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Biomedical subjects

Daniel Le Bars

Publications and source records attributed to Daniel Le Bars.

15 recordsLinked to original sources
PubMed2006

Tolerance to morphine analgesia: evidence for stimulus intensity as a key factor and complete reversal by a glycine site-specific NMDA antagonist.

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

Analgesics, Opioid↗
PubMed2005

Hyperalgesia and allodynia: peripheral mechanisms.

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.

Humans↗
PubMed2002

Depressant effect on a C-fibre reflex in the rat, of RB101, a dual inhibitor of enkephalin-degrading enzymes.

The effect of N-[(R,S)-2-benzyl-3[(S)-(2-amino-4-methylthio)butyldithiol]-1-oxopropyl]-L-phenylalanine benzyl ester (RB101), a dual inhibitor of the enkephalin-degrading enzymes, neutral endopeptidase and aminopeptidase N, was assessed in anaesthetised rats on the C-fibre reflex elicited by electrical stimulation within the sural nerve territory and recorded from the ipsilateral biceps femoris muscle. The temporal evolution of the pharmacological response was monitored by the repeated application of a constant stimulus intensity, namely three times threshold (3 T). In addition, recruitment curves were built by varying the stimulus intensity from 0 to 7 T. RB101 (7.5, 15 and 30 mg kg(-1), i.v.) induced a dose-dependent, naloxone-reversible depression of the reflex, which lasted around 60 min with the highest dose. The ED(50) was calculated as 16.9 mg kg(-1). Analyses of the recruitment curves revealed: (1) a significant increase of threshold; (2) a significant depression of the reflex in the ascending part of the curve; and (3) a lack of major depressive effects on the responses elicited by the strongest stimuli (corresponding to the plateau of the curve). The increase in the nociceptive threshold by enkephalin-degrading enzyme inhibitors, confirms previous data obtained from behavioural tests. In addition, the present study revealed an efficacy of these compounds over a wide range of stimulus intensities, albeit excluding the highest.

Aminopeptidases↗
PubMed2002

The whole body receptive field of dorsal horn multireceptive neurones.

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

Animals↗
PubMed2001

Activation of diffuse noxious inhibitory controls (DNIC) in rats with an experimental peripheral mononeuropathy.

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

Animals↗
PubMed1995

Dorsal horn convergent neurones: negative feedback triggered by spatial summation of nociceptive afferents.

In order to investigate the effects of spatial summation on the spinal transmission of nociceptive information, we compared in intact and spinal anaesthetized rats, responses of lumbar convergent neurones elicited by noxious heat stimuli applied to areas of the body much greater in size than their individual excitatory receptive fields, located distally on the hindpaw. Twenty-four neurones were recorded in each group of animals. For each neurone, 4 successive immersions of increasing areas (1.9-18 cm2) of the ipsilateral hindpaw in a 48 degrees C water bath (15-sec duration) were performed with 10-min intervals in a randomized and balanced order. In intact animals, the responses of convergent neurones progressively decreased when the area of noxious thermal stimulation reached and then exceeded approximately twice the area of their individual excitatory receptive fields. This decrease was highly significant for 18 cm2 which represents approximately 10-fold the mean of the receptive field areas. Such a phenomenon was not observed for neurones recorded in spinal animals although their excitatory receptive field areas were not significantly different. These results suggest that the activation of a large population of nociceptive afferents triggers supraspinally mediated negative feed-back loop modulating the responses of convergent neurones.

Analysis of Variance↗
PubMed1992

Morphine blocks descending pain inhibitory controls in humans.

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.

Adult↗
PubMed1988

Effects of tizanidine (DS 103-282) on dorsal horn convergent neurones in the rat.

The effects of tizanidine, a new muscle relaxant, 5-chloro-4-(2-imidazolin-2-yl-amino)-2,1,3-benzothiazole (DS 103-282) were studied on the activity of lumbar dorsal horn convergent neurons in anaesthetized paralysed rats. Following i.v. administration of tizanidine both the A- and C-fibre evoked responses were depressed in a dose-dependent manner in the 0.125-1.0 mg/kg range. The smaller dose employed (0.125 mg/kg) induced a significant depression of the C-fibre evoked responses (39.6 +/- 13.4% of the control responses) and a total recovery was observed 10 min after the injection: when the doses were increased, stronger and longer-lasting depressant effects were obtained. Identical but less powerful effects were observed on A-fibre responses. None of the depressive effects was correlated with variations in blood pressure. Microelectrophoretically applied tizanidine was found to depress current-dependently, the discharges of convergent neurones evoked by microelectrophoretically applied DL-homocysteic acid. In contrast, tizanidine (0.5, 1 mg/kg; i.v.) was found to be ineffective against the activities of non-nociceptive neurones triggered by mechanical stimulation of their receptive fields. It is concluded that tizanidine depresses specifically the activities of dorsal horn convergent neurones, probably in part by a post-synaptic inhibitory action. Owing to the role of convergent neurones in pain processes, the present result could explain, at least partially, the analgesic action of this compound.

