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Biomedical subjects

G Guilbaud

Publications and source records attributed to G Guilbaud.

At least 73 records · Page 4Linked to original sources
PubMed1991

The spectrum of fiber loss in a model of neuropathic pain in the rat: an electron microscopic study.

Recently, Bennett and Xie reported that when the sciatic nerve of the rat is ligated loosely, the rat develops a pain syndrome with many features similar to those observed in neuropathic pain states in man. Anatomical and physiological studies to date indicate that the major pathology is a loss of large diameter myelinated fibers distal to the ligatures, with more subtle changes in small myelinated fibers. With a view to evaluating possible changes in the unmyelinated fibers, we have performed an electron microscopic analysis of the sciatic nerve 2 weeks after four ligatures were applied, at which time the animals displayed profound hyperalgesia and mechanical and thermal allodynia. Cross-sectional photomontages of regions proximal and distal to the ligatures were studied. Consistent with light microscopic and electrophysiological studies, we found a near complete loss of large myelinated fibers distal to the ligatures. Phagocytosis of large fibers was common. There was also considerable variation in the damage to small myelinated fibers. In some fascicles many small (less than 3 microns) myelinated axons remained; in other fascicles none could be detected. Importantly, we also found significant changes in the unmyelinated fiber spectrum. Counts of unmyelinated axons revealed a 34% and 71% decrease in the distal compared to the proximal nerve, in the two rats studied. The large clusters of unmyelinated axons that characterize normal nerve (and the nerve proximal to the ligatures) were rarely found distally. Rather, many of the unmyelinated axons coursed singly or in very loose bundles. Many of the surviving axons were shrunken and distorted, although still in contact with Schwann cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Central neurophysiological processing of joint pain on the basis of studies performed in normal animals and in models of experimental arthritis.

On the basis of anatomical and electrophysiological studies, this review summarizes first, the data dealing with the transmission of joint inputs in the central nervous system of normal animals at the spinal and supraspinal levels. It appears that in these conditions neuronal responses to mechanical noxious stimuli of the joints are relatively few and (or) weak. Second, in sharp contrast, the studies performed in polyarthritic rats have emphasized the profound changes in the activities (spontaneous firing and responsiveness) of the somatosensory neurones at various levels of the central nervous system (CNS), including the thalamus and primary somatosensory cortex; many were spontaneously active and a majority of them could be maximally activated by gentle mechanical stimuli applied to the inflamed joints. Although the change in the sensitivity of the peripheral mechanoreceptors has a major role in the modifications described in the CNS, additional observations have suggested a complex interaction between peripheral and central processes. On the basis of the recent data obtained in poly- and mono-arthritic animals; the following phenomena have been successively considered: the segmental and hetero-segmental "cross-talk" and their possible relationship with referred pain; the involvement of "new" neuronal populations as a possible basis of a selective system for joint pain; and the possible involvement of changes in the various control systems that normally modulate the nociceptive inputs at different levels of the CNS.

Animals↗
PubMed1991

[A better understanding of clinical pain. Experimental data on 3 animal models of pain].

For a better understanding of clinical pain, several groups involved in the study of basic pain mechanisms have proposed the use of various experimental models close to clinical situations. These models are based either on neurogenic or inflammatory process. Data obtained with three of these models will be developed in the paper: rats rendered arthritic by Freund's adjuvant injection into the tail, rats with an intraplantar injection of carrageenin in one hindpaw, rats with a moderate ligature of one common sciatic nerve. The various pharmacological approaches revealed dramatic changes of the analgesic effects of morphine and other opioid substances, and a spectacular modification of the endogenous opioid reactivity. A further enhancement of the initial hyperalgesia was observed with high doses (1-3 mg/kg i.v.) of naloxone (known as an antagonist of morphine), contrasting with the paradoxical analgesia induced with the low dose (peaking up for 3 micrograms/kg i.v.). Electrophysiological studies emphasized dramatic changes of neuronal responsiveness in structures involved in the transmission of the nociceptive messages, from the periphery to the cortex. In each of these models electrophysiological data provide new insights on the physiopathological mechanisms of the related clinical pain.

