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Opioid receptors are localized throughout peripheral and central nervous system and interact with endogenous opioid peptides and drugs including heroin, synthetic opioids, and pain relievers (codeine, morphine). If several opioid PET tracers exist for preclinical studies, only a few have been used in human. Some tracers are selective for one subtype of opioid receptors (e.g., [ 11 C]CAF (carfentanil) for μ receptor) while others are not ([ 11 C]DPN (diprenorphine)). As shown by imaging studies, the opioid system is involved in pain processing, but also in addiction, neuropsychiatric manifestations (harm avoidance, sadness, novelty seeking behavior), feeding and food disorders and, finally, movement disorders and levodopa-induced dyskinesias. However, no imaging study has analyzed the potential dysfunction of opioid system in pain manifestations in Parkinson's disease. In addition, the involvement of opioid system in impulse control disorders and neuropsychiatric manifestations has never been studied in Parkinson's disease. Thus, there is an urgent need to understand the impact of opioid system dysfunctions in Parkinson's disease., (© 2018 Elsevier Inc. All rights reserved.)

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.

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.

Objective: To bring together the most recent data concerning the physiology of nociceptors at a time when there has been significant progress in the understanding of these., Data Sources: References were obtained from computerised bibliographic data banks (Medline and others) and the authors' personal documents., Data Synthesis: Nociceptive impulses are generated at the periphery in unmyelinated fibres called nociceptors, the responses of which depend on the tissue environment. Numerous mediators can activate, sensitise or "wake up" nociceptor: kinins (bradykinin, kallidin and their metabolites), pro-inflammatory cytokines (TNF alpha, IL-6, IL-1 beta, IL-8), anti-inflammatory cytokines (IL-4, IL-6, IL-10, IL-12, IL-13), prostanoids (PGE2, PGI2), lipo-oxygenases (leucotrienes such LTB4 or 15-HETE), the "central mediators of the immune response" (NF-kappa B), growth factors such as neurotrophins (NGF, BDNF, NT-3 and NT-4/5), peptides (substance P, CGRP, Neurokinin A), nitric oxide, histamine, serotonin, proteases, excitatory amino acids, adrenergic amines and opioids. The release of neuromediators by primary afferent fibres in the spinal cord may be summarised by successively considering calcium channels, presynaptic receptors, excitatory amino acids and peptides., Conclusion: Sensitisation phenomena are not exclusively peripheral but also central in origin and these are interlinked.

Objective: To analyse models of acute pain in experimental animals., Data Sources: References were obtained from computerised bibliographic data banks (Medline and others) and the authors' personal documents., Data Synthesis: The majority of tests permit only a measurement of threshold, whereas clinical pain is almost always prolonged. The relationships between tests of acute pain and motor activity are reviewed from a number of standpoints; in particular we consider the influence, which postural adjustments of the animal may exert on motor responses in the limbs and the significance of flexor and extensor reflexes. In analysing the problem of the sensitivity of tests, we raise the following questions: 1) what type(s) of fibres underlie the observed responses and might these be different depending on whether one is stimulating a healthy or an inflamed tissue; 2) what significance do measurements of "latency" have when a stimulus is increasing; 3) how valid are the methods of analysing the results? The influence of species and the genetic line used in tests and the specificity and predictivity of tests are considered. Finally, we review those factors, which may distort behavioural measurements in animals, notably--pharmacokinetics, interactions between heterotopic stimuli, environmental factors and related psychophysiological/psychological considerations (subjective "undesirable" phenomena, learning phenomena). We pay particular attention to related physiological functions (thermoregulation, vasomotricity, blood pressure). These considerations lead us to re-position nociception within a much larger homeostatic framework which in addition to pain, includes phenomena such as anxiety and vegetative functions. They also suggest that we should define an "effective stimulus" as one, which activates nociceptive nerve terminals after a physical stimulus, has passed through a "peripheral lens" which regulates its intensity for reasons, which are physical, albeit of biological origin. Finally they remind us that the "system of pain" forms part of a whole set of subsystems--sensory, motor, vegetative, emotional, motivational--which scientific method, being reductionist by nature, cannot study in its entirety. However one must consider results of nociceptive tests within this general context., Conclusion: It is only by taking the approach described in this review, that fundamental and clinical research can interact usefully.

