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Biomedical subjects

A Eschalier

Publications and source records attributed to A Eschalier.

At least 37 records · Page 2Linked to original sources
PubMed2001

Effects of acetaminophen on monoaminergic systems in the rat central nervous system.

Although acetaminophen is a well established analgesic, its mechanism of action is still unknown. We investigated whether this drug could affect central monoaminergic neurotransmission in rats. Significant increases in serotonin (5-HT) levels were found in the posterior cortex, hypothalamus, striatum, hippocampus and brain stem, but not spinal cord, 45 min after per os administration of 200-400 mg/kg of acetaminophen. However, this treatment altered neither the levels of 5-hydroxyindoleacetic acid nor the accumulation of 5-hydroxytryptophan after blockade of aromatic L-amino acid decarboxylase. On the other hand, a decrease in both the levels of the dopamine (DA) metabolite, dihydroxyphenylacetic acid, and the accumulation of dihydroxyphenylalanine were noted in the striatum of acetaminophen-treated rats. Finally, acetaminophen administration significantly increased noradrenaline (NA) levels in the posterior cortex. In vitro studies showed that acetaminophen (1 mM) enhanced K+-evoked overflow of [3H]5-HT, but not [3H]DA and [3H]NA, previously taken up in brain slices, and exerted no direct effect on monoamine oxidase A, tyrosine hydroxylase and catechol-O-methyl-transferase activities. These results indicate that acetaminophen affects central monoaminergic neurotransmission, thereby suggesting that monoamines (especially 5-HT) might participate in its analgesic action.

Acetaminophen↗
PubMed2001

Potentiation of the antinociceptive effect of clomipramine by a 5-ht(1A) antagonist in neuropathic pain in rats.

The benefit of antidepressant treatment in human neuropathic pain is now well documented, but the effect is limited and slow to appear. It has been demonstrated that the association of a 5-HT(1A) antagonist and a serotoninergic antidepressant reduced the delay of action and increases the thymoanaleptic effect of the drug. The purpose of this work was to evaluate the combination of an antidepressant and a 5-HT(1A) antagonist in animal models of chronic neuropathic pain. We studied the antinociceptive effect of the co-administration of clomipramine and a 5-HT(1A) antagonist (WAY 100,635) in a pain test applied in normal rats and in two models of neurogenic sustained pain (mononeuropathic and diabetic rats). The results show an increase in the antinociceptive effect of acutely injected clomipramine due to WAY 100,635 in these models, which is majored when the two drugs are repeatedly injected. The 5-HT(1A) antagonist reduced the delay of onset and increased the maximal antinociceptive effect of clomipramine. These new findings argue for using the combination of an antidepressant and a 5-HT(1A) antagonist in human neuropathic pain therapy.

Animals↗
PubMed2001

Enhancement of the effects of a complete inhibitor of enkephalin-catabolizing enzymes, RB 101, by a cholecystokinin-B receptor antagonist in diabetic rats.

1. RB 101, a complete inhibitor of enkephalin-catabolizing enzymes, has been previously shown to produce antinociception in normal rats after systemic administration. Moreover, its coadministration with a cholecystokinin-B (CCK-B) receptor antagonist has been shown to strongly enhance its antinociceptive effect in normal rats. In this work, we determined whether RB 101 was able to reduce hyperalgesia and allodynia in diabetic rats, a model of neuropathic pain. The type of opioid receptors (mu or delta) involved was determined using naloxone and naltrindole, respectively, and the interactions between endogenous enkephalins and CCK on nociception control was investigated using coadministration of RB 101 and the CCK-B receptor antagonist CI-988. 2. RB 101 suppressed mechanical hyperalgesia (paw pressure-induced vocalization test), partially alleviated mechanical allodynia (von Frey hair test), and was ineffective in thermal allodynia (tail immersion test). The analgesic effect was completely cancelled by naloxone or naltrindole, suggesting that is requires the availability of mu- and/or delta-opioid receptors. 3. The combination of an inactive dose of CI-988 with the lowest effective dose of RB 101 resulted in a stronger increase in the vocalization threshold comparatively to RB 101 alone. 4. The present study demonstrates that the antinociception generated by RB 101 induced by elevation of extracellular levels of endogenous enkephalins, can be extended to neuropathic pain in diabetic rats and that blockade of CCK-B receptors potentiated antinociceptive effects elicited by RB 101.

Aminopeptidases↗
PubMed2001

Role of spinal NMDA receptors, protein kinase C and nitric oxide synthase in the hyperalgesia induced by magnesium deficiency in rats.