Animals↗
PubMed1990

The bidirectional dose-dependent effect of systemic naloxone is also related to the intensity and duration of pain-related disorders: a study in a rat model of peripheral mononeuropathy.

In an experimental model of mononeuropathy in the rat, created by 4 ligatures around the sciatic nerve, i.v. naloxone 1 week after surgery induces bidirectional effects (antinociceptive effects at very low doses, hyperalgesic effects with high doses). Using the same nociceptive test (vocalization thresholds to paw pressure), the activity of the same doses of naloxone (3 micrograms/kg, and 1 mg/kg) was investigated 2 weeks after sciatic ligation, when the behavioural pain-related disorders are at a maximum. Three micrograms/kg naloxone produced a significant antinociceptive effect on the lesioned and non-lesioned paw, which was clearly related to the degree as well as to the duration of pain-related signs in the rat. By contrast, the high dose of naloxone did not induce a mean significant effect when tested on either paw; however, it elicited a potent hyperalgesic effect in those rats which had recovered from hyperalgesia at this 2 week time point after the sciatic injury.

Animals↗
PubMed1990

Repeated low doses of morphine do not induce tolerance but increase the opioid antinociceptive effect in rats with a peripheral neuropathy.

In rats with a mononeuropathy, repeated low doses of morphine slightly enhanced its own effect in a paw pressure test of the lesioned limb. While the very effectiveness of morphine in neuropathic rats suggests that at least some nociceptive components of neuropathic pain might be sensitive to opioid receptor mechanisms, the absence of a rapid tolerance in this model indicates that tachyphylactic phenomena do not contribute to the reputed clinical ineffectiveness of opioids in neuropathic pain.

Analgesics↗
PubMed1990

Alterations in myelinated fibres in the sciatic nerve of rats after constriction: possible relationships between the presence of abnormal small myelinated fibres and pain-related behaviour.

Morphology or peripheral myelinated fibres was analyzed in rats exhibiting hyperalgesia and allodynia with mechanical and thermal stimuli, consecutive to a mononeuropathy induced by 4 loose ligatures around a sciatic nerve. This preliminary study was based on weeks 2-3 after surgery, the time of the maximum alterations of the pain-related behaviour. At this time, contrasting with a marked decrease of the large afferent fibres a consistent number of much less than 5 micron fibres was pointed out. In addition to their extremely short internodal length, the majority of these fibres had an abnormal g-ratio, thus an abnormal myelin sheath. It is suggested that this group of abnormal fibres might be related to the A delta fibres described in neuromas and involved in pain-related behaviours seen in the mononeuropathic rats.

Animals↗
PubMed1990

Deafferentation in the rat increases mechanical nociceptive threshold in the innervated limbs.

In this study in the rat, we evaluated the effect of unilateral, multiple cervical dorsal rhizotomy (C5-T1) on nociceptive thresholds in the unoperated limbs. This was tested by measuring the vocalization threshold to paw pressure. We report that deafferentation by dorsal rhizotomy results in a delayed, but transient increase in mechanical nociceptive thresholds in the 3 innervated limbs.

Afferent Pathways↗
PubMed1990

Differential effects of various doses of morphine and naloxone on two nociceptive test thresholds in arthritic and normal rats.

In an attempt to clearly gauge the influence of the test used on opioid effects, the present study systemically compares the effects of various doses of morphine and naloxone with 2 differentially integrated tests: a suprasegmentally integrated test, the vocalization threshold to paw pressure and a spinally coordinated reflex, the paw withdrawal to pressure. In both normal and arthritic rats, clear differential effects of the drugs were observed: low doses of morphine (0.3 and 1 mg/kg i.v.) produced marked effects on the vocalization test, especially in arthritic rats, while it was less effective on the paw withdrawal test. Naloxone and morphine at extremely low doses (3-10 micrograms/kg, and 6 micrograms/kg i.v. respectively) clearly produced marked effects on the vocalization test, but failed to modify the paw withdrawal threshold in arthritic rats. By contrast, a high dose of naloxone (1 mg/kg i.v.) induced a comparable decrease in thresholds in both tests. This comparative study clearly shows the interest of using the vocalization threshold to paw pressure as a nociceptive test for evaluation of the antinociceptive effect of opioids. In addition, it provides useful information for a better understanding of the complex effects of morphine and the opioid antagonist naloxone in arthritic rats.