Action Potentials↗
PubMed1987

Dorsal horn (convergent) neurones in the intact anaesthetized arthritic rat. II. Heterotopic inhibitory influences.

Recordings were made from dorsal horn neurones in the spinal cord and trigeminal nucleus caudalis of intact anaesthetized rats. These rats had been rendered polyarthritic by s.c. injection of Mycobacterium butyricum suspended in oil into the base of the tail. The experiments were carried out during the acute phase of the illness (3-4 weeks post inoculation) during which hyperalgesia occurred. The disease mainly affected the hind paws and the tail and, to a lesser extent, the forepaws. The facial area of the animals was not at all affected. As described in a previous paper, recordings from lumbar dorsal horn neurones revealed that two subpopulations could be described on the basis of their electrophysiological characteristics. Namely, 'typical' units which include convergent, non-noxious and proprioceptive neurones and which have properties essentially similar to those found in healthy rats, and 'atypical' cells which have no counterpart in healthy rats and which include convergent and non-noxious neurones. All the typical convergent neurones were inhibited by noxious stimuli applied to heterotopic body areas, whereas typical non-noxious and proprioceptive neurones were not; these observations are similar to those described in healthy rats as diffuse noxious inhibitory controls (DNIC). However, it was also found that 88% of the atypical convergent and 85% of the atypical non-noxious cells were inhibited by various heterotopic stimuli. The most important observation was that gentle stimulation such as mild pressure applied to the inflamed contralateral ankle joint--a stimulus intensity which has never been found to be effective in healthy animals--was capable of triggering inhibition of both typical and atypical convergent neurones. Recordings from trigeminal nucleus caudalis neurones revealed that the entire population presented essentially the same properties as those observed in healthy animals in terms of activity evoked by natural or electrical stimulation of their excitatory receptive fields. The activity of non-noxious neurones was never modified by any heterotopically applied stimuli. By contrast, all convergent neurones were inhibited by heterotopic stimuli, noxious (52 degrees C, pinch) or non-noxious (light and mild pressure), applied to inflamed areas. While the inhibition triggered by noxious stimuli was reminiscent of that observed in healthy rats, the inhibition triggered by non-noxious mechanical stimuli was related to the inflammatory state of the part of the body stimulated, the most sensitive areas being the hind paws.(ABSTRACT TRUNCATED AT 400 WORDS)

Afferent Pathways↗
PubMed1987

Dorsal horn (convergent) neurones in the intact anaesthetized arthritic rat. I. Segmental excitatory influences.

Recordings were made from dorsal horn neurones in intact anaesthetized rats rendered polyarthritic by s.c. injection into the base of the tail, of Mycobacterium butyricum suspended in oil; the experiments were carried out during the acute phase of the illness (3-4 weeks post inoculation) during which hyperaesthesia occurred. The majority (60.8%) of the neurones studied had properties close to those of corresponding groups of units in healthy rats. These 'typical' neurones could be subdivided into convergent (13.2%), non-noxious (34.4%) and proprioceptive (13.2%) units. By contrast, and in agreement with a previous study in the unanaesthetized spinal arthritic rat, the segmental electrophysiological characteristics of the remaining large proportion of neurones were changed both in terms of the size and distribution of their excitatory receptive fields and their responsiveness to peripheral stimuli; these were designated as 'atypical' neurones. According to their electrophysiological properties, these neurones were differentiated as atypical convergent (27.8%) and atypical non-noxious (11.4%) units. The main qualitative difference between the typical and atypical neurones was that the atypical had an additional receptive field on the oedematous ipsilateral ankle and, in several cases, showed high levels of background activity with sometimes dramatic increases. By comparison with neurones recorded in healthy rats, quantitative data revealed other modifications: typical and atypical convergent neurones and atypical non-noxious neurones had larger classical excitatory receptive fields; while C-fibre responses evoked by transcutaneous electrical stimulation were facilitated in the case of typical convergent neurones, 47% of the atypical convergent neurones had no C-fibre responses, and when present (53%) the threshold for obtaining these C-fibre responses was higher with suprathreshold stimuli producing a minimal number of spikes; in these cells, gentle mechanical stimuli gave rise to high rates of firing which sometimes resulted in dramatic, long lasting after-discharges. The possibility that typical convergent, atypical convergent and atypical non-noxious neurones were derived from the homogeneous population of convergent neurones in the healthy rat is discussed; the atypical properties could be the result of a change in the characteristics of convergent neurones, resulting from arthritis.