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

Although electrical stimulation of the precentral gyrus (MCS) is emerging as a promising technique for pain control, its mechanisms of action remain obscure, and its application largely empirical. Using positron emission tomography (PET) we studied regional changes in cerebral flood flow (rCBF) in 10 patients undergoing motor cortex stimulation for pain control, seven of whom also underwent somatosensory evoked potentials and nociceptive spinal reflex recordings. The most significant MCS-related increase in rCBF concerned the ventral-lateral thalamus, probably reflecting cortico-thalamic connections from motor areas. CBF increases were also observed in medial thalamus, anterior cingulate/orbitofrontal cortex, anterior insula and upper brainstem; conversely, no significant CBF changes appeared in motor areas beneath the stimulating electrode. Somatosensory evoked potentials from SI remained stable during MCS, and no rCBF changes were observed in somatosensory cortex during the procedure. Our results suggest that descending axons, rather than apical dendrites, are primarily activated by MCS, and highlight the thalamus as the key structure mediating functional MCS effects. A model of MCS action is proposed, whereby activation of thalamic nuclei directly connected with motor and premotor cortices would entail a cascade of synaptic events in pain-related structures receiving afferents from these nuclei, including the medial thalamus, anterior cingulate and upper brainstem. MCS could influence the affective-emotional component of chronic pain by way of cingulate/orbitofrontal activation, and lead to descending inhibition of pain impulses by activation of the brainstem, also suggested by attenuation of spinal flexion reflexes. In contrast, the hypothesis of somatosensory cortex activation by MCS could not be confirmed by our results.

To define the counterirritation phenomenon, we might refer to the Hippocratic aphorism: 'If two sufferings take place at the same time, but at different points, the stronger one makes the weaker silent'. On the basis of this clinically common observation, often used advantageously by the patients themselves, a number of therapeutic methods have been developed which are grouped under the terms counterirritation or counterstimulation. This phenomenon has not been scientifically analysed until recent years. Experimental results gathered during the last decade have shown that counterirritation phenomena have a well-defined neural substrate both in animals and in man. In particular, they have proved not to rely on segmental mechanisms, but rather imply spino-bulbo-spinal loops involving ascending pathways in the anterolateral spinal columns, integration in the lower brain stem, and descending influences reaching dorsal horn neurons via the dorsolateral quadrant. The results also suggest that the study of counterirritation is essential for accessing the physiology of nociception and pain control. The very existence of the counterirritation phenomenon is the easiest demonstrable index of a specific system for pain modulation in man. Besides its scientific interest, the elucidation of its neurophysiological bases has clinical importance, in as much as it may ameliorate our understanding of certain pain syndromes and contribute to the development of new investigative and therapeutic procedures.

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

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

Brief electrical pulses applied to the rat tail elicit a complex vocal response which includes audible (peeps, chatters) and ultrasonic (USV) components. Aspirin and amitriptyline had no effect on the vocal responses. Morphine showed a dose-dependent and naloxone reversible antinociceptive effect on the 1st and 2nd audible peeps by decreasing their intensity (evaluated by their envelopes which correspond to the outer bounds of the soundwave amplitude plotted as a function of time), with ED50 values of 1.96 mg/kg and 0.36 mg/kg i.v. respectively. Paracetamol significantly reduced only the intensity of the second peep at the dose of 200 mg/kg iv. Chatter intensity was decreased by doses of 1 and 3 mg/kg i.v. of morphine which would suggest an effect on emotional components of pain. The intensity of USV was affected by morphine injection although the variations observed were non-significant. These data clearly implicate a specific role for the opioid analgesics in modifying the vocal pain related behaviors.

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.

Brief electrical pulses applied to a rat's tail elicit complex vocal responses including audible ("peeps," "chatters") and ultrasonic components. These responses, particularly the two first peeps which have been shown to be triggered by A delta- and C-fibers, could provide a useful tool in pain studies. In the present study, we aimed to optimize this test by investigating the influence of respiration on the vocal responses. The following results were obtained: 1) As expected, the vocalization periods were concomitant with expiration; 2) The phase of the respiratory cycle at the onset of stimulation did not modify the mean intensities of the peeps; 3) The lung volume at the onset of stimulation significantly influenced the intensity and duration of the first peep and the latency of the second peep. Taking account of respiratory parameters in pain tests based on a quantified analysis of vocal responses could improve their sensibility by reducing variability and their specificity by detecting confounding factors such as effects of drugs on respiratory centres or on motor function.

