del sistema de dolor en humanos y animales. En la segunda se presentarán los mecanismos periféricos del sistema nociceptivo. En la tercera se estudiará la profunda transformación que sufren estos mecanismos durante la inflamación. En la cuarta se considerarán los mecanismos espinales en condiciones fisiológicas e inflamatorias. Las contribuciones recientes de la neuroimagen han requerido el desarrollo de un quinto parágrafo dedicado a los mecanismos cerebrales implicados en el dolor. Se evalúa la especificidad de una red de estructuras cerebrales involucradas en la percepción del dolor. Un sexto parágrafo está dedicado a los mecanismos de control de la actividad espinal nociceptiva, con particular atención al paradigma de modulación condicionante del dolor. Los primeros tres parágrafos se desarrollan en el artículo 36-020-A-10 de esta obra y los parágrafos cuarto, quinto y sexto están en el presente.

Desde 2003, fecha de la última revisión de los autores de este artículo sobre la fisiología del dolor, se ha logrado un progreso fenomenal, sobre todo en las áreas de biología molecular y neuroimagen funcional (electroencefalograma, tomografía por emisión de positrones y resonancia magnética). Los autores de este artículo han tratado de sintetizar estas nuevas adquisiciones, sin olvidar los fundamentos de la fisiología, para extraer los datos más sólidos. En efecto, esta riqueza se acompaña de una paradoja : la traducción en medios terapéuticos de este nuevo conocimiento, a menudo adquirido con modelos animales, sigue siendo decepcionante. En la primera parte se analizarán los medios de exploración del sistema de dolor en humanos y animales. En la segunda se presentarán los mecanismos periféricos del sistema nociceptivo. En la tercera se estudiará la profunda transformación que sufren estos mecanismos durante la inflamación. En la cuarta se considerarán los mecanismos espinales en condiciones fisiológicas e inflamatorias. Las contribuciones recientes de la neuroimagen han requerido el desarrollo de un quinto parágrafo dedicado a los mecanismos cerebrales implicados en el dolor. Se evalúa la especificidad de una red de estructuras cerebrales involucradas en la percepción del dolor. Un sexto parágrafo está dedicado a los mecanismos de control de la actividad espinal nociceptiva, con especial atención al paradigma de modulación que condiciona el dolor. Los primeros tres parágrafos se desarrollan en este artículo (los parágrafos cuarto, quinto y sexto se desarrollan en el artículo 36-020-A-20 de esta misma obra).

La nostra conoscenza della fisiologia del dolore ha visto progressi fenomenali negli ultimi decenni e, in particolare, nei settori della biologia molecolare e della neurodiagnostica per immagini funzionale (elettroencefalografia e risonanza magnetica). Abbiamo cercato di sintetizzare queste nuove acquisizioni senza dimenticare, peraltro, i fondamenti della fisiologia, per estrarne i dati più solidi. In effetti, questa ricchezza è accompagnata da un paradosso : la traduzione in mezzi terapeutici di queste nuove conoscenze, spesso acquisite con modelli animali, rimane deludente. Nella prima parte, affrontiamo i mezzi di esplorazione del sistema del dolore nell’uomo e nell’animale. Nella seconda, presentiamo i meccanismi periferici del sistema nocicettivo e le profonde trasformazioni che subiscono durante l’infiammazione. Nella terza, sono affrontati i meccanismi spinali in condizione fisiologica e infiammatoria. I recenti contributi della neurodiagnostica per immagini hanno richiesto lo sviluppo di un quarto capitolo sui meccanismi cerebrali coinvolti nel dolore. È valutata la specificità di una rete di strutture cerebrali coinvolte nella percezione del dolore. Un quinto e ultimo capitolo è dedicato ai meccanismi di controllo dell’attività nocicettiva spinale, con una particolare attenzione per il paradigma di modulazione condizionante del dolore. Questo articolo è completato da allegati incentrati su argomenti più specifici come l’analgesia attraverso stimolazione somatosensoriale, le tecniche di neurodiagnostica per immagini funzionale, il concetto di “matrice dolore” e la classificazione meccanicistica delle sindromi dolorose.

La queue et les pattes postérieures des rongeurs sont à la fois des organes cibles très utilisés pour effectuer des tests dans les modèles de douleur aiguë ou chronique et essentiels pour leur thermorégulation. Ces tests doivent être conduits dans des conditions stables de thermoneutralité. On observe dans ces conditions des fluctuations cycliques de la vasomotricité des pattes et de la queue. Quand, au cours d’un cycle, la température centrale (Tc) est suffisamment basse, une activation sympathique est déclenchée, ce qui conduit à une augmentation de la pression artérielle, immédiatement suivie par une augmentation de la fréquence cardiaque (HR) et une vasoconstriction de la queue et des pattes postérieures. Il en résulte une diminution de la déperdition de chaleur et une augmentation de la Tc. Cette augmentation se poursuit jusqu’au moment où la Tcest suffisamment élevée pour déclencher le phénomène inverse, ce qui boucle le cycle, réitéré trois à sept fois par heure. Ces variations ne dépassent pas quelques dixièmes de degré. Elles sont corrélées avec les activités des neurones de la région bulbaire rostroventrale, région présumée contrôler la transmission spinale des informations nociceptives. Quand la limite inférieure de Tcd’un cycle est atteinte, les cellules « on » sont inhibées puis les cellules « off » activées, de façon concomitante à l’augmentation de pression artérielle et de HR. La vasoconstriction de la queue suit invariablement dans les trois minutes, souvent complétée par une vasoconstriction des pattes postérieures. Il en résulte une diminution de la déperdition thermique et une augmentation de la Tc. Lorsque l’augmentation de la Tc atteint quelques dixièmes de degré, les variations inverses se produisent, bouclant le cycle lui-même réitéré trois à sept fois par heure. Les activités des cellules « on » et « off » sont donc corrélées à l’inhibition et à l’activation du système sympathique, respectivement. L’ordre chronologique des variations est le suivant:Tc→cellule « on »→cellule « off »~pression artérielle → HR → température cutanée → Tc. Un blocage fonctionnel de cette région cérébrale entraîne une vasodilatation des pattes et de la queue et une augmentation de leur température cutanée. Si l’on applique un stimulus nociceptif thermique sur la peau de l’animal à ce moment, le temps de sa réaction réflexe chute, une observation généralement interprétée comme témoin d’une hyperalgésie, mais qui n’est en réalité qu’un biais secondaire à la variation de la température cutanée. En outre, la délimitation anatomique précise de la région impliquée dans la vasomotricité correspond très exactement à celle qui contient les neurones dits « on » et « off », activés et inhibés par stimulation nociceptive, dont on a fait le pivot du contrôle de la transmission spinale des messages nociceptifs. Ce rôle doit être réévalué dans un cadre plus vaste incluant le système nerveux végétatif. The tail and paws of rodents are the chief target organs used in acute or chronic models of pain. But they are also involved in thermoregulation. Obviously, the behavioral nociceptive tests must be performed in stable conditions of thermoneutrality. In such conditions, however, one observes cyclic fluctuations of the vasomotricity of tail and paws. When, during a cycle, the central temperature is low enough, a sympathetic activation is triggered that elicits an increase of blood pressure, immediately followed by an increase of heart rate, and a vasoconstriction of the tail and paws. This produces a drop in heat loss that elicits an increase of the central temperature. Such an increase continues till the central temperature is sufficiently raised to activate the inverse phenomenon, which buckles the cycle. These variations do not exceed a few tenth of degree and are reiterated 3–7 times per hour. They are correlated to the firing of neurons of the rostral ventro-medial medulla (RVM), presumably controlling the spinal transmission of the nociceptive information. When the lower limit of central temperature of a cycle is reached, on-cells are inhibited, then the off-cells are activated concomitantly with the increase of blood pressure and heart rate. The vasoconstriction of the tail follows invariably within 3 min, often completed by a vasoconstriction of the paws. This results in the decrease of thermal loss, thus increasing the central temperature. When the central temperature increase reaches a few tenths of degrees, the inverse variations occur completing the cycle, itself repeated 3–7 times per hour. The activities of on- and off-cells are thus correlated to the inhibition and activation of the sympathetic system, respectively. The chronological order of the variations is as follows: central temperature → oncells→ off-cells→blood pressure→heart rate→skin temperature→ central temperature. A functional blockade of the RVMelicits the vasodilatation of tail and paws that increases their epidermic temperature. If one applies a nociceptive thermal stimulus to the skin of the animal at this very moment, then its reflex reaction time falls, an observation generally interpreted as resulting from hyperalgesia, but is actually a bias, secondary to the variation of the superficial temperature. The precise anatomical demarcation of the brain region involved in vasomotricity corresponds exactly to those containing the on- and off-cells, activated and inhibited by nociceptive stimulation, respectively, believed to control the spinal transmission of nociceptive messages. This role must be revalued in a larger framework including the autonomic nervous system.