1. Magnesium (Mg)-deficient rats develop a mechanical hyperalgesia which is reversed by a N-Methyl-D-Aspartate (NMDA) receptor antagonist. Given that functioning of this receptor-channel is modulated by Mg, we wondered whether facilitated activation of NMDA receptors in Mg deficiency state may in turn trigger a cascade of specific intracellular events present in persistent pain. Hence, we tested several antagonists of NMDA and non-NMDA receptors as well as compounds interfering with the functioning of intracellular second messengers for effects on hyperalgesia in Mg-deficient rats. 2. Hyperalgesic Mg-deficient rats were administered intrathecally (10 microl) or intraperitoneally with different antagonists. After drug injection, pain sensitivity was evaluated by assessing the vocalization threshold in response to a mechanical stimulus (paw pressure test) over 2 h. 3. Intrathecal administration of MgSO4 (1.6, 3.2, 4.8, 6.6 micromol) as well as NMDA receptor antagonists such as MK-801 (0.6, 6.0, 60 nmol), AP-5 (10.2, 40.6, 162.3 nmol) and DCKA (0.97, 9.7, 97 nmol) dose-dependently reversed the hyperalgesia. Chelerythrine chloride, a protein kinase C (PKC) inhibitor (1, 10.4, 104.2 nmol) and 7-NI, a specific nitric oxide (NO) synthase inhibitor (37.5, 75, 150 micromol x kg(-1), i.p.) induced an anti-hyperalgesic effect in a dose-dependent manner. SR-140333 (0.15, 1.5, 15 nmol) and SR-48968 (0.17, 1.7, 17 nmol), antagonists of neurokinin receptors, produced a significant, but moderate, increase in vocalization threshold. 4. These results demonstrate that Mg-deficiency induces a sensitization of nociceptive pathways in the spinal cord which involves NMDA and non-NMDA receptors. Furthermore, the data is consistent with an active role of PKC, NO and, to a lesser extent substance P in the intracellular mechanisms leading to hyperalgesia.

2-Amino-5-phosphonovalerate↗
PubMed2001

Involvement of hypogastric and pelvic nerves for conveying cystitis induced nociception in conscious rats.

PURPOSE: We determined the sites of the antinociceptive action of morphine in the experimental model of cyclophosphamide induced cystitis and investigated the afferent nerve fibers involved in nociception transmission originating from the bladder. MATERIALS AND METHODS: Cyclophosphamide (200 mg./kg.) given intraperitoneally was used to induce cystitis in male rats and their behavior was observed and scored. The effect of 2 mg./kg. systemic morphine given intravenously on cyclophosphamide induced behavioral modifications was tested when administered alone and after 100 microg. naloxone per rat given intrathecally at the L1 to L2 or L6 to S1 level. The spinal antinociceptive effect of morphine was also tested when administered intrathecally alone at 10, 100 and 200 microg. per rat at L1 to L2, alone at 100 microg. per rat at L1 to L2 or L6 to S1, alone at 100 microg. per rat at L1 to L2 and L6 to S1 simultaneously, alone at 200 microg. per rat at L1 to L2 and after 100 microg. naloxone per rat given intrathecally at L6 to S1 at 100 microg. per rat at L1 to L2. RESULTS: Cyclophosphamide induced marked modifications in the behavior of the rats, including a decreased breathing rate, eye closing and specific postures. Morphine given intravenously reversed these behavioral disorders and this reversal was completely prevented by pretreatment with intrathecal naloxone. A dose of 100 microg. per rat given intrathecally also reversed these behavioral disorders by about 25% at the L1 to L2 and L6 to S1 levels. In addition, a dose of 100 microg. morphine per rat administered intrathecally and simultaneously at L1 to L2 and L6 to S1 produced an effect equal to the sum of those observed when administered separately, that is about 50%, whereas morphine at an intrathecal dose of 200 microg. at L1 to L2 produced the same effect as 100 microg. given intrathecally at the same level or at L6 to S1 (25%). Also, 100 microg. naloxone per rat administered intrathecally at L6 to S1 prevented the effect of 100 microg. morphine at L1 to L2. CONCLUSIONS: These results confirm the previously reported antinociceptive effect of systemic morphine in this model of cyclophosphamide cystitis, suggest that this antinociceptive action is completely located at the spinal site and most importantly demonstrate by the pharmacological approach and behavioral analysis that nociceptive sensations originating from the bladder are conveyed by hypogastric and pelvic nerves in this cyclophosphamide cystitis model in the conscious rat.

Animals↗
PubMed2000

Description of a short-term Taxol-induced nociceptive neuropathy in rats.