The involvement of the dorsal part of the caudal medulla in both the transmission and modulation of pain is supported by recent electrophysiological and anatomical data. In this review, we analyse the features of a well-delimited area within the caudal-most aspect of the medulla, the subnucleus reticularis dorsalis (SRD) which plays a specific role in processing cutaneous and visceral nociceptive inputs. From a general viewpoint, the reciprocal connections between the caudal medulla and spinal cord suggest that this area is an important link in feedback loops which regulate spinal outflow. Moreover, the existence of SRD-thalamic connections put a new light on the role of spino-reticulo-thalamic circuits in pain transmission.

Nociception is related to the mechanisms elicited by stimuli threatening the integrity of the organism. At the peripheral level, unmyelinated C fibres (C polymodal nociceptores) or fine myelinated A delta fibres are excited by noxious stimulation, directly or indirectly by inflammatory processes. Nociceptive afferent fibres terminate in the superficial laminae of the dorsal horn of the spinal cord where informations are integrated and controlled. These first synapses are modulated by excitatory amino acids (glutamate and aspartate) and many peptides (substance P, CGRP, CCK, endogenous opiods). The majority of ascending pathways involved in nociception are located in the ventrolateral controlateral quadrant of the cord (spinorelicular and spinothalamic tracts). Many supraspinal sites are activated following nociceptive stimuli, with relays in the reticular formation of the brain stem (including the subnucleus reticularis dorsalis), the ponto-mesencephalic regions (periaqueducal gray matter and parabrachial area) and thalamic sites. Amygdala and hypothamic targets could be involved in motivational reactions and neuroendocrine adaptations to a noxious event. The cingular, insular and somatosensory cortices also receive nociceptive informations. Nociceptive signals are modulated at all levels of their transmission; the more extensively studied controls are located at the spinal level. Segmental controls are inhibitory effects produced by non-noxious mechanical stimuli. Spinal signals can also be inhibited following activation of bulbopinal descending inhibitor pathways and release of serotonin, norepinephrine and, indirectly, endogenous opiods. Inhibitory controls triggered by noxious stimuli could facilitate the extraction of the nociceptive tone of informations having priority over other stimuli.

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 rats. Such reflex responses can be inhibited by applying noxious conditioning stimuli to heterotopic areas of the body. These inhibitory processes have been termed diffuse noxious inhibitory controls. The responses were recorded before, during and after the immersion of the tail in a thermoregulated waterbath (at 50 degrees C) for 1 min. The C-fibre reflex responses were depressed by a maximum of 71 +/- 3% at 45 s after the start of such conditioning stimuli. A dose of 3 mu g/kg buprenorphine completely blocked the inhibition and post-stimulus effects triggered by the heterotopic noxious stimuli. In the 0.3-3 mu g/kg range, buprenorphine increased, in a dose-dependent manner, the magnitude of the inhibition. These doses did not produce any changes in the C-fibre reflex itself. The results are discussed in terms of the mechanisms underlying the analgesic properties of buprenorphine.

In normal subjects, the application of heterotopic painful stimuli induces simultaneous and parallel decrease in the sensation of pain and of the spinal nociceptive flexion (RIII) reflex evoked by electrical stimulation of the sural nerve. This inhibition of the RIII reflex is absent in tetraplegic patient with clinically complete spinal cord transections and can be triggered only from the analgesic hand in patients with Wallenberg's syndrome. These findings suggest that the inhibitory phenomena observed in normal subjects are likely to be examples of diffuse noxious inhibitory controls (DNICs), being sustained by a loop involving supraspinal structures, the ascending part of which is localized in the spinoreticular tract. We now report an exceptional case of a patient with Brown-Séquard syndrome due to a 4-year-old spinal cord lesion (left side, T-6 level) produced by a knife-wound in the back. Nociceptive flexion (RIII) reflexes elicited by stimulation of cutaneous afferents in the ulnar and sural nerves were studied in the upper and lower limbs by recording from the biceps brachialis and biceps femoris muscles, respectively. For each limb, the RIII reflex threshold was determined. The reflex was then elicited regularly by stimuli of 1.2 times threshold before, during, and after periods of nociceptive electrical conditioning stimulation (15 mA; 4 Hz; 1 min) applied successively to the other three limbs.(ABSTRACT TRUNCATED AT 250 WORDS)

A C-fibre reflex elicited by electrical stimulation within the receptive field of the sural nerve was recorded from the ipsilateral biceps femoris muscle in anaesthetized rats. Recruitment curves were built by varying the stimulus intensity from 0 to 50 mA and temporal evolution was studied by using a constant level of stimulation. At a constant level of stimulation, intrathecal administration of morphine resulted in a depressive effect on the C-fibre reflex in the 0.18-0.75 microgram range (ED50 = 0.2 microgram). Study of the recruitment curves showed that, in the 0.18-0.375 microgram range, morphine had little effect on the threshold, but induced significant decreases in the slopes. At doses above 0.75 microgram, morphine modified both the threshold and the slope of the recruitment curves. Systemic naloxone totally reversed these effects. It is concluded that intrathecal morphine not only produces a shift in the encoding functions of the spinal cord but also reduces the gain of these functions. It is suggested that this method is reliable for the pharmacological study of the spinal transmission of nociceptive signals.