A 250 year simulation of a strongly eddying global version of the Parallel Ocean Program (POP) model reveals a new mode of intrinsic multidecadal variability, the Southern Ocean Mode (SOM), with a period of 40–50 year. The peak‐to‐peak difference in the global ocean heat content within a multidecadal cycle is up to 60 ZJ. This change results from surface heat flux variations in the South Atlantic and propagation of temperature anomalies along the Antarctic Circumpolar Current and into the Weddell gyre around 30°E. The temperature anomalies propagate as deep as 5000 m along the isopycnals between 50°S and 30°S and induce multidecadal changes in the Atlantic Meridional Overturning Circulation. A positive feedback loop between the generation of eddies through baroclinic instability and the dynamics of the mean circulation is essential for the existence of the SOM. The dominant physics appears similar to that responsible for variability found in a three‐layer quasi‐geostrophic eddy‐resolving model. This combined with the fact that the SOM is not found in a noneddying version of the same global POP model further suggests that eddy processes are crucial for its existence and/or excitation. A new mode of internal ocean variability is identified in the Southern OceanIt has an important impact on global ocean heat uptakeIt depends on baroclinic instabilities from mesoscale eddies in the Antarctic Circumpolar Current

Les interactions entre thermorégulation et nociception s’exercent sur deux fronts, périphérique et central. Sur le front périphérique, plusieurs éléments sont à prendre en compte, qui sont des sources importantes de variation pour les « tests de douleur ». En outre, les structures cérébrales qui contrôlent la thermorégulation et la transmission spinale des messages nociceptifs sont très intimement liées sur le plan anatomique, notamment en ce qui concerne les voies effectrices descendantes, issues de la région bulbaire rostroventrale. Nous faisons le point sur l’acquisition des informations thermiques et sur les réponses de l’organisme qu’elles suscitent par l’intermédiaire des « thermoeffecteurs ». Nous décrivons les mécanismes centraux qui déterminent ces réponses qui, après intégration dans l’hypothalamus, sont déterminées par la mise en route de neurones sympathiques prémoteurs situés dans la région bulbaire rostroventrale et dont les axones cheminent dans les funiculus dorsolatéraux (DLF). Ainsi mis en place, ces éléments nous permettront d’envisager dans un prochain article les conséquences fonctionnelles des interactions entre thermorégulation et nociception qui s’exercent centralement. Interactions between thermoregulation and nociception are carried out on two fronts–peripheral and central. On the peripheral, a number of elements should be taken into account. These are significant sources of variation for “pain tests”. Furthermore, the brain structures which control thermoregulation and the spinal transmission of nociceptive messages are closely linked in the human anatomy, especially with regard to descending effector pathways, arising from the rostroventral bulbar region. We are reviewing the acquisition of thermal information and the body’s responses arising through the use of “thermoeffectors”. We will detail the central mechanisms which determine these responses which, after integration of the hypothalamus, are determined by the introduction of sympathetic premotor neurons located in the rostroventral bulbar region, including the axons routing through the dorsolateral funiculus (DLF). Thus implemented, in an upcoming article these elements enable us to envisage the functional consequences of interactions between thermoregulation and nociception carried out centrally.

Serotonin and its various receptors are involved in numerous brain functions and neuropsychiatric disorders. The 5-HT1A family is the best characterized subtype of the fourteen currently known 5-HT receptors. The 5-HT1A receptor is closely involved in the pathogenesis of anxiety, depression, epilepsy and eating disorders and therefore is an important target for drug therapy. The development in the 1980s of molecules specifically targeting this receptor was followed by the rapid development of corresponding PET neuroimaging. Because this receptor represents a crucial target in neuroscience, a large number of radioligands have been developed by academic and industry centers for visualization and quantification, first in living animals and ultimately in humans. After a brief account of some of the structural and functional characteristics of brain 5-HT1A receptors, this review focuses on the main lines of evolution opened up by preclinical and clinical 5-HT1A PET radiopharmaceuticals, illustrating the potential value of PET for clinical research and drug development.

Recent studies have suggested modifications of serotonin cerebral metabolism and of 5-HT1Areceptors density in Alzheimer disease (AD). This study aims at exploring hippocampus 5-HT1Areceptor density in patients at the amnesic mild cognitive impairment (aMCI) and mild AD dementia stages.

To investigate the anatomic substrates underlying the beneficial effect of prism adaptation in five patients with persistent left neglect following right stroke.

[1‐11C]Acetate is prepared by carboxylation of a Grignard reagent, CH3MgBr, on a simple polyethylene loop with cyclotron‐produced [11C]carbon dioxide, followed by hydrolysis and purification on solid‐phase extraction cartridges. Copyright © 2006 John Wiley & Sons, Ltd.

Classification and treatment strategy of Oligodendrogliomas (ODG) remain controversial. Imaging relies essentially on contrast enhancement using CT or MRI. The aim of our study was to use positron emission tomography (PET) using [18F]-flurodeoxyglucose (FDG) and [11C]-L-methyl-methionine (MET) to evaluate metabolic characteristics of (ODG). We studied 19 patients with proven ODG, comparing standardised uptake values (SUV) and maximal tumor/contralateral normal tissues ratios (T/N). Imaging findings were compared with WHO, Smith and Daumas—Duport classifications. Uptake of FDG was decreased only in 8 patients, independently of grading, while MET uptake was always increased. MET uptake was significantly higher for high grade tumors grouped according to Smith or Daumas—Duport classifications, while no significant difference in MET uptake was found when using WHO classification. A different correlation was found between FDG and MET uptakes in normal tissues and high grade tumors. A trend for improved progression free survival was found for tumors that lacked contrast enhancement on MRI or those showing low FDG or MET uptake. In conclusion, MET appeared more sensitive than FDG to detect proliferation in ODG. The preferential protein metabolism, already noticeable for low-grade tumor, correlated with glucose metabolism and helped to separate, in vivo, high and low grade tumors.