Animals↗
PubMed1990

Further evidence for 'pain-related' behaviours in a model of unilateral peripheral mononeuropathy.

A model of experimental peripheral neuropathy producing pain-related disorders has recently been described in the rat. The present study aimed to investigate, using a different and quantifiable behavioural approach, the abnormal pain-related sensations in the animals. The neuropathy was produced by 4 ligatures tied loosely around the common sciatic nerve. 6-8 days after surgery, most of the rats exhibited pain-related disorders ipsilateral to the sciatic ligation, which became maximal 2 weeks after surgery. Mechanical noxious stimulation (pinching of the hind paw) revealed hyperalgesia in all the animals. Rats also exhibited allodynia when tested with the vocalization threshold test to paw pressure (mean vocalization thresholds were 65.5 +/- 3.6% of the preoperative control, P less than 0.01, n = 95). Tests using heat (40, 42, 44, 46 degrees C) and cold (10 degrees C) stimulation (immersion of the rat's hind paw in a bath until it was observed to struggle) indicated hyperalgesia to noxious heat (decrease of 30% in the immersion duration (ID) at a temperature of 46 degrees C), and allodynia to non-noxious heat (decrease of 30% in the temperature of the struggle threshold) and to cold stimulation (decrease by 40% in the ID). In addition, the animals showed modifications in the spontaneous postures of the affected hind paw in a natural setting, suggesting a 'spontaneous' pain-related behaviour (the mean 'pain' rating, derived from the technique used for the formalin test and numbered 0-5, was 2.8 +/- 0.4, P less than 0.01, n = 12). Lastly, sensitized responses were observed to mechanical stimulation after thermal stimulation in the non-noxious range applied to the lesioned but not the non-lesioned paw. The time course of pain-related disorders was comparable whatever the behavioural test, with recovery 2 months after surgery. These results clearly show that the neuropathy produces abnormal pain-related disorders in the rat, which are reminiscent of those observed in some human neuropathies.

Animals↗
PubMed1990

Potent and long lasting antinociceptive effects after injection of low doses of a mu-opioid receptor agonist, fentanyl, into the brachial plexus sheath of the rat.

The effect of administering low doses (0.5-1.5 micrograms) of the mu-opioid receptor agonist fentanyl into the right brachial plexus sheath of the rat was examined using the vocalization threshold to paw pressure test. Both forepaws were tested in each rat. Fentanyl injected into the right brachial plexus sheath at 0.5-1.5 micrograms/kg produced a localized, dose-dependent, potent and long lasting antinociceptive effect, as gauged on the right forepaw. At the lower dose used (0.5 microgram/kg of fentanyl), the antinociceptive effect was restricted to the right forepaw and lasted for more than 2 h. Increasing doses of fentanyl (1 and 1.5 micrograms/kg) induced potent effects, lasting up to 5-6 h or even longer. In complete contrast, fentanyl administered i.v. at the dose of 1 microgram/kg had a very transient effect, only lasting up to 25 min. The results of injection of low doses of the opioid antagonist naloxone when administered either i.v. or locally into the paw, on the effect of fentanyl suggest the involvement of a peripheral site of action of the opioid. The present findings suggest that, as already observed in patients in clinical situations, low doses of opiates delivered using this administration route may provide prolonged regional analgesia, with the potential of avoiding centrally mediated side effects.

Animals↗
PubMed1990

[Use of animal models of clinical pain].