The aim of this study was to investigate whether the rostral ventromedial medulla (RVM) participates in the lifting of diffuse noxious inhibitory controls (DNIC) by systemic morphine. The effects of morphine (1 mg/kg i.v.) on DNIC were compared in sham-operated rats and animals with electrolytic lesions of the RVM performed one or three weeks earlier. The C-fibre-evoked responses of spinal dorsal horn convergent neurones were similar in the sham-operated and lesioned animals. DNIC acting on these responses were also similar in these groups. DNIC were similarly reduced naloxone reversibly following morphine injections in sham-operated animals and animals tested one week after lesioning of the RVM. In contrast, DNIC were not significantly altered by morphine in animals tested three weeks after lesioning. The lesions were similar in both groups of animals. This time-dependent attenuation of the effects of morphine indicates that the RVM is not directly involved in the reduction of DNIC induced by systemic morphine. However, it is suggested that lesions in this region can induce a reorganization of brainstem opioidergic systems.

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.

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)

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 degrees 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.

Small amounts of the retrograde tracer WGA-apoHRP-Au complex were injected in the caudal medulla to study the spinal afferents to the subnucleus reticularis dorsalis (SRD). Labelled neurones were found at all levels of the spinal cord: the highest numbers were in the ipsilateral cervical spinal cord (mainly laminae I, V, VI, VII, VIII and X), the lowest were at the thoracic and lumbar levels bilaterally, while an intermediate density was found bilaterally at the sacral level. When injection sites were located in the underlying subnucleus reticularis ventralis (SRV), labelling was bilateral and mainly in the deep layers of the cervical spinal cord. Together with our previous electrophysiological and anatomical data, this study suggests that the SRD provides a link in spino-reticulo-spinal loops implicated in the processing of pain.

Recordings were made from neurons in subnucleus reticularis dorsalis of the rat. Two populations of neurons could be distinguished: those with total nociceptive convergence which were driven by activating A delta- and C-fibers from any part of the body and those with partial nociceptive convergence which were driven by activating A delta-fibers from any part of the body or C-fibers from some, mainly contralateral, regions. The effects on subnucleus reticularis dorsalis neurons of manual acupuncture, performed by a traditional Chinese acupuncturist at the "Renzhong", "Sousanli", "Changqiang", and "Zusanli" acupoints and at a non-acupoint next to "Zusanli", were studied. Acupuncture stimulation for 30 s at the acupoints or the non-acupoint strongly excited all the total nociceptive convergence neurons tested; these neurons responded with a discharge of rapid onset which was often followed by after-discharges lasting for approximately 30-60 s. The majority but not all of the partial nociceptive convergence neurons responded to 30 s of acupuncture stimulation at the acupoints or the non-acupoint. This was especially the case when the stimulus was applied to contralateral or midline parts of the body. The potency of acupuncture as a means of activating subnucleus reticularis dorsalis neurons varied significantly with the area of the body being stimulated such that: contralateral greater than midline greater than ipsilateral areas. The levels of induced activity were of similar magnitude to those evoked by noxious mechanical stimuli applied under identical experimental conditions. No differences were found between the capacities to activate subnucleus reticularis dorsalis neurons of the "Zusanli" point and the adjacent non-acupoint, no matter whether these were stimulated ipsi- or contralaterally; this suggests a lack of topographical specificity in the activation of these neurons. Since subnucleus reticularis dorsalis neurons are activated exclusively or preferentially by noxious inputs, it is concluded that the signals elicited by manual acupuncture travel through pathways responsible for the transmission of nociceptive information. Since acupuncture, a manoeuvre which is known to elicit widespread extrasegmental antinociceptive effects, activates subnucleus reticularis dorsalis neurons which, anatomically, send dense projections to the dorsal horn at all levels of the spinal cord, we would suggest that this structure may be involved not only in signalling pain but also in modulating pain by means of spino-reticulo-spinal feed-back mechanisms.

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.