Whether the intrinsic epileptogenicity of hypothalamic hamartomas (HH) is responsible for the entire clinical spectrum of epileptic, neuropsychological and behavioural disorders associated with HH, remains an open issue, in as much as morphologically similar HH can be associated with dramatically different seizure types and cognitive outcomes. The aim of this study was to investigate brain glucose metabolism in patients with epileptogenic HH, in an attempt to identify signs of focal cortical and subcortical dysfunction which might correlate with other clinical data. We have studied five patients with epileptogenic HH using [18F]‐fluorodesoxyglucose and positron emission tomography (FDG‐PET). All our patients also underwent an optimal MRI and a video‐EEG monitoring, as well as an intra‐cranial EEG recording in one of them. The anatomical distribution of FDG‐PET abnormalities was compared to that of interictal and ictal electroclinical findings. All five patients demonstrated focal hypometabolism, ipsilateral to the predominant EEG abnormalities and side of HH. Hypometabolic areas greatly varied between patients, but were grossly concordant with the cortical regions suspected to participate in the ictal discharges in each individual. Epileptogenic hypothalamic hamartomas are usually associated with focal cortical hypometabolism in regions which might participate in the overall HH‐driven epileptic network. Whether these cortical abnormalities only reflect the propagation of ictal discharges, or a potentially independent seizure onset zone remains unknown.

We have observed a falsely lateralizing mesial temporal 11C-flumazenil binding asymmetry in three patients who had temporal lobe epilepsy (TLE) with normal hippocampal volumes. This abnormality was not detected 3 months later in two of the patients who underwent a second PET study. We conclude that transient and falsely lateralizing changes of flumazenil binding might occur in patients with TLE and no hippocampal sclerosis.

The roles of mu, delta and kappa opioid receptor subtypes in spinal morphine-induced antinociception were investigated. A C-fiber reflex elicited by electrical stimulation within the territory of the sural nerve was recorded from the ipsilateral biceps femoris muscle in anesthetized rats. Recruitment curves were built by varying the stimulus intensity from 0 to 7x threshold and temporal evolutions were studied by using a constant level of stimulus intensity (3x threshold). Intrathecal administration of naloxone, Cys2-Tyr3-Orn5-Pen7 amide (mu opioid receptor antagonist) and nor-binaltorphimine (nor-BNI, a kappa opioid receptor antagonist) completely antagonized the depression of the C-fiber reflex induced by 4 nmol of intrathecal morphine, whereas the antagonistic effect of naltrindole (a delta receptor antagonist) was limited, with a ceiling effect of 56%. The AD50 were 12 pmol and 1, 4.3 and 39 nmol for Cys2-Tyr3-Orn5-Pen7 amide, naloxone, nor-BNI and naltrindole, respectively. When injected alone, only naltrindole induced a short-duration depressive effect. Intrathecal administration of DAGO resulted in a depressive effect on the C-fiber reflex in a dose-dependent manner; for a stimulus intensity of 3x threshold, the ED50 was 9 pmol. DAGO was found to be 60 times more potent than morphine. Interestingly, nor-BNI, at doses which reversed the blockade of the C-fiber reflex by morphine, also reversed the effects of an equipotent dose of DAGO, which suggested an action on a mu receptor subtype.

A C-fiber reflex elicited by electrical stimulation within the territory of the sural nerve, was recorded from the ipsilateral biceps femoris muscle in anesthetized 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 i.v. administration of aspirin, indomethacin, ketoprofen, paracetamol (= acetaminophen) and lysine clonixinate resulted in dose-dependent depressions of the C-fiber reflex by up to 30 to 40%. By contrast, saline was ineffective. High doses of the effective drugs that produced large disturbances in heart rate and/or acid-base equilibrium were not considered in the pharmacological analysis. When a constant level of stimulation was used, different dose-dependent profiles of drug action were observed. Aspirin induced a slow and gradual depression, although indomethacin, ketoprofen and paracetamol produced a peak effect within the first 10-min period and then reached a steady state phase for up to 30 min. The depressive effects of lysine clonixinate appeared more stable. When recruitment curves were built with a range of nociceptive stimulus intensities, all the drugs produced a dose-dependent decrease in the slopes and the areas under the recruitment curves without any major modification in the thresholds. The order of potency was the same for both stimulation paradigms, e.g., aspirin < paracetamol < lysine clonixinate = ketoprofen < indomethacin. It is concluded that NSAID elicit significant antinociceptive effects at a central level, which do not depend on the existence of a hyperalgesic or inflammatory state.

1. Extracellular recordings were made from fourteen non‐noxious only and nineteen convergent neurones in trigeminal nucleus caudalis of halothane‐anaesthetized rats. All the neurones studied were excited by the continuous micro‐electrophoretic ejection of an excitatory amino acid, DL‐homocysteic acid (DLH), with mean currents of 38.0 +/‐ 7.2 and 39.8 + 6.5 nA producing steady discharges of 35.0 +/‐ 3.3 and 31.8 +/‐ 1.3 spikes/s from the non‐noxious only and convergent neurones respectively. 2. The repeated percutaneous application (100 trials; 0.66 Hz) of single square‐wave stimuli (10 mA; 2 ms) to the tail always induced a biphasic depression of the activity of the convergent, but never of the non‐noxious only, neurones. Both the early and late components of this inhibition occurred at shorter latencies when the base rather than the tip of the tail was stimulated. Differences in latencies from the two sites of stimulation (100 mm apart) were used to estimate the conduction velocities of the peripheral fibres which were triggering the inhibitions. 3. The cumulated results showed that, for the onset of the earlier component of the inhibition, the mean difference between the latencies from the two sites of stimulation was 13.6 +/‐ 1.9 ms, corresponding to a peripheral conduction velocity of 7.3 +/‐ 0.3 m/s, which is in the A delta‐fibre range. For the onset of the late component of inhibition, the mean difference was 147.7 +/‐ 14.9 ms, corresponding to a peripheral conduction velocity of 0.68 +/‐ 0.07 m/s, which is in the C‐fibre range. 4. When currents of different intensities were applied percutaneously to the two stimulation sites, the thresholds for obtaining the A delta component were in the range 0.25‐0.5 mA whereas the C component appeared with currents 1‐2 mA. A clear relationship between current intensity and magnitude of inhibition was observed in the 0.25‐2 mA range for the A delta component and in the 1‐5 mA range for the C component. 5. In an additional series of experiments recordings were made from eleven convergent neurones in the dorsal horn of the lumbar spinal cord. By using essentially the same experimental procedure the effects of repetitive application (100 trials, 0.66 Hz) of percutaneous electrical stimuli (1 or 10 mA, 2 ms) applied to the muzzle, were studied on the steady discharges (42.3 +/‐ 5.4 spikes/s) induced by DLH. The application of the 10 mA stimuli induced a biphasic depression of activity, whereas only an early component was observed following 1 mA stimuli.(ABSTRACT TRUNCATED AT 400 WORDS)

