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Alain Eschalier

Publications and source records attributed to Alain Eschalier.

At least 37 records · Page 2Linked to original sources
PubMed2005

Spinal 5-HT1A receptors differentially influence nociceptive processing according to the nature of the noxious stimulus in rats: effect of WAY-100635 on the antinociceptive activities of paracetamol, venlafaxine and 5-HT.

The regulation of nociceptive processing by 5-HT at the spinal level is intricate since the neurotransmitter has been implicated in both pro and antinociception. The aim of our study was to investigate, according to the nature of the noxious stimulus, how the blockade of spinal 5-HT(1A) receptors could influence the antinociceptive actions of exogenous 5-HT as well as two analgesics involving endogenous 5-HT, paracetamol and venlafaxine. Rats were submitted either to the formalin test (tonic pain) or the paw pressure test (acute pain). WAY-100635 (40 microg/rat, i.t.), a selective 5-HT(1A) receptor antagonist, had no intrinsic action in either test. However, in the formalin test, it blocked the antinociceptive action of 5-HT (50 microg/rat, i.t.) and paracetamol (300 mg/kg, i.v.) in both phases of biting/licking behaviour and that of venlafaxine (2.5 mg/kg, s.c.) in the late phase only. In the paw pressure test, the combination of sub-effective doses of 5-HT (0.01 microg/rat, i.t.), paracetamol (50 mg/kg, i.v.) or venlafaxine (20 mg/kg, s.c.) with WAY-100635 led to a significant antinociceptive effect, which seems to depend on the reinforcement of the activity of inhibitory GABAergic interneurones. In conclusion, both direct stimulation of the spinal 5-HT(1A) receptors by 5-HT, and indirect stimulation using paracetamol or venlafaxine can differently influence pain transmission. We propose that the nature of the applied nociceptive stimulus would be responsible for the dual effect of the 5-HT(1A) receptors rather than the hyperalgesic state or the supraspinal integration of the pain message.

Acetaminophen↗
PubMed2005

Rectal instillation of butyrate provides a novel clinically relevant model of noninflammatory colonic hypersensitivity in rats.

BACKGROUND & AIMS: The treatment of irritable bowel syndrome (IBS), characterized by abdominal pain and bloating, is empirical and often poorly efficient. Research lacks suitable models for studying the pathophysiologic mechanisms of the colonic hypersensitivity and new pharmacologic targets. The present study aimed to develop a novel model of colonic hypersensitivity possessing several of the characteristics encountered in patients with IBS. METHODS: Rats received enemas of a butyrate solution (8-1000 mmol/L) twice daily for 3 days. A time course was determined for colonic hypersensitivity (colorectal distention test) and referred cutaneous lumbar hyperalgesia (von Frey hairs). Macroscopic and histologic analyses were performed on colonic mucosa. The efficacy of morphine, U50488H (a kappa opioid agonist), and trimebutine on the 2 pain parameters was determined. Finally, the involvement of peptidergic C-fibers was evaluated using capsaicin-pretreated animals and treatments with calcitonin gene-related peptide (CGRP) and neurokinin 1 receptor antagonists. RESULTS: Butyrate enemas induced a sustained, concentration-dependent colonic hypersensitivity and, to a lesser extent, a referred cutaneous mechanical hyperalgesia, particularly in female rats, but no macroscopic and histologic modifications of the colonic mucosa, as observed in patients with IBS. Both pain parameters were sensitive to morphine, U50488H, trimebutine, neonatal capsaicin treatment, and the CGRP receptor antagonist but not to the neurokinin 1 receptor antagonist. CONCLUSIONS: These results present our noninflammatory model of chronic colonic hypersensitivity as a useful novel tool for studying IBS. The CGRP receptor antagonist-induced reduction of colonic hypersensitivity suggests that CGRP receptors may provide a promising target for treatment of IBS.

Animals↗
PubMed2005

Patterns of P-glycoprotein activity in the nervous system during vincristine-induced neuropathy in rats.

Vincristine (VCT) is a neurotoxic agent and also a substrate of multidrug resistance (MDR) transporters such as P-glycoprotein (P-gp) and MDR-associated proteins 1 and 2 (MRP1 and MRP2). These proteins are expressed in the central and peripheral nervous systems (CNS and PNS) and normally protect these structures against the harmful effects of VCT. The aim of this study was to elucidate the paradoxical relation between the MDR transporters and the VCT neurotoxicity. With a validated rat model of VCT-induced neuropathy, (1) the expressions of mdr1a (P-gp), mdr1b (P-gp), mrp1 (MRP1), and mrp2 (MRP2) genes were assessed by quantitative real-time polymerase chain reaction, and (2) the transporter activity was monitored using a radioactive tracer, (99m)Tc-sestamibi, in the CNS and PNS. The results showed higher expression of mdr1a and mdr1b genes (x3 and x35, respectively) in the brain than in the spinal ganglia in both control and treated animals. Transporter activity was higher (x10) in the CNS than in the PNS. Hence, P-gp protection may be lower in the PNS than in the CNS, and this may be responsible for the peripheral neurotoxicity of P-gp substrates. VCT treatment increased expression of the mdr1a gene in the CNS and PNS (both x1.7), mrp1 gene in the PNS (x1.7), and transporter activity in both the CNS and the PNS (x4 and x8, respectively). This transporter induction may induce adverse effects when analgesic drugs are administered to treat neuropathic pain.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2004

Silencing of the Cav3.2 T-type calcium channel gene in sensory neurons demonstrates its major role in nociception.