For a better understanding of clinical pain, several groups involved in the study of basic pain mechanisms have proposed the use of various experimental models close to clinical situations. They are based either on neurogenic or inflammatory processes. Data obtained with three of these models will be developed in the paper: rats rendered arthritic by Freund's adjuvant injection into the tail, rats with an intraplantar injection of carrageenin in one hind-paw, rats with a moderate ligature of one common sciatic nerve. The various pharmacological approaches revealed dramatic changes of the analgesic effects of morphine and other opioid substances, and a spectacular modification of the endogenous opioid reactivity. A further enhancement of the initial hyperalgesia was observed with high doses (1-3 mg/kg iv) of naloxone (known as an antagonist of morphine), contrasting with the paradoxical analgesia induced with the low dose (peaking up for 3 micrograms/kg iv). Electrophysiological studies emphasized dramatic changes of neuronal responsiveness in structures involved in the transmission of the nociceptive messages. In each of these models, electrophysiological data provide new insights on the physiopathological mechanisms of the related clinical pain.

Animals↗
PubMed1990

Neuronal responsiveness in the ventrobasal thalamic complex of rats with an experimental peripheral mononeuropathy.

1. Single-unit recordings were made, under moderate gaseous anesthesia (33% O2-66% N2O + 0.5/0.6% halothane), in the ventrobasal (VB) thalamic complex of rats (n = 42) with a mononeuropathy created 2-3 wk beforehand, by four loose ligatures around the common sciatic nerve. Before the recording session, three behavioral nociceptive tests to both mechanical and thermal stimuli revealed that these rats exhibited clear hyperalgesia (excessive reactions to noxious stimuli) and allodynia (nociceptive reactions to stimuli usually perceived as nonnoxious). 2. Neurons, characterized by their responses to manual mechanical stimuli, were classified into two groups: group 1 neurons exclusively driven by light tactile stimuli applied to the receptive field (RF), strictly contralateral to the recording site; and group 2 neurons, driven by sustained pinch applied to a large RF, often bilateral. 3. From the total population of neurons (n = 386), only those responding to stimuli applied to one posterior paw were studied; the proportion (35-40%) of these cells was comparable in each of the two VB: n = 93/262 and 44/124 in the VB contralateral (VBc) and ipsilateral (VBi) to the damaged nerve, respectively. The proportions of each functional group of neurons (group 1 or 2) were also similar on each side. 4. For all group 1 neurons the RFs size was comparable to that observed in normal rats. In the VBi the responses of these neurons presented the classical response pattern observed for VB neurons involved in touch transmission, as did the VBc group 1 neurons with RFs in the saphenous (Sa) territory. In sharp contrast, activities of VBc group 1 neurons with RFs in the sciatic (Sc) nerve territory exhibited several abnormalities: higher background activity, fading of the response with repetitive stimulation, and afterdischarges outlasting the applied stimulus. 5. As in normal rats, 52% of VB group 2 neurons exhibited bilateral symmetrical RFs. Their responses to mechanical stimuli were often greater for stimuli applied to the affected paw, and some of them could be activated by moderate pressure to this paw. Heat responses also illustrated the profound increased sensitivity of the lesioned side, and the activation threshold to thermal stimulation of these group 2 neurons was lowered by 4-6 degrees C compared to normal values. In addition, these neurons responded to immersion of the lesioned paw in a 10 degrees C water bath, a stimulus that was ineffective when applied to the opposite paw.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Evidence for peripheral serotonergic mechanisms in the early sensitization after carrageenin-induced inflammation: electrophysiological studies in the ventrobasal complex of the rat thalamus using a potent specific antagonist of peripheral 5-HT receptors.

The effect of ICS 205-930 (ICS), a specific 5-HT3 receptor antagonist, was analyzed on the sensitization of ventrobasal (VB) thalamic neuronal responses produced by an intraplantar injection of carrageenin. ICS was injected locally in the plantar paw, simultaneously, or after carrageenin (at 20 min or later than 70 min). The progressive increase of the VB neuronal responses to pinch (total number of spikes in the discharge) due to carrageenin sensitization, was prevented, blocked, or reversed, by intraplantar ICS, at a dose as low as 3.2 ng/kg, when injected, simultaneously or in the first half-hour following the carrageenin injection itself. The carrageenin sensitization then reappeared, 50-90 min after the initiation of the inflammation. By contrast to these early injections of ICS, a later administration of ICS (70 min or more, after the carrageenin injection), did not influence the sensitization. The time course of the effects of this 5-HT3 antagonist receptor agrees well with the time course of 5-HT release into the inflammatory exudate. These data, and those previously reported on the action of aspirin and of a peripheral antihistamine on carrageenin sensitization, are compared. These results indicate the relative participation of the various inflammatory substances released in the exudate, and the importance of timing of administration for an effective antagonism of the hyperalgesia elicited by this inflammation.