1. Previous electrophysiological, pharmacological and anatomical evidence had suggested a possible participation of rostral ventromedial medulla (RVM) in the supraspinal part of the loop underlying diffuse noxious inhibitory controls (DNICs). In order to test this hypothesis, two experimental series were performed during which DNICs were compared in control sham‐operated rats and rats with lesions of the RVM and of an adjacent candidate for such a role, the nucleus gigantocellularis reticularis (Gi). 2. In the first experimental series, lesions were induced, in anaesthetized animals, by injections of quinolinic acid (0.3‐0.8 microliter of a 360 nmol/microliter solution) into the RVM or Gi. In the control animals (n = 10), the vehicle alone (artificial cerebrospinal fluid) was injected. Histological lesion reconstructions were performed after each electrophysiological experiment. Three groups of animals were considered: in the first group (n = 5), the lesion was centered on the RVM, including the two caudal thirds of nucleus raphe magnus (NRM) and adjacent reticular areas; in the second group (n = 5), the lesions extended more rostrally and involved the rostral pole of NRM; in the third group (n = 5), the lesion extended more laterally and dorsally and included nucleus reticularis gigantocellularis pars alpha (GiA), nucleus reticularis paragigantocellularis lateralis (LPGi) and the Gi. In each case, all the neuronal cell bodies within the lesioned area were destroyed. 3. In the second experimental series, electrolytic lesions of the total rostrocaudal extent of the NRM (n = 5) were induced, in anesthetized animals, by passing cathodal current (5 mA, 8 s). In the control animals (n = 5), the electrode was lowered but current was not applied. 4. One week after lesioning, the animals were anaesthetized, paralysed, artificially ventilated and recordings were made from convergent neurones in trigeminal nucleus caudalis. These neurones gave responses due to activation of A and C fibres when percutaneous electrical stimuli were applied to their receptive fields. DNICs were triggered by immersion of each paw in a 50 degrees C water‐bath. Both the general properties of the convergent neurones and the inhibitions of the C fibre‐evoked responses produced by these heterotopic noxious stimuli were compared in the different groups of animals. 5. The sizes of receptive field, spontaneous activities, thresholds for C fibre‐evoked responses and responses to C fibre activation were not different in the control and lesioned animals. The percentage inhibitions of the C fibre‐evoked responses both during and in the 44s following the conditioning periods were also very similar in the different groups of animals.(ABSTRACT TRUNCATED AT 400 WORDS)

1. In anaesthetized rats, recordings were made in the medullary subnucleus reticularis dorsalis. Neurones with total nociceptive convergence (TNC) responded to percutaneous electrical stimuli with early and late peaks due to the activation of A delta and C fibres respectively, no matter which part of the body was stimulated. Neurones with partial nociceptive convergence (PNC) responded with an A delta peak regardless of which part of the body was stimulated, and with a C peak of activation from some, mainly contralateral, parts of the body. 2. All TNC neurones responded to noxious thermal stimulation of the limbs with a phasic discharge followed by tonic activity that lasted throughout the stimulation. Discharges elicited by applying stimuli simultaneously to both forepaws or to a hindpaw and a forepaw were lower than the individual responses to stimulation of a single limb. Similar negative interactions were observed in the responses of PNC neurones following noxious thermal stimulation of two paws. 3. In both neuronal populations, the simultaneous application of noxious thermal stimuli and microelectrophoretic application of D,L‐homocysteic acid (DLH) induced responses of greater magnitude than those evoked by each stimulus alone. 4. TNC neurones responded to electrical stimulation of the contralateral hindpaw with A delta and C fibre responses. Noxious thermal stimuli applied to different areas of the body induced an excitatory response during the period that preceded the electrical stimulation, but an inhibition of both A delta and C fibre responses. By contrast, using a similar protocol, application of DLH induced a steady discharge in the period preceding the electrical stimulation and also in between the A delta and C fibre responses, which were not themselves inhibited. 5. The negative heterotopic influences in normal rats during simultaneous immersion of the ipsi‐ and contralateral hindpaws was strongly reduced in rats with bilateral lesions of the dorsolateral funiculi at the cervical level (C3‐C4). 6. It is concluded that strong negative interactions elicited by heterotopic noxious stimuli are observed in the spinoreticular system. Such interactions do not occur at the subnucleus reticularis dorsalis level but are mediated by supraspinal structures which control, through the dorsolateral funiculi, the spinal transmission of nociceptive information.

1. Electromyographic recordings were made from the biceps femoris muscle through a pair of noninsulated platinum/iridium needle electrodes in male Sprague-Dawley rats artificially ventilated and anesthetized with 0.8% halothane in a N2O-O2 mixture (2/3:1/3). The animals' ventilation, heart rates, and body temperatures were continuously monitored. Electrical stimuli (2-ms duration, 0.16 Hz) were delivered to the sural nerve territory through a pair of noninsulated platinum/iridium needle electrode inserted subcutaneously in the medial aspect of the 4th and the lateral part of the 5th toe. Such stimulation elicited a two-component reflex response in the ipsilateral biceps femoris muscle: The first had a short latency (17.5 +/- 2.3 ms), short duration (20.7 +/- 2.6 ms), and low threshold (1.5 +/- 0.6 mA), whereas the second had a longer latency (162.4 +/- 5.1 ms), longer duration (202.3 +/- 6.2 ms), and higher threshold (5.7 +/- 0.5 mA). 2. Lidocaine (0.02-0.1%; 0.1 ml), but not saline, injected subcutaneously over the proximal part of the sural nerve, produced a selective depression of the late component of the reflex response, whereas the first component remained unchanged. The conduction velocity of the afferent fibers was estimated from the stimulation needles in the sural nerve territory to the nerve's projection in the lumbar spinal cord: it was concluded that the second, late component of the reflex response was due to afferent signals transmitted via unmyelinated C-fibers, whereas the first component was related to activation of fine myelinated fibers (A delta group). 3. Electrical stimulation of the sural nerve was still able to elicit the two-component reflex responses in the ipsilateral biceps femoris muscle of chronic spinal rats, indicating that these responses were genuine reflex responses, transmitted completely through a spinal circuit. 4. The C-fiber reflex was recorded when the duration and frequency of the stimuli applied to the sural nerve varied within the 0.5- to 4-ms and 0.02- to 1-Hz ranges, respectively. It was concluded that a single 2-ms duration shock at an intensity of 1.2 times the C-fiber reflex threshold, delivered every 6 s (0.16 Hz), constituted an acceptable and optimal protocol for experiments in which the C-fiber reflex was studied as a function of time. These parameters were used throughout the subsequent experiments.(ABSTRACT TRUNCATED AT 400 WORDS)

Recordings were made from convergent neurons in trigeminal nucleus caudalis of the rat. These neurons were activated by both innocuous and noxious mechanical stimuli applied to their excitatory receptive fields located on the ipsilateral part of the muzzle. Transcutaneous application of suprathreshold 2-ms square-wave electrical stimuli to the center of the excitatory field resulted in responses to C-fiber activation being observed (mean latencies 63.6 +/- 5.5 ms). This type of response was inhibited by applying noxious conditioning stimuli to heterotopic body areas, namely immersing either the left or right hindpaw in a 52 degrees C water bath. A virtually total block of the response was observed during the application of the noxious conditioning stimulus, and this was followed by long-lasting poststimulus effects. Such inhibitory processes have been termed diffuse noxious inhibitory controls (DNIC) (39, 40). The effects on these inhibitions of various transverse lesions of the cervical spinal cord were investigated in acute experiments; tests were performed before and at least 30 min after the spinal section. While the unconditioned C-fiber responses were unaltered, the inhibitory processes could be impaired by the cervical lesions, although these effects depended on the part of the cervical cord destroyed and the side of application of the conditioning stimulus. Lesioning dorsal, dorsolateral, and ventromedial parts of the cervical cord was found not to affect inhibitory processes triggered from either hindpaw. The overlapping of the regions of these ineffective lesions revealed that two remaining regions were not destroyed, that is, the left and right ventrolateral quadrants. In experiments where the left anterolateral quadrant was affected by the surgical procedure the inhibition triggered from the right hindpaw was strongly reduced, whereas that elicited by left hindpaw stimulation was not diminished. The loss of inhibitory effects was characterized by a complete disappearance of poststimulus effects, whereas inhibition observed during the application of the noxious thermal conditioning stimulus was only partially, albeit very significantly, blocked. To ascertain further the mainly crossed nature of the pathways responsible for the heterotopic inhibitory processes, the effects of lumbar commissurotomy were investigated. Again the unconditioned C-fiber responses were unaltered by this procedure, whereas the inhibitory processes, whether triggered from the left or right hindpaw, were strongly depressed in all the experiments.(ABSTRACT TRUNCATED AT 400 WORDS)