This work describes a new animal model of neuropathic pain produced by the single intraperitoneal administration of Taxol (32 mg/kg) to male Sprague-Dawley rats. During the course of the experiment, the clinical status of the rats remained satisfactory and motor function was not altered. A number of classical behavioural tests of nociception as well as histological and electrophysiological investigations were performed. Taxol administration produced an important and rapidly developing mechanical hyperalgesia, a thermal hypoalgesia but no mechanical or thermal allodynia. Degenerative changes were observed in the sciatic nerve, the nerve fibres in the paw subcutaneous tissue and in the lumbar spinal cord. When Taxol or vehicle (a mix of Cremophor and ethanol) were repeatedly injected once a week for 5 weeks, similar nociceptive disorders were observed in addition to a decrease in peripheral nerve conduction velocity. The selective dysfunction of high-diameter myelinated fibres observed after one single administration of Taxol (32 mg/kg) may be attributable to paclitaxel-induced neuropathy, however other mechanisms causing neurochemical dysfunction must also be involved.

Animals↗
PubMed2000

Magnesium and MK-801 have a similar effect in two experimental models of neuropathic pain.

Considering that magnesium and non-competitive NMDA receptor antagonists inhibit the opening of the channel linked to the NMDA receptor, we assessed their effects on mechanical hyperalgesia in two animal models of neuropathic pain (rats with a sciatic nerve ligature and diabetic rats). Our data show that magnesium reverses the hyperalgesia, as does MK-801. These results suggest that magnesium could be an alternative for the treatment of neuropathic pain in patients.

Animals↗
PubMed2000

Effect of intrathecal administration of serotonin in chronic pain models in rats.

The present study examined the effects of intrathecal (i.t.) administration of 5-hydroxytryptamine (5-HT; 0.1-100 microg) on mechanical hyperalgesia associated with neuropathic pain (chronic constriction of the sciatic nerve model and diabetic model) and inflammatory pain (carrageenan and polyarthritic models) in rats. Results demonstrated that the hyperalgesia observed in the mononeuropathic and diabetic rats was attenuated by 5-HT; the active dose, however, was 100- to 1000-fold higher than that required in normal rats, and was moderately effective. In the two experimental models of inflammatory pain, 5-HT was not markedly or similarly active. In the carrageenan model, 5-HT at the highest dose was only weakly effective whereas in the polyarthritic model it was inactive. Together, these results show that 5-HT has antinociceptive effects in several rat pain models, except in the model of diffuse pain (polyarthritic rats). Its antinociceptive effects in these models, however, are slight and differ from those observed in normal rats.

Animals↗
PubMed2000

Assessment of allodynia and hyperalgesia after cisplatin administration to rats.

This work describes the behavioural responses of Sprague-Dawley rats to mechanical or thermal stimuli during and after administration of ten intraperitoneal injections of, alternatively, 1 and 2 mg/kg cisplatin every three days (cumulative dose: 15 mg/kg). Nociceptive signs including mechanical allodynia and hyperalgesia appeared after 3 and 6 cisplatin injections, respectively, and were maintained until 15 days after the last injection. The conservation of a good clinical status and fast appearance of symptoms are favourable criteria for using this animal model to understand the pathophysiological mechanisms implicated in the cisplatin-induced sensory peripheral neuropathy.

Animals↗
PubMed2000

Vocalization thresholds related to noxious paw pressure are decreased by paradoxical sleep deprivation and increased after sleep recovery in rat.

The aim of this study was to assess the effect of paradoxical sleep deprivation (PSD) and sleep recovery on the vocalization threshold in rats submitted to a mechanical noxious stimulus. Sixteen male Wistar rats were randomly assigned in two groups: controls (n=8), paradoxical sleep deprived rats (n=8). PSD was performed using the 'inverted flower pot' technique. Paw pressure test was used to assess the sensitivity to mechanical noxious stimulus (vocalization threshold). The experiment was divided into three periods: baseline (day 1, day 2), PSD (day 3, day 4, day 5) and recovery (day 6, day 7, day 8, day 9). After 48 and 72 h of PSD, the vocalization thresholds decreased significantly in comparison to the control rats (day 4: 245+/-21 vs. 303+/-20 g, P=0.05; day 5: 256+/-17 vs. 324+/-22 g, P=0.02). In PSD group, relative to controls, vocalization thresholds increased significantly after 48, 72, and 96 h of recovery sleep periods (day 7: 378+/-24 vs. 307+/-8 g P=0.01; day 8: 384+/-27 vs. 316+/-23 g, P=0.02; day 9: 395+/-24 vs. 328+/-15 g, P=0.02). Vocalization thresholds on day 6 were not significantly different in both groups (375+/-20 vs. 324+/-24 g, P=0.08). In conclusion, experimental PSD in rats induces a significant decrease in vocalization threshold to mechanical noxious stimulus, which is totally reversed during the sleep recovery period.