In normal subjects, heterotopic painful stimuli induce simultaneous and parallel decreases in the sensation of pain and in the spinal nociceptive flexion (RIII) reflex evoked by electrical stimulation of the sural nerve. This inhibition of the RIII reflex is not seen in tetraplegic patients with clinically complete spinal cord transection, suggesting that supraspinal structures are involved in this type of inhibition, mediated through 'Diffuse Noxious Inhibitory Controls' (DNIC). In the present study, the effects of heterotopic nociceptive stimuli on the RIII reflex were examined in 3 patients with unilateral thalamic vascular lesions and in 3 with Wallenberg's syndrome (WS). In the former, as in normal subjects, nociceptive electrical conditioning stimuli applied to the analgesic hand produced a profound inhibition of the RIII reflex followed by long-lasting after-effects. No inhibition was observed in the WS patients. The same conditioning procedure applied to the nonanalgesic hand of the WS patients resulted in inhibition and after-effects similar to those observed in normal subjects. The fact that noxious but nonpainful stimuli triggered DNIC in the patients with thalamic lesions excludes the possibility that masking of pain by a second painful focus is mainly due to attentional processes. It is also concluded that lemniscal and spinothalamic pathways are not involved in the triggering of DNIC in man and it is suggested that the brainstem and probably the spinoreticular tract are key neuronal links in the loop subserving DNIC in man.

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.

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.

Electrophysiological recordings were made from spinal and trigeminal dorsal horn convergent neurones which allowed the investigation of some mechanisms underlying Diffuse Noxious Inhibitory Controls (D.N.I.C.) to be made. These controls are exclusively triggered by the activation of A delta and/or C peripheral fibres and involve a supraspinal loop. The ascending and descending parts of the looped pathway are confined within the anterolateral quadrants and the posterolateral funiculi respectively.

Assuming a relatively high background activity of convergent neurons, we have suggested that their pain-signalling message could consist in the contrast between the high rate of firing in the segmental neuronal pool induced by the painful focus and the D.N.I.C.-mediated silence of the remaining neuronal population. This notion is substantiated by several observations in the rat regarding morphine analgesia: a clear lifting of D.N.I.C. is observed following systemic (0.1-1 mg/kg; i.v.), intraventricular (0.6-2.5 micrograms) or intrathecal (15 micrograms) morphine. All these procedures could restore the initial level of background activity, analgesia resulting from the attenuation of the postulated contrast.

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.

The effects of ES 52, a highly potent derivative of the enkephalinase (enkephalin-dipeptidylcarboxypeptidase) inhibitor thiorphan, were studied on nociceptive activities of dorsal horn convergent neurones in the anaesthetized rat. Neither the C-fibre component of the responses elicited by supramaximal electrical stimulation of the hindpaw excitatory receptive fields nor diffuse noxious inhibitory controls triggered by immersion of the tail in 46-48 degrees C waterbaths, were affected by ES 52. Thus we conclude that, in our experimental conditions, modulations of the transmission of nociceptive messages at the spinal level are not greatly modified by specifically blocking the degradation of enkephalins. If a major role for enkephalinase (vs aminopeptidase) in the catabolism of enkephalins at the spinal level can be confirmed, then comparison of the present data with our previous results obtained using the opioid antagonist naloxone, might suggest a predominant role for proenkephalin B products (i.e. dynorphins and/or alpha-neo-endorphin) in modulating nociceptive transmission in the spinal cord.

The heterotopic effects of peritoneo-visceral pain were investigated in behavioural and electrophysiological experiments performed on rats. The intraperitoneal administration of acetic acid (i.p. AA), an algesic agent commonly used to induce writhing behaviour in rodents, was used as a conditioning stimulus in two parallel series of experiments involving 3 behavioural tests and recordings of dorsal horn convergent neurones. The responses to a nociceptive stimulus applied to the tail or paws were lowered by i.p. AA but these effects depended on the behavioural test used: in the tail-flick test, AA produced a transient low magnitude increase in latencies; the threshold for vocalization induced by electrical stimulation of the tail was clearly (25%) and sustainedly (full recovery taking up to 1 h) increased; the jump latency in hot plate was markedly increased (100% at 15 min). Intraperitoneal AA strongly depressed the C fibre evoked responses of coccygeal convergent neurones to suprathreshold transcutaneous electrical stimulation applied on their tail excitatory receptive fields. The time course of these inhibitory effects roughly paralleled the behavioural hypoalgesic effect observed in the vocalization test. These results are discussed with reference to diffuse noxious inhibitory controls (DNIC). Analogies with counter-irritation phenomena are emphasized.