Recordings were made from convergent neurons in the lumbar dorsal horn of the spinal cord of the rat. These neurons were activated by both innocuous and noxious mechanical stimuli applied to their excitatory receptive fields located on the extremity of the hindpaw. Transcutaneous application of suprathreshold 2-ms square-wave electrical stimuli to the center of the excitatory field, resulted in responses to C-fiber activation being observed. This type of response was inhibited by applying a noxious thermal conditioning stimulus on the muzzle. The immersion of the muzzle in a 52 degrees C waterbath resulted in a strong reduction of the response during the application of the noxious conditioning stimulus and this was followed by long lasting poststimulus effects. Such inhibitory processes have been termed diffuse noxious inhibitory controls (DNIC). The effects on these inhibitions of lesions including the dorsolateral funiculus (DLF) were investigated in acute experiments: tests were performed before and at least 30 min after the DLF lesion. A lesion including the DLF ipsilateral to the neuron under study completely abolished the inhibitory processes triggered from the muzzle. Concomitantly, a facilitation of C-fiber responses was observed. Nevertheless, DNIC was still impaired even using a juxtathreshold current to elicit a weak C-fiber response. To ascertain further the main, if not entire, participation of the ipsilateral DLF in the descending projections responsible for the heterotopic inhibitory processes, the effects of a lesion of the contralateral DLF were investigated. Neither the inhibitory processes nor the unconditioned C-fiber responses were altered by this procedure. Again, a second lesion including the ipsilateral DLF induced a blockade of DNIC. It is concluded that the descending projections involved in the triggering of DNIC are mainly, if not entirely, confined to the DLF ipsilateral to the neuron under study. The contralateral DLF did not appear to play a role in these processes.

1. Recordings were made from neurons in the left medullary subnucleus reticularis dorsalis (SRD) of anesthetized rats. Two populations of neurons were recorded: neurons with total nociceptive convergence (TNC), which gave responses to A delta- and C-fiber activation from the entire body after percutaneous electrical stimulation, and neurons with partial nociceptive convergence (PNC), which responded to identical stimuli with an A delta-peak regardless of which part of the body was stimulated and with a C-fiber peak of activation from some, mainly contralateral, parts of the body. 2. The effects of various, acute, transverse sections of the cervical (C4-C5) spinal cord on the A delta- and C-fiber-evoked responses were investigated by building poststimulus histograms (PSHs) after 50 trials of supramaximal percutaneous electrical stimulation of the extremity of either hindpaw (2-ms duration; 3 times threshold for C-fiber responses), before and 30-40 min after making the spinal lesion. 3. In the case of TNC neurons, hemisections of the left cervical cord blocked the responses elicited from the right hindpaw and slightly, but not significantly, diminished those evoked from the left hindpaw. Conversely, hemisections of the right cervical cord abolished TNC responses elicited from the left hindpaw without significantly affecting the responses elicited from the right hindpaw. 4. Lesioning the dorsal columns or the left dorsolateral funiculus was found not to affect the TNC neuronal responses elicited from either hindpaw. By contrast, lesioning the left lateral funiculus or the most lateral part of the ventrolateral funiculus, respectively, reduced and blocked the responses elicited from the right hindpaw without affecting those evoked from the left hindpaw. 5. After lesions that included the most lateral parts of the left ventral funiculus, PNC neuronal responses elicited from the right hindpaw were also abolished, whereas those elicited from the left hindpaw remained unchanged. 6. We conclude that the signals responsible for the activation of SRD neurons travel principally in the lateral parts of the ventrolateral quadrant, a region that classically has been implicated in the transmission of noxious information. Both a crossed and a double-crossed pathway are involved in this process. The postsynaptic fibers of the dorsal columns and the spinocervical and spinomesencephalic tracts do not appear to convey signals that activate SRD neurons. 7. The findings also suggest that lamina I nociceptive specific neurons, the axons of which travel within the dorsolateral funiculus, do not contribute very much to the activation of SRD neurons.

1. Recordings were made in anesthetized monkeys from neurons in the medullary reticular formation (MRF) caudal to the obex. Responses of 19 MRF neurons to mechanical, thermal, and/or electrical stimulation were examined. MRF neurons exhibited convergence of nociceptive cutaneous inputs from widespread areas of the body and face. 2. MRF neurons exhibited low levels of background activity. Background activity increased after periods of intense cutaneous mechanical or thermal stimulation. Nearly all MRF neurons tested failed to respond to heterosensory stimuli (flashes, whistle sounds), and none responded to joint movements. 3. MRF neurons were excited by and encoded the intensity of noxious mechanical stimulation. Responses to stimuli on contralateral limbs were greater than those to stimuli on ipsilateral limbs. Responses were greater to stimuli on the forelimbs than to stimuli on the hindlimbs. 4. MRF neurons responded to noxious thermal stimulation (51 degrees C) of widespread areas of the body. Mean responses from stimulation at different locations were generally parallel to those for noxious mechanical stimulation. Responses increased with intensity of noxious thermal stimulation (45-50 degrees C). 5. MRF neurons responded with one or two peaks of activation to percutaneous electrical stimulation applied to the limbs, the face, or the tail. The differences in latency of responses to stimulating two locations along the tail suggested that activity was elicited by activation of peripheral fibers with a mean conduction velocity in the A delta range. Stimulation of the contralateral hindlimb elicited greater responses, with lower thresholds and shorter latencies, than did stimulation of the ipsilateral hindlimb. 6. Electrophysiological properties of monkey MRF neurons resembled those of neurons in the medullary subnucleus reticularis dorsalis (SRD) in the rat. Neurons in the caudal medullary reticular formation could play a role in processing nociceptive information. Convergence of nociceptive cutaneous input from widespread areas of the body suggests that MRF neurons may contribute to autonomic, affective, attentional, and/or sensory-motor processes related to pain.

1. Diffuse noxious inhibitory controls (DNIC) were compared in control sham-operated rats and in rats with lesions of mesencephalic structures involved in the modulation of pain, namely the periaqueductal gray (PAG), cuneiformis nucleus (CNF), and parabrachial nucleus (PB). 2. Lesions were induced by ibotenic acid: 4 micrograms (0.2 microliter) injected bilaterally in the PAG or the CNF-PB area or 10 micrograms (0.5 microliter) injected unilaterally in the CNF or PB. Control animals were microinjected with the vehicle (artificial CSF) alone. Histological controls were performed at the end of each electrophysiological experiment. Only the animals in which the target structure (PAG, CNF, or PB) was completely destroyed in its entire rostrocaudal length were selected. With the exception of the cell bodies of the trigeminal mesencephalic nucleus, all neurons were destroyed in these regions. 3. At least 1 wk after the microinjection procedure, recordings were made from convergent neurons in both the right and left trigeminal nucleus caudalis. These neurons were activated by both noxious and nonnoxious stimuli applied to their excitatory receptive fields and gave responses due to activation of both A- and C-fibers after percutaneous electrical stimulation of their receptive fields. These types of response were inhibited by applying noxious conditioning stimuli to heterotopic areas of the body, namely immersing a paw in a 50 degrees C water bath. A virtually total block of the responses was observed during the application of the noxious conditioning stimulus, and this was followed by long-lasting poststimulus effects. 4. The general properties of neurons (sizes of receptive fields, spontaneous activity, thresholds to obtain C-fiber-evoked responses, responses to C-fiber activation) were all found to be similar in the control and the lesioned animals. The percentage inhibition of the C-fiber-evoked responses of the trigeminal convergent neurons elicited by the noxious conditioning stimuli were found to not be significantly different in any group of animals; in all the animals, inhibitions exceeded 85% during the immersion of either paw and were followed by long-lasting poststimulus effects. 5. We conclude that the PAG, CNF, and PB, three structures that are putatively involved in the modulation of pain, do not participate directly in the supraspinal part of the loop subserving DNIC. The involvement of other structure(s) and a possible indirect modulation of DNIC are discussed. It is also concluded that the PAG, CNF, and PB do not participate directly in the tonic descending inhibitory controls, which are presumed to modulate the activity of convergent neurons.