Animals↗
PubMed2000

Evidence for an involvement of tachykinins in allodynia in streptozocin-induced diabetic rats.

A better knowledge of the pathophysiology of chronic pain could help to improve the treatment of patients with such syndrome. The aim of the present work was to elucidate the possible involvement of spinal substance P and neurokinin A in the mechanical and thermal allodynia observed in streptozocin-induced diabetic rats. A tachykinin NK(1) receptor antagonist, RP-67,580 ((3aR,7aR) -7, 7-diphenyl-2-(1-imino-2(2-methoxy phenyl)-ethyl) perhydroisoindol-4-one hydrochloride), a tachykinin NK(2) receptor antagonist, SR-48,968 ((S)-N-methyl (4-(acetylamino-4phenylpiperidino)-2-(3, 4-dichlorophenyl) butyl) benzamide) and their respective enantiomers were intrathecally administered 4 weeks after the induction of diabetes. Mechanical and thermal allodynia were evaluated before and up to 60 min after injection. The tachykinin receptor antagonists at the highest doses (10 and 25 microgram) significantly reduced allodynia, their enantiomers being inactive. Both of these data suggest the involvement of substance P and neurokinin A in the neuropathy-induced allodynia and offer a novel hypothesis to treat chronic pain due to diabetes.

Analgesics↗
PubMed2000

Potentiation of morphine and clomipramine analgesia by cholecystokinin -B antagonist CI-988 in diabetic rats.

The aim of this study was to determine the influence of an intrathecally injected cholecystokinin-B (CCK-B) receptor antagonist, CI-988, on the analgesic effect of morphine and clomipramine in diabetic rats. Administered alone, morphine (0.1 mg/kg, i.v.) and clomipramine (3 mg/kg, i.v.) have respectively no effect and only a slight effect on vocalization thresholds to paw pressure in diabetic rats, but, when coadministered with CI-988 (0.1 microg/rat, i.t.), an appreciable antinociceptive effect was observed. This suggests that a spinal blockade of cholecystokininergic system increases the analgesia induced by morphine or clomipramine. A CCK-B receptor antagonist could thus be used to lower dosages of morphine or antidepressant drugs in the management of neuropathic pain in humans, and thereby reduce their side effects.

Analgesia↗
PubMed2000

Serotonin receptor subtypes involved in the spinal antinociceptive effect of 5-HT in rats.

The present study was designed to investigate which subtypes of spinal 5-HT receptors are involved in 5-HT-induced antinociception using the mechanical pain test. Serotonin and various selective antagonists or agonists for 5-HT receptor subtypes (5-HT(1A), 5-HT(1B), 5-HT(2A), 5-HT(2C), 5-HT(3) and 5-HT(4)) were administered intrathecally (i.t.) in rats. The i.t. injection of 5-HT (1 microg) produced significant antinociceptive effects using the paw pressure test. Pretreatment with the 5-HT(2C) receptor antagonist mesulergine (1 and 10 microg) and the 5-HT(3) receptor antagonist tropisetron (1 and 10 microg) reversed totally the antinociception induced by 5-HT. Furthermore, at a dose of 10 microg, both the 5-HT(2A) receptor antagonist ketanserin and the 5-HT(1B) receptor antagonist penbutolol, but neither the 5-HT(1A) receptor antagonist WAY 100635 nor the 5-HT(4) receptor antagonist GR113808, attenuated the antinociceptive effect induced by 5-HT. In addition, an i.t. injection of the 5-HT(3) agonist mCPBG induced significant antinociceptive effects whereas the 5-HT(2) agonist DOI did not produce analgesia. These results suggest that although the precise degree of the involvement of spinal serotonergic 5-HT(3) receptors remains to be elucidated due to some differences in the effect of agonists or antagonists, these receptors seem to play a role in the antinociceptive effect of 5-HT against a mechanical acute noxious stimulus. The involvement of 5-HT(2C) is more questionable due to the observed discrepancies between the effects of the used agonist and antagonist. 5-HT(1A) and 5-HT(4) receptors do not seem to be involved. In addition, a possible functional interaction between spinal serotonergic receptors may exist.

Analgesics↗
PubMed2000

Age-related changes in nociception and effect of morphine in the Lou rat.