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)

It has been shown that morphine could interact with supraspinal inhibitory controls which modulate the transmission of nociceptive messages at the spinal level. However, the way in which such interactions occur is still a subject of controversy. Based on behavioural experiments, it has been proposed that systemic morphine increases descending inhibitory controls travelling via the dorsolateral funiculus (DLF). To directly test this hypothesis from an electrophysiological standpoint, we have investigated the effects of morphine upon C-fibre responses of dorsal horn convergent neurones in rats with bilateral lesions of the DLF. Previous studies by our group have shown that 6 mg/kg morphine chlorhydrate was the intravenous mean effective dose for depressing by 50% (ED50) the C-fibre evoked responses of convergent neurones recorded at the lumbar level. In the present work, the effects of 6 mg/kg morphine were investigated under identical experimental conditions, except that a bilateral destruction of the dorsolateral funiculus (DLF) was performed previously. These lesions did not change the mean C-fibre evoked responses. Following morphine administration, the C-fibre evoked responses were depressed by 47.1 +/- 10.1% (n = 13) and reversal of these effects by naloxone was always observed. The A-fibre evoked responses, concurrently recorded, were not modified by the drug. As the depressive effects observed with this dose of morphine appear to be essentially of the same magnitude as those previously found in the intact or spinal preparations, we conclude that the DLF is not involved in the depressive effects of systemic morphine on dorsal horn convergent neurones.

Activity produced by direct microelectrophoretic application of glutamate onto 19 convergent neurones in trigeminal nucleus caudalis, was strongly depressed during and after the application of heterotopic noxious conditioning stimuli: noxious heat (52 degrees C) applied to the tail, noxious pinches applied to the tail or hindpaws and intraperitoneal injections of bradykinin produced mean reductions in activity of 80-90%. The same noxious conditioning stimuli had no effect on the activities of any of 5 noxious-only or 5-non-noxious-only neurones. These effects were similar to those previously reported to influence peripherally evoked activities of nucleus caudalis convergent neurones and which have been termed diffuse noxious inhibitory controls (DNIC). It is therefore proposed that DNIC act on nucleus caudalis convergent neurones by a final post-synaptic inhibitory mechanism involving hyperpolarization of the neuronal membrane. Consistent with this hypothesis, it was also found that the noxious conditioning stimuli could restore firing of convergent neurones which had been excessively depolarised by large doses of glutamate.

Fifty-eight lumbar dorsal horn and trigeminal nucleus caudalis neurones which could be activated by both innocuous and noxious peripheral stimuli have been recorded in the anaesthetized rat. Using transcutaneous electrical stimulation to produce A and C fibre activity in these neurones from the hindpaw or facial receptive fields the ability of a distant noxious (mechanical or thermal) stimulus applied to the nose, tail, ears and paws to inhibit the neuronal activity was demonstrated. These effects have been termed diffuse noxious inhibitory controls (DNIC). DNIC produced powerful long-lasting inhibitions on all units studied in accordance with our previous results. Approximately 40% of these convergent neurones could be antidromically activated from the contralateral ventrobasal thalamus. Similar neuronal characteristics, effects of DNIC and proportions of projection cells were found in both the dorsal horn and trigeminal complex. However, the spinothalamic tract cells conducted more rapidly than the trigeminothalamic neurones. These results indicate that DNIC can produce comparable effects on the thalamic representation of the efferent activity of these spinal cord and trigeminal neurones. The possible role of DNIC in nociception is discussed.

Recordings were made from convergent neurones in the nucleus caudalis of the trigeminal complex. They could be excited by both innocuous and noxious stimuli applied to their excitatory receptive field located on the ipsilateral part of the muzzle. The responses to A- and C-fibre activation induced by supramaximal transcutaneous electrical stimulation of their receptive fields were conditioned by thermal stimuli applied to the tail, and the relationship between the conditioning temperatures and their ability to induce inhibitions of the evoked discharges of convergent neurones were investigated. During sequences of repetitive stimulation, the posterior two-thirds of the tail were immersed in a waterbath at various temperatures (36-52 degrees C) and the resultant inhibitions of responses were calculated. The threshold for obtaining an inhibitory effect ranged between 40 and 44 degrees C. Above this level, there was a highly significant correlation between the conditioning temperature and the degree of inhibition, which was very strong for the highest temperature (i.e. for 52 degrees C: 54.4 +/- 7.3 and 92.3 +/- 3.7% inhibitions being obtained for A- and C-fibre-evoked responses respectively); such a correlation concerned the inhibitions observed both during immersion of the tail and after the removal of the conditioning stimuli. In further experiments, identical conditioning stimuli were tested upon responses of trigeminal convergent neurones to microelectrophoretic applications of an excitatory amino acid, DL-homocysteate, and very similar results were obtained: a threshold for inhibition in the 40-44 degrees C range and a significant correlation between the conditioning temperature and the degree of inhibition in the 44-52 degrees C range (52 degrees C giving inhibitions of 98.8 +/- 0.4%.(ABSTRACT TRUNCATED AT 250 WORDS)