1. In order to study descending influences of the brain stem upon the transmission of nociceptive messages at the spinal level, the activities of lumbar lamina V dorsal horn cells, induced by intra‐arterial injection of brandykinin into the limbs, were recorded in unanaesthetized cats in both decerebrate and temporary spinal states (reversible cold block applied at the thoracic level). 2. In the decerebrate state, the intra‐arterial injection of bradykinin had little or no effect. 3. During the reversible spinalization, the effects of bradykinin were revealed or considerably enhanced. As described in a previous study, in the C1‐transected cat, three types of effects were encountered: excitatory, inhibiitory and mixed (inhibitory‐excitatory). 4. These modifications observed after spinalization were generally associated with a large increase of the spontaneous firing rate. 5. These results emphasize, in the decerebrate cat, the importance of descending inhibitory controls exerted by the brain stem upon the transmission of nonciceptive messages at the spinal cord level.

1. Recordings were made from thirty‐nine convergent neurones in the lumbar enlargement of the rat spinal cord. These neurones were activated by both innocuous and noxious stimuli applied to their excitatory receptive fields located on the extremity of the ipsilateral hind paw. Transcutaneous application of suprathreshold 2 ms square‐wave pulses to the centre of the receptive field resulted in responses to A‐ and C‐fibre activation being observed; a mean of 18.8 +/‐ 1.8 C‐fibre latency spikes was evoked per stimulus. This type of response was inhibited by applying noxious conditioning stimuli to heterotopic body areas; immersing the tail in a 52 degrees C water‐bath caused a mean 54.5 +/‐ 2.3% inhibition of the C‐fibre‐evoked response; such inhibitory processes have been termed diffuse noxious inhibitory controls (d.n.i.c.). 2. The effects of microinjections of morphine (5 micrograms; 0.2 microliter) on both the unconditioned C‐fibre‐evoked response and inhibitory processes triggered from the tail were investigated in an attempt to answer two questions: (a) does morphine increase tonic descending inhibitory processes and (b) what are the effects of morphine on descending inhibitory processes triggered by noxious stimuli? 3. The predominant effect of periaqueductal grey matter (p.a.g.) morphine on the C‐fibre‐evoked responses was a facilitation: 51% of cells had their C‐fibre‐evoked responses increased by morphine (by roughly 50%); 31% of cells were not influenced while the remaining 18% of units were depressed; however the cells classified as depressed were only marginally so. No clear relationships were found either between the microinjection sites in the p.a.g. and their corresponding effects or between the number of C‐fibre‐spikes evoked in the control sequences and the subsequent effect of morphine. 4. While d.n.i.c. was not altered by morphine in 56% of cases, it was clearly reduced in the remaining cells. The effects were immediate but peaked at 40 min following the microinjection (a mean 77% reduction) and then returned towards control values. All but three of the corresponding microinjection sites were such as to include the medio‐ventral p.a.g. including the nucleus raphé dorsalis. In contrast none of the cases where d.n.i.c. was unaltered included microinjection sites in this region. 5. No relationship was found between the changes in d.n.i.c. and the number of spikes evoked in the control sequences, or the changes in the C‐fibre responses. 6. Autoradiographic controls using [3H]morphine showed a large diffusion of the drug within an area of about 0.75 mm around the tip of the cannula.(ABSTRACT TRUNCATED AT 400 WORDS)

1. In anaesthetized rats, recordings were made within the medullary subnucleus reticularis dorsalis (SRD) from neurones that exhibited convergence of nociceptive inputs from the entire surface of the body. Neurones with total nociceptive convergence responded to supramaximal percutaneous electrical stimuli (2 ms duration) with early and late peaks due to the activation of A delta and C fibres, respectively, no matter which part of the body was stimulated. Neurones with partial nociceptive convergence responded to identical stimuli with an A delta peak of activation regardless of which part of the body was stimulated and with a C peak of activation from some, mainly contralateral, parts of the body. The characteristics of the responses of these neurones to graded colo‐rectal distension (< or = 100 mmHg) were analysed. 2. The majority of neurones with total nociceptive convergence (n = 13 out of 16) responded to colo‐rectal distension by increasing their firing rates. Although these neurones were virtually unresponsive to the lowest pressure employed (12.5 mmHg), they increased their discharges monotonically for distensions in the 26‐100 mmHg range and these responses were sometimes followed by after‐discharges. One of these neurones, which exhibited a high level of spontaneous activity, was inhibited during colo‐rectal distension. None of the neurones with partial nociceptive convergence recorded (n = 10) ever changed its firing rate during increases of intracolonic pressure up to 100 mmHg. 3. It is concluded that neurones with total nociceptive convergence give monotonic stimulus‐response relationships for colo‐rectal distensions. Thus, neurones with total nociceptive convergence can encode the strength of visceral stimuli, probably within the noxious range, just as they have previously been shown to do for thermal and mechanical cutaneous stimuli. Together with previous electrophysiological and neuroanatomical findings, this study provides further evidence for the convergence of noxious inputs onto single SRD neurones. 4. It is suggested that neurones with total nociceptive convergence could be a link in spino‐bulbospinal loops involved in autonomic reactions to strong visceral stimulation. In addition, SRD neurones could be an important supraspinal relay in the mechanisms of visceral pain.

The effects on C fiber evoked activity in lumbar dorsal horn convergent neurones of i.v. morphine alone, of Tyr-D-Thr-Gly-Phe-Leu-Thr (DTLET) alone or of either of these drugs in association with 5-deoxyadenosylcobalamine (dibencozide) were investigated in anesthetized rats. Both morphine and DTLET depressed the neuronal responses in a dose-related fashion, with the former requiring lower doses. Although dibencozide alone was devoid of any effect, it significantly enhanced the depressive effects of all doses of morphine tested and of the lower two doses of DTLET. It is concluded that dibencozide enhances the spinal depression of nociceptive information elicited by mu and delta opioid agonists. This drug could provide a useful tool for the study of interactions between opioids and opioids receptors. It is also suggested that dibencozide could be useful in clinical practice for reducing the dosage of opioids.