Animals↗
PubMed1986

Indirect effects of intrathecal morphine upon diffuse noxious inhibitory controls (DNICs) in the rat.

Diffuse noxious inhibitory controls (DNICs) affect all convergent neurones recorded in the dorsal horn of the spinal cord or the nucleus caudalis of the trigeminal system. They are triggered specifically by heterotopic noxious stimulation. DNICs acting at the trigeminal level were triggered by noxious thermal stimulation of caudal parts of the body, and the effects of intrathecal morphine applied at the coccygeal level were tested. The immersion of the right hind paw or of the tail induced inhibitions on C-fibre responses of trigeminal convergent neurones of 95.8 +/- 2.8% and 93.8 +/- 2.4+ respectively. Intrathecal morphine (15 micrograms; 20 microliters) produced an almost complete blockade of inhibitions triggered from the tail without significantly affecting those triggered from the hind paw. A reversal by systemic naloxone (0.4 mg/kg i.v.) was obtained in all cases. These results indicate that intrathecal morphine induced a segmental depression of nociceptive messages strong enough to prevent the spinal initiation of DNICs. We suggest that the segmental depression of nociceptive transmission induced by morphine led to a consequent blockade of DNICs acting on the whole population of convergent neurones not initially affected by the noxious stimulus. These findings are discussed with regard to the strong analgesic effects of intrathecal morphine observed in both behavioural and clinical studies.

Animals↗
PubMed1983

Do convergent neurones in the spinal dorsal horn discriminate nociceptive from non-nociceptive information?

Thirty convergent neurones responding to both noxious and non-noxious cutaneous stimuli were recorded at the lumbar level in either anaesthetized 'intact' rats or unanaesthetized 'spinal' rats. Their responses to radiant heat application and to repetitive innocuous mechanical stimulation of the centre of their receptive fields were analysed, both in terms of the maximal and the mean firing rates. These neurones increased their discharge rates in relation to the temperature applied to their receptive fields with the highest levels being produced by noxious intensities. This finding confirms earlier reports suggesting the capacity of these neurones to encode nociceptive information of thermal origin. However, a very high level of firing could also be evoked by repetitively applied innocuous mechanical stimuli. This was a consistent finding, observed both in intact and spinal animals, which was true for the two subgroups into which we divided the convergent neurones (warming/noxious heat units and noxious heat units). These results are discussed in terms of the role of convergent neurones in nociception. It is suggested that a single channelled signal emanating from these neurones could not be the basis of a clear nociceptive message to the brain; two alternative hypotheses involving multichannelled organizations of impulses are proposed for discussion.

Animals↗
PubMed1979

Diffuse noxious inhibitory controls (DNIC). I. Effects on dorsal horn convergent neurones in the rat.

(1) Sixty-eight convergent dorsal horn neurones have been recorded at the lumbar level in anaesthetized intact rats. All cells received prominent A alpha and C fibre afferents and correspondingly could be activated by high and low threshold stimuli applied to the peripheral excitatory receptive field. (2) The activity of 67/68 of these neurones was powerfully inhibited by noxious stimuli applied to various parts of the body. Since non-noxious stimuli were ineffective in this respect, the term "diffuse noxious inhibitory controls" (DNIC) is proposed. (3) DNIC could be evoked by noxious pinch applied to the tail, the contralateral hind paw, the forepaws, the ears and the muzzle; the most effective areas were the tail and muzzle. Noxious heat applied to and transcutaneous electrical stimulation of the tail were extemely effective in eliciting DNIC as was the intraperitoneal injection of bradykinin. (4) DNIC strongly depressed by 60-100% both the C fibre response following suprathreshold transcutaneous electrical stimulation and the responses to noxious radiant heat. (5) The spontaneous activity and the responses to low threshold afferents induced either by A alpha threshold electrical or natural stimulation were also powerfully inhibited. (6) In the majority of cases, long lasting post-effects directly related to the duration of conditioning painful stimulus were observed.

Animals↗
PubMed1979

Diffuse noxious inhibitory controls (DNIC). II. Lack of effect on non-convergent neurones, supraspinal involvement and theoretical implications.

(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.

Acupuncture Therapy↗