Little is known about how the ageing process affects pain sensitivity and a relevant animal model is therefore required. The effect of age on pain reactivity in animals has been investigated by several experimenters but the results are conflicting. Four groups of male and female Lou/C/Jall rats (4-29 months old) were used for our study. Four pain tests based on evaluation of reflex or more integrated behaviours after a thermal (tail immersion test) or mechanical (paw pressure test and von Frey test) stimulation were used. With mechanical stimulus, a significant decrease in the pain threshold across age was observed, females were more sensitive than males. This increase in nociceptive sensitivity to mechanical stimulation was more pronounced on integrated behaviours (struggle reaction) than on withdrawal reflex. An age-related increase in sensitivity was found on von Frey test. No effect on the latency of reflex induced by thermal stimulation was observed. In addition, a decrease in the spontaneous motor activity during exploration was observed across ageing; this effect was more marked for the females. The effect of morphine at doses of 1, 3 and 9 mg/kg (s.c.) decreased in intensity across ageing. These data demonstrate the need to use (1) various noxious stimuli because differences were observed in the modification of pain reactivity according to the nature of the stimulus; (2) various pain parameters and particularly integrated behaviours; (3) several age groups. In addition, Lou/C/Jall rat could be a useful model for studying of effect of age on pain.

Aging↗
PubMed2000

Cyclophosphamide-induced cystitis in freely-moving conscious rats: behavioral approach to a new model of visceral pain.

PURPOSE: To develop a model of visceral pain in rats using a behavioral approach. Cyclophosphamide (CP), an antitumoral agent known to produce toxic effects on the bladder wall through its main toxic metabolite acrolein, was used to induce cystitis. MATERIALS AND METHODS: CP was administered at doses of 50, 100 and 200 mg./kg. i.p. to male rats, and their behavior observed and scored. The effects of morphine (0.5 to 4 mg./kg. i.v.) on CP-induced behavioral modifications were tested administered alone and after naloxone (1 mg./kg. s.c.). In addition, 90 minutes after CP injection, that is, at the time of administration of morphine, the bladder was removed in some rats for histological examination. Finally, to show that the bladder is essential for the CP-induced behavioral modifications, female rats also received CP at doses of 200 mg./kg. i.p. and of 20 mg. by the intravesical route, and acrolein at doses of 0.5 mg. by the intravesical route and of 5 mg./kg. i.v. RESULTS: CP dose-relatedly induced marked behavioral modifications in male rats: breathing rate decrease, closing of the eyes and occurrence of specific postures. Morphine dose-dependently reversed these behavioral disorders. A dose of 0.5 mg./kg. produced a reduction of almost 50% of the behavioral score induced by CP 200 mg./kg. This effect was completely prevented by pretreatment with naloxone. At the time of administration of morphine, histological modifications of the bladder wall, such as chorionic and muscle layer edema, were observed. In female rats, CP 200 mg./kg. i.p. produced the same marked behavioral modifications as those observed in male rats. Administered at the dose of 20 mg. intravesically, CP did not produce any behavioral effects, whereas acrolein at 0.5 mg. intravesically induced behavioral modifications identical to those under CP 200 mg./kg. i.p., with the same maximal levels. Conversely, acrolein 5 mg./kg. i.v. did not produce any behavioral effects at all. CONCLUSIONS: Overall, these results indicate that this experimental model of CP-induced cystitis may be an interesting new behavioral model of inflammatory visceral pain, allowing a better understanding of these painful syndromes and thus a better therapeutic approach to them.

Acrolein↗
PubMed2000

[Pathophysiology of pain].

Progress in the knowledge of the pathophysiology of pain allow to associate clinical symptoms of painful syndroms to physiological, morphological and neurobiochemical changes observed both at peripheral and central sites. Thus, nociceptive pains involve both a sensitisation of nociceptors and a secondary central sensitisation. Numerous mediators are involved in these phenomena which reflect neuroplasticity. Peripherally, they come from plasma, immune cells and afferent fibres involved in neurogenic inflammation. Their number explains how the peripheral mechanisms of pain are complex and how it is difficult to pharmacologically suppress the activity of nociceptors. Other mediators are involved in the dorsal horn of the spinal cord. Excitatory amino acids are particularly involved by acting on NMDA receptors; substance P seems to work as a facilitatory neuromodulator rather than as a neurotransmitter. The mechanisms of neuropathic pains are different because both small and large diameter afferent fibers are involved. Ectopic discharges from lesional sites of C fibers, sprouting and abnormal neuronal connections have been described. Up regulation of ionic, especially sodic, channels has been demonstrated and could explain spontaneous discharges. Here again, central sensitisation is also observed but present knowledge does not allow to distinguish specific mechanisms. These progress in the knowledge of pathophysiology of pain allow to improve the understanding of the mechanism of action of analgesic drugs. They also give basis to the discovery of novel drugs with original mechanisms.

Humans↗