1. In anesthetized rats recordings were made from neurons in the medulla caudal to the obex. In the medullary dorsal horn, typical trigeminal noxious specific, nonnoxious specific, and convergent neurons were found. In nucleus cuneatus, typical dorsal column units were recorded. In subnucleus reticularis dorsalis (SRD), recordings were made from neurons which exhibited convergence of nociceptive inputs from the entire body. In subnucleus reticularis ventralis (SRV) we recorded both from neurons with spontaneous activity that were either unaffected or inhibited by noxious stimuli applied to various parts of the body and from respiratory neurons. The present paper deals particularly with the nature of the stimuli that activated reticular neurons exhibiting nociceptive convergence. 2. Neurons with nociceptive convergence could be activated by mechanical, thermal, or chemical noxious stimuli applied to widespread areas of the body. By using percutaneous electrical stimulation, we found that they responded to the activation of peripheral fibers in the A delta- and C-range. Two neuronal subpopulations were defined according to the way in which SRD neurons responded to the electrical stimuli, namely: "neurons with total nociceptive convergence" (TNC) and "neurons with partial nociceptive convergence" (PNC). 3. The great majority (84%) of TNC neurons did not exhibit spontaneous activity and none of these neurons gave responses to heterosensory (flashes, whistle sounds) or proprioceptive stimuli. Most (88%) did not respond to any kind of innocuous cutaneous stimuli. By contrast, the entire population of TNC neurons responded to noxious mechanical, thermal, and visceroperitoneal stimuli. In the majority of cases (71%) long-lasting afterdischarges were observed following cessation of the application of the nociceptive stimulus. 4. All the TNC neurons responded to suprathreshold percutaneous electrical stimulation (2-ms duration) with two peaks of activation no matter which part of the body was stimulated. By stimulating two regions of the tail, 100 mm apart, we determined that the early and late peaks of activation were triggered by activities in peripheral fibers with mean conduction velocities of 10.8 +/- 0.5 and 0.74 +/- 0.05 (SE) m/s, respectively, i.e., A delta- and C-fibers. The mean thresholds for obtaining A delta-fiber components were found in the 0.4-0.7-mA range; the mean thresholds for obtaining C-fiber components were found in the 6-7.5- and 3-4-mA range for the face and the other parts of the body, respectively.(ABSTRACT TRUNCATED AT 400 WORDS)

1. In anesthetized rats, recordings were made within the medullary subnucleus reticularis dorsalis (SRD) from neurons that exhibited convergence of nociceptive inputs from the entire body. Neurons with total nociceptive convergence (TNC) responded to suprathreshold percutaneous electrical stimuli (2-ms duration) with an early and a late peak due to activation of A delta- and C-fibers, respectively, no matter which part of the body was stimulated. Neurons with partial nociceptive convergence (PNC) responded to the same stimuli with an A delta-peak regardless of which part of the body was stimulated and with a C-peak of activation from some, mainly contralateral, parts of the body. The characteristics of the responses of these neurons to the application of graded intensities of electrical, thermal, and mechanical stimuli were analyzed. 2. All TNC neurons and 85% of PNC neurons responded to A delta- and C-fiber activation following percutaneous electrical stimulation of the contralateral hindpaw. With regard to A delta-fiber-evoked responses, a linear relationship between the logarithm of the applied current and the magnitude of the responses was found within the 0.25- to 6.0-mA and 0.5- to 24-mA ranges for TNC and PNC neurons, respectively; however, these curves were essentially similar. With regard to C-fiber-evoked responses, such a linear relationship was found within the 1.5- to 6.0-mA range for both types of SRD neurons, although the TNC neurons presented larger C-fiber-evoked responses than did the PNC neurons. 3. TNC and PNC neurons linearly increased their discharges during the application of noxious thermal stimuli to the contralateral hindpaw within the range 44-52 degrees C; the mean responses evoked by noxious heat from TNC neurons were of higher magnitude than those from PNC neurons. The majority of SRD neurons presented long-lasting afterdischarges, especially with the highest temperature employed (52 degrees C). 4. TNC neurons monotonically increased their discharges during graded mechanical or thermal stimulation of the tail. When mechanical stimuli were applied, a linear relationship was found between the logarithm of the strength of the mechanical stimulus and the neuronal discharges, in the 5.3- to 7.4-N/cm2 range. With thermal stimulation, TNC neurons linearly increased their discharges in the 44-52 degrees C range. When increasing amounts of the tail were immersed in a 50 degrees C waterbath, TNC neurons increased their discharges within a restricted range of tail surface areas (0.9-5.7 cm2); further increases in the stimulated surface size were not followed by increases in firing rate.(ABSTRACT TRUNCATED AT 400 WORDS)

1. It has previously been shown that, in normal humans, heterotopic painful thermal conditioning stimuli induce parallel increase in the thresholds of a spinal nociceptive flexion reflex (RIII reflex) and the concurrent sensation of pain elicited by electrical stimulation of the sural nerve. On the basis of analogous animal studies, we proposed that such phenomena could be related to diffuse noxious inhibitory controls (DNIC), which have been described in the rat. The present study, which was carried out on normal volunteer subjects, was particularly concerned with the extent and temporal characteristics of the depressive effects of DNIC triggered by painful thermal stimuli on RIII reflex activity. In addition, because it was possible that these depressive effects could have resulted from a direct postsynaptic inhibition of motoneurons, a second part of the study was aimed at determining whether or not the heterotopic noxious thermal stimuli also affected the excitability of alpha-motoneurons, as monitored by the monosynaptic Hoffmann reflex (H reflex) technique. 2. In the 11 subjects under study, application of moderate, nonnoxious temperatures (40-44 degree C) to the contralateral hand (via a thermoregulated and agitated waterbath) did not modify the RIII reflex nor the associated sensation of pain. By contrast noxious temperatures clearly depressed the RIII reflex and the concurrent sensation of pain, both during and after the conditioning procedure (CP), in a direct linear relationship to the temperature of the waterbath in the 45-47 degree C range; the maximal depressive effect was observed with the highest conditioning temperature. A significant relationship was also found between the extent of the RIII depression during the CP and that during a 10-min period of post-CP observation. 3. The depressive effects observed on both the RIII reflex and pain were not associated with clear change in autonomic functions. Respiration remained stable during the sessions, with no significant relationship between the temperatures of the waterbath and respiratory rate. Heart rate was slightly but significantly increased during the immersion of the hand in the 46 or 47 degree C waterbaths; this increase, however, ceased with the end of CP. 4. Application of thermal conditioning stimuli produced a slight but nonsignificant increase of the monosynaptic H reflex during the first minute of CP, no matter what was the temperature of the waterbath. However, there were no subsequent variations during the 6-min period of post-CP observation.(ABSTRACT TRUNCATED AT 400 WORDS)

The effects of the novel mixed peptidase inhibitor, kelatorphan [N-(R)-3-(N-hydroxyaminocarbonyl-2-benzyl-1-oxopropyl)-L-alanine], were compared to those of a combination of the potent "enkephalinase" inhibitor thiorphan and the nonselective aminopeptidase inhibitor bestatin, on the catabolism of [3H]Met-enkephalin and on the release of endogenous Met-enkephalin by the rat spinal cord in vitro and in vivo. At 20 microM, kelatorphan almost prevented completely the degradation of exogenous [3H] Met-enkephalin by slices of the dorsal zone of the lumbar enlargement. Similarly, the addition of 20 microM kelatorphan to a [3H] Met-enkephalin-containing artificial cerebrospinal fluid superfusing the whole spinal cord of halothane-anesthetized rats efficiently protected the exogenous peptide from enzymatic degradation. In contrast, in the same in vitro and in vivo models, thiorphan (1 microM) or bestatin (20 microM) alone was inactive, and only their combination induced a significant protection of the exogenous peptide. In vitro and in vivo, kelatorphan (20 microM) increased markedly the spontaneous outflow of endogenous Met-enkephalin-like material as well as the peptide overflow due to K+-induced depolarization (in vitro and in vivo) or noxious stimulation (in vivo). Under similar conditions, thiorphan (1 microM) plus bestatin (20 microM) also enhanced the efflux of Met-enkephalin-like material, but generally to a lower extent than kelatorphan. Compared to thiorphan plus bestatin, kelatorphan exerts additional inhibitory effects on dipeptidylaminopeptidase activity and the present results could indicate that this enzyme also may be involved in the inactivation of extracellular Met-enkephalin at the spinal level in rats.