Analgesic therapies are still limited and sometimes poorly effective, therefore finding new targets for the development of innovative drugs is urgently needed. In order to validate the potential utility of blocking T-type calcium channels to reduce nociception, we explored the effects of intrathecally administered oligodeoxynucleotide antisenses, specific to the recently identified T-type calcium channel family (CaV3.1, CaV3.2, and CaV3.3), on reactions to noxious stimuli in healthy and mononeuropathic rats. Our results demonstrate that the antisense targeting CaV3.2 induced a knockdown of the CaV3.2 mRNA and protein expression as well as a large reduction of 'CaV3.2-like' T-type currents in nociceptive dorsal root ganglion neurons. Concomitantly, the antisense treatment resulted in major antinociceptive, anti-hyperalgesic, and anti-allodynic effects, suggesting that CaV3.2 plays a major pronociceptive role in acute and chronic pain states. Taken together, the results provide direct evidence linking CaV3.2 T-type channels to pain perception and suggest that CaV3.2 may offer a specific molecular target for the treatment of pain.

Animals↗
PubMed2004

Blockade of supraspinal 5-HT1A receptors potentiates the inhibitory effect of venlafaxine on wind-up activity in mononeuropathic rats.

In mononeuropathic rats submitted to a C-fiber reflex responses paradigm, repeated administration (five successive injections every half-life) of 10 mg/kg, s.c. of venlafaxine, but not of 2.5 mg/kg, s.c., a mixed monoamine reuptake inhibitor with preferential inhibitory activity in 5-HT reuptake, induced a progressive reduction of spinal wind-up. Repeated co-administration of the selective 5-HT1A receptor antagonist WAY 100,635 i.c.v. (50 microg/injection) significantly increased the effect of venlafaxine s.c., indicating that venlafaxine-induced inhibition of spinal wind-up in mononeuropathic rats is potentiated by blockade of central 5-HT1A receptors.

Animals↗
PubMed2004

Decrease in non-selective, non-sustained attention induced by a chronic visceral inflammatory state as a new pain evaluation in rats.

The aim of this study was to develop a new behavioral pain test based on the evaluation of cognitive capacity impairments in rats with colitis and to determine the impact of different acute analgesic treatments. Colitis was induced in rats by an enema containing 2,4,6-trinitrobenzen sulfonic acid. Visual non-selective, non-sustained attentional level was assessed by a new behavioral testing procedure. Animals were familiarized on three consecutive days with an open field containing four small, similar, familiar objects. On the day of testing, one of the objects was randomly replaced by a new one. Attentional level was determined by the ability of the rat to perceive this small modification to its familiar environment. The effect of morphine, acetaminophen, aspirin or ibuprofen treatment was assessed on testing day and compared with that observed during a Von Frey test to assess referred tactile hypersensitivity of the skin of the lower back. Rats with colitis had decreased attentional level but no change in their locomotor activity, interest in the environment or memory encoding. Morphine (1 mg/kg, s.c. and 10 microg/rat, i.t.) and acetaminophen (200 mg/kg, p.o.) had a beneficial effect on attentional level and on referred tactile hypersensitivity. Testing for the latter showed that aspirin and ibuprofen (400 mg/kg, p.o.) were ineffective. The decrease in visual non-selective, non-sustained attention induced by chronic inflammatory painful state can be relieved by effective analgesic treatments. This finding could lead to the development of a new behavioral test to assess spontaneous pain in chronic painful subjects.

Acetaminophen↗
PubMed2004

Evidence for an exclusive antinociceptive effect of nociceptin/orphanin FQ, an endogenous ligand for the ORL1 receptor, in two animal models of neuropathic pain.

Nociceptin/orphanin FQ (noci/OFQ), the endogenous ligand for the orphan ORL1 (opioid receptor-like1), has been shown to be anti- or pronociceptive and modify morphine analgesia in rats after central administration. We comparatively examined the effect of noci/OFQ on hyperalgesia and morphine analgesia in two experimental models of neuropathic pain: diabetic (D) and mononeuropathic (MN) rats. Noci/OFQ, when intrathecally (i.t.) injected (0.1, 0.3, or 1, to 10 microg/rat) was ineffective in normal rats, but reduced and suppressed mechanical hyperalgesia (paw-pressure test) in D and MN rats, respectively. This spinal inhibitory effect was suppressed by naloxone (10 microg/rat, i.t.) in both models. Combinations of systemic morphine with spinal noci/OFQ resulted in a strong potentiation of analgesia in D rats. In MN rats, an