Action Potentials↗
PubMed1989

Potent antinociceptive effects of kelatorphan (a highly efficient inhibitor of multiple enkephalin-degrading enzymes) systemically administered in normal and arthritic rats.

The effects of various i.v. doses (2.5, 5, 10 and 15 mg/kg) of the highly efficient inhibitor of multiple enkephalin-degrading enzymes, Kelatorphan, were evaluated on the vocalization threshold to paw pressure in normal rats and in rats with Freund's adjuvant-induced arthritis. In normal rats, Kelatorphan at doses as low as 2.5 mg/kg i.v. at which the enkephalinase inhibitor acetorphan was ineffective, produced potent antinociceptive effects, comparable to that induced by 1 mg/kg i.v. morphine. In contrast, for the higher doses used (5, 10, 15 mg/kg i.v.), the effects of Kelatorphan were not more pronounced than that of acetorphan. Unlike acetorphan, Kelatorphan was found to be much more effective in arthritic than in normal rats in raising the vocalization threshold, even at the lower concentration, 2.5 mg/kg i.v.: 244% in arthritic vs 144% in normal rats. The effects of Kelatorphan were prevented by naloxone at the dose of 0.5 mg/kg i.v. The enhanced potency of Kelatorphan is discussed in relation with the increase in peptidase-sensitive dynorphin fragments in arthritic rats.

Animals↗
PubMed1989

Behavioural evidence for a bidirectional effect of systemic naloxone in a model of experimental neuropathy in the rat.

In animal models of inflammatory pain, we have demonstrated that the opioid antagonist naloxone induces a paradoxical analgesic effect at very low systemic doses, and a hyperalgesic effect at high doses. We have therefore proposed, that opioid systems are modified in these animals with persistent pain. The aim of the present study was to investigate the activity of naloxone through another model of pain in the rat due to a peripheral neuropathy of the sciatic nerve. The neuropathy was created by 4 ligatures around the sciatic nerve. We analyzed the effects of i.v. naloxone (3 and 10 micrograms/kg, 1 mg/kg) on the vocalization thresholds to paw pressure 8 days after the sciatic ligation. Three and 10 micrograms/kg naloxone produced a significant paradoxical antinociceptive effect on responses from the affected paw (with a mean increase of about 50 and 30% of the preinjection values, respectively) and also from the non-affected paw, although the effect was less potent. By contrast, 1 mg/kg naloxone elicited a significant hyperalgesia on responses from the affected and non-affected paw. The effects of the microdoses, but not those of the high dose, were clearly related to the vocalization thresholds measured for each rat just before injection. This study clearly shows that naloxone induces bidirectional effects in a rat model of neuropathic pain, which contradicts the current statement that neuropathic pain is opioid-resistant. The present results also suggest that these effects are not related to inflammatory processes, and may be due to modifications of opioid systems in these animals with persistent pain.

Animals↗
PubMed1989

Evidence for central phenomena participating in the changes of responses of ventrobasal thalamic neurons in arthritic rats.

In this study performed in the Freund's adjuvant-induced arthritic rat, a local injection of lidocaine in one hind paw strongly depressed the ventrobasal thalamic neuronal responses to mild stimulation of both ankles. In parallel, a behavioral study provided evidence for a bilateral hypoalgesia, tested by the vocalization threshold to paw pressure, after a unilateral anesthetic block. The involvement of central phenomena in the changes of neuronal responsivity described in this model of experimental pain is therefore suggested.

Action Potentials↗