A C-fiber reflex elicited by electrical stimulation within the territory of the sural nerve was recorded from the ipsilateral biceps femoris muscle in anesthetized rats. The temporal evolution of the response was studied by using a constant stimulus intensity (3 x threshold) and recruitment curves were built by varying the stimulus intensity from 0 to 7 x threshold. Low (0.5-1 mg/kg) and high doses (4-10 mg/kg) of i.v. morphine induced a facilitation and a depression of the C-fiber reflex, respectively, in a dose-dependent manner. The ED50 (95% confidence limit) for the depressive effect with a stimulus intensity of 3 x control threshold was 3.8 (3.1-4.8) mg/kg. Increasing the stimulus intensity was associated with a shift of the dose-response curve to the right, without a change of slope. In the 1.5 to 7 x threshold range, ED50 were linearly related to the stimulus intensity. Intravenous naloxone (0.4 mg/kg) completely antagonized the facilitation or depression induced by morphine. Low doses (1-10 micrograms/kg; i.v.) of buprenorphine facilitated the reflex in a fashion similar to morphine. Higher doses (30-1000 micrograms/kg; i.v.) elicited a biphasic effect on the C-fiber reflex: depressive and facilitatory with weak and strong stimulus intensities, respectively. These results are discussed in terms of there being an intrinsic efficacy for the depressive effects of morphine and buprenorphine and of their clinical potencies. Various hypotheses are suggested regarding the facilitations of the C-fiber reflex.

A C-fiber reflex elicited by electrical stimulation within the territory of the ipsilateral sural nerve, was recorded from the biceps femoris muscle in anesthetized rats. The temporal evolution of the reflex was studied using a constant level of stimulus intensity (3 x threshold) and recruitment curves were built by varying stimulus intensity from 0 to 7 x threshold. Intrathecal doses of buprenorphine in the 0.2 to 10 micrograms range, elicited a facilitation of the C-fiber reflex in a dose-dependent manner. A large dose (100 micrograms) depressed but did not block the reflex. Intracerebroventricular doses of buprenorphine in the 0.1 to 10 micrograms range, facilitated the C-fiber reflex. A higher dose (100 micrograms) elicited a biphasic effect: depressive when the stimulus intensity was weak and facilitatory when the stimulus intensity was strong. It is concluded that the antinociceptive properties of buprenorphine cannot be related to a direct or indirect depressive spinal effect. In terms of spinal and supraspinal effects of buprenorphine, it is likely that buprenorphine facilitates the C-fiber reflex via a supraspinal mechanism that acts on sensory and/or motor components of the reflex arc although the depression of the reflex involves a spinal mechanism. The lipophilic properties of buprenorphine could explain a substantial diffusion from its spinal injection site to the brain. From a clinical standpoint, this study confirms that intrathecal administration of buprenorphine is an inadequate way of accessing spinal opioid receptors.

Recordings were made from convergent neurons in the lumbar dorsal horn of the rat. These neurons were activated by both innocuous and noxious stimuli applied to their excitatory receptive fields located on the extremity of the ipsilateral hindpaw. Transcutaneous application of suprathreshold 2-msec square-wave pulses to the center of the receptive field resulted in responses to A- and C-fiber activation being observed: 27.2 +/- 2.2 (mean +/- S.E.M.) C-fiber latency spikes were evoked per stimulus. This type of response was inhibited by applying noxious conditioning stimuli to heterotopic areas of the body; in particular, immersing the tail in a 52 degrees C waterbath caused a 74.2 +/- 2.0% inhibition of the C-fiber evoked responses; such inhibitory processes have been termed diffuse noxious inhibitory controls (DNIC). The effects of microinjections of morphine (0.6-40 micrograms; 2 microliter) within the 3rd ventricle on both the unconditioned C-fiber-evoked responses and the inhibitory processes triggered from the tail were investigated in an attempt to answer two questions: 1) does i.c.v. morphine increase tonic descending inhibitory processes? and 2) what are the effects of i.c.v. morphine on descending inhibitory processes triggered phasically by noxious stimuli? The predominant effect of i.c.v. morphine on the C-fiber-evoked responses was a facilitation (17 of 26 cases). Such a facilitation was dose-related in the 0.6 to 40 microgram range and naloxone reversible; it plateaued from 20 min after the microinjection. No clear relationship was found between the number of C-fiber evoked responses in the control sequences and the subsequent effect of i.c.v. morphine. Intracerebroventricular morphine clearly reduced DNIC in the majority of cases (21 of 26). Such a reduction was dose-related in the 0.6 to 2.5 microgram range and naloxone reversible; it plateaued within 90 min of microinjection. No clear relationship was found between the changes in DNIC and either the number of C-fiber-evoked spikes in the control sequences or the changes in the C-fiber responses induced by i.c.v. morphine. Autoradiographic controls using [3H]morphine showed a labeling along the ventricle wall including the hypothalamus, the periaqueductal gray matter and the floor of the 4th ventricle, three regions which have been implicated in the control of nociceptive transmission at the spinal level. Diffusion from the ventricle wall was over a distance of 0.5 mm and was identical whether observed 20 or 95 min after the microinjections.(ABSTRACT TRUNCATED AT 400 WORDS)

We describe audible and ultrasonic vocalization elicited in rats by a short electrical pulse applied to the tail. Three types of vocal emissions were recorded: (1) ‘peep’, characterized by a repartition of energy Over a wide range (0–50 kHz) of frequencies without any clear structure; (2) ‘chatters’, characterized by an audible (frequencies in hearing range of humans) fundamental frequency (2.47 ± 0.03 kHz) and harmonics; and (3) ‘ultrasonic emissions’, characterized by a succession of slightly modulated pulses with frequencies in the 20–35 kHz range. Peeps and chatters were never recorded before the application of the stimuli. Several different vocalization patterns were described in terms of these types of responses. Just after the stimulation, all the animals emitted a 1st peep, which was generally (61%) followed by a 2nd one. They appeared with reproducible latencies, durations and envelopes. The envelopes of the audible (peeps and chatters) responses were intensity-dependent. Experimental data (moving the stimulation site, lidocaine injection) indicated that the 1st and 2nd peeps were triggered by two different groups of peripheral fibres with mean conduction velocities of 7.3 ± 0.8 and 0.7 ± 0.1 m/ sec, respectively. This suggested an involvement of Aδ and C fibres. Morphine showed a naloxone-reversible and dose-dependent antinociceptive effect by decreasing the 1st and 2nd peep envelopes. It is concluded that a short stimulus applied to the tail triggers a complex behavioural repertoire. It is proposed that this model will be a useful tool for physiological and pharmacological studies Of nociception.

Multiple descending systems for pain control originate from the rostral medulla and midbrain. These systems are involved in the antinociceptive action produced by opioids. One category of descending inhibitory controls is activated specifically by noxious stimuli and has been termed diffuse noxious inhibitory controls. These controls have been described in both animal and man, but their supraspinal circuitry has not been fully localized. To determine the supraspinal level of integration of nociceptor activated controls and hence their potential relationships with previously described descending controls, we studied in halothane-anesthetized rats the effects of transections performed at various levels in the brainstem. The physiological properties of dorsal horn convergent neurons, including supraspinallymediated inhibitory processes elicited by heterotopic noxious stimuli, i.e. diffuse noxious inhibitory controls, were not altered in rats in which the brainstem had been completely transected up to 200 μm caudal to the caudal end of the rostral ventromedial medulla. In contrast, the spontaneous activity of these neurons was significantly enhanced and the inhibitory phenomena significantly reduced in animals with transections more than 500 μm caudal to the caudal end of the rostral ventromedial medulla. These effects were not related to cardiovascular changes induced by the transections.

Although its exact mechanism of action is still open to debate, morphine causes a significant depression of nociceptive impulses from the first step in CNS transmission. The accumulating evidence in favour of direct spinal opiate effects has led to clinical trials for the relief of severe pain.