In order to investigate possible changes induced by noxious thermal stimuli in the activity of enkephalinergic neurones at various levels of the spinal cord, either the whole cord, the cervicotrigeminal area or the lumbar area were perifused with artificial CSF at a rate of 0.1 ml/min in halothane anaesthetized rats, and Met-enkephalin-like material (MELM) was measured in 0.5 ml fractions collected from the perifusates. Immersing the muzzle of intact rats in water at 52 degrees C produced a significant enhancement of MELM content in perifusates from both the whole spinal cord and the cervicotrigeminal area but not from the lumbar area. Heating the tail resulted in an increase in MELM release from the whole spinal cord of intact as well as of cervically transected rats. It is concluded that noxious thermal stimuli can induce a segmental release of MELM, i.e., only within spinal zones receiving the nociceptive inputs.

Reciprocal inhibitory influences of heterotopic nociceptive stimuli have been known for centuries (counter-irritation phenomena). To assess whether such phenomena could be measured objectively in a chronic pain model, we have investigated the writhing behaviour induced by a viscero-peritoneal nociceptive stimulus (i.p. acetic acid) in arthritic rats. The latter was induced by s.c. injection of mycobacterium butyricum suspended in oil into the base of the tail and experiments carried out at various (1-9 weeks) post-inoculation periods. To assess the arthritis-induced hyperaesthesia, the threshold for struggle triggered by a calibrated pressure applied on an inflamed hindpaw (Randall-Selitto test) was measured before each experiment. A clear relationship was observed between the two parameters during the evolution of the disease. In the most severe phase (2nd to 5th week post-inoculation), when arthritis-induced hyperaesthesia was most pronounced (50% reduction of the threshold for struggle), writhing behaviour was strongly reduced (80%). At that time, writhing behaviour was enhanced by naloxone (0.4 mg/kg i.v.). In the following period (5-9 weeks), the progressive decrease of hyperaesthesia was correlated with a recovery of the writhing behaviour. We conclude that in this chronic pain model, the behavioral reaction to a viscero-peritoneal nociceptive stimulus is impaired. Endogenous opioid systems could be involved in this phenomenon. Such heterotopic inhibitory processes could be relevant to some paradoxical clinical observations such as the masking of a pain by the experience of pain at another locus.

In spinal preparation, morphine exerts a specific direct inhibitory action on the activities of dorsal horn neurones induced by noxious stimuli. The effect of morphine is preferential for the responses evoked by A delta and C fibre afferents and its specificity of action has been demonstrated pharmacologically in terms of isomerism, dose dependency and reversal of the inhibitions by opiate antagonists. These results are in good agreement with recent data related to the localization at the spinal level of opiate receptors, and terminal rich in Enkephalin and substance P. Numerous behavioural and pharmacological investigations suggest that morphine is also acting at the level of the brainstem by reinforcing the activity of descending control systems which modulate the transmission of noxious inputs at the spinal level. However this second modality of action remains extremely difficult to demonstrate from an electrophysiological point of view.

Intensely noxious peripheral stimuli of the anaesthetized rat produce two changes in the activity of convergent dorsal horn units: the segmental neuronal pool is activated, while all other convergent neurones are inhibited. These Diffuse Noxious Inhibitory Controls (DNIC) are highly potent (60-80% inhibition) and suppress all convergent neuronal activity, whether spontaneous or evoked by noxious or nonnoxious stimuli. On the other hand, they have no effect on other dorsal horn cell types, including noxious-only and proprioceptive units. The "DNIC" circuits include at least one supraspinal relay since DNIC is not seen in spinal animals. Furthermore, they are greatly reduced by lesions of the Nucleus Raphé Magnus (NRM). It has been shown that this nucleus massively projects onto the spinal cord, in particular onto the dorsal horn, and that stimulation of the NRM results in convergent unit inhibition of the same degree of magnitude as with DNIC. The role of serotonergic mechanisms in DNIC can be demonstrated pharmacologically: pCPA pre-treatment (3 daily I.P. injections, 300 mg/kg) or cinanserin (4 mg/kg I.V.) both result in a potent decrease (50-80%). We have proposed that the nociceptive message from the convergent units could result in a contrast between activity of the activated segmental pool and silence of the remaining convergent units. If this hypothesis can be verified, then some raphé nuclei and brain stem serotonergic pathways may function as filters in the detection of nociceptive messages, allowing extraction of information from somatic background activity including the firing from peripheral mechanoreceptors. While superficially paradoxical in fact our hypothesis fits well with the observation of profound analgesia following NRM stimulation: indeed, this hypothetical contrast would be completely eliminated by NRM stimulation since both neuronal pools would then be inhibited.

(1) Diffuse noxious inhibitory controls (DNIC) were tested for their effect on noxious only, non-noxious and proprioceptive cells in the dorsal horn of the intact anaesthetized rat. Unlike convergent neurones, as described in the previous paper, there was no effect of DNIC on these neurones. It is concluded that convergent neurones are specifically inhibited by DNIC. (2) The effect of DNIC could not be demonstrated for convergent neurones in the spinal animal. Thus the neuronal substrate for DNIC must involve supraspinal structures. (3) Because of the level of firing in convergent neurones induced by hair and touch receptors, presumably constantly and randomly activated in the freely moving animal, a noxious message arriving at higher centres may be partly masked by this background noise. On the basis of the known role of convergent neurones in nociception, we propose the following mechanism which may interpret this paradoxical convergence: two pools of convergent neurones are influenced by a painful peripheral stimulation, one segmental pool being activated whilst the remaining population of cells is inhibited; the "contrast" between the messages from these two pools may well produce a significant pain signalling output from the convergent dorsal horn cells. (4) These results and their theoretical implications are discussed with regard to the concept of the "analgesic system", certain clinical observations and the paradoxical pain relieving effects of counterirritation and some forms of acupuncture.

Perfusion of the intrathecal space with artificial CSF was achieved in control and arthritic rats under halothane anaesthesia in order to collect the met-enkephalin-like material (MELM) released from the whole spinal cord. On the fourth week following the intradermal injection of Freund's adjuvant to induce arthritis, a marked reduction (-56%) in the spontaneous outflow of MELM was noted in arthritic rats. This effect did not involve changes in the degradation process of MELM, since it persisted when kelatorphan was added to the perfusing fluid in order to inhibit completely the peptidases acting on met-enkephalin. Raising the K+ concentration in the perfusing fluid from 2.4 to 40 mM, as well as moving the hind paws, produced a significant enhancement of MELM release which was (at least) as pronounced in arthritic as in control rats. These results suggest that the basal activity of spinal enkephalinergic neurones, but not that triggered by various stimuli, is reduced in arthritic rats.

Nineteen convergent neurones, 19 'non-noxious only' neurones and 13 'proprioceptive' neurones all with peripheral excitatory receptive fields on the ipsilateral hindpaw, were recorded in the lumbar dorsal horn of non-spinalized, anaesthetized rats. These neurones were all excited by the electrophoretic application of glutamate; using 20 s applications of appropriate electrophoretic currents, almost identical levels of activity (around 30 spikes/s) were produced for each of the 3 types of neurones. The application of heterotopic noxious stimuli resulted in strong inhibitions of the glutamate-evoked activity of the convergent neurones. During the application of noxious heat (52 degrees C) to the tail and noxious pinches to the tail, contralateral hindpaw and muzzle, the glutamate-evoked activity was depressed by 78%, 84%, 63% and 59%, respectively. It was also found that these inhibitions outlasted the period of conditioning stimulation by several minutes (post-effects). Twenty seconds after i.p. injection of bradykinin (20 micrograms) the glutamate-evoked activity was depressed by 56% and this effect also lasted for several minutes. The application of identical heterotopic noxious stimuli did not affect the glutamate-evoked activity of the 'non-noxious only' neurones or the 'proprioceptive' neurones. The application to convergent neurones, of doses of glutamate, which were very much larger than the threshold for firing, produced an intense discharge followed by a progressive decrease in spike amplitude and finally a blocking of the spike discharge. During such sequences, which are typical of excessive depolarization, the application of noxious conditioning stimuli (e.g pinch of the contralateral hindpaw or muzzle) resulted in recovery of the spike discharge. In several cases, this recovery long outlasted the period of conditioning noxious stimulation.(ABSTRACT TRUNCATED AT 250 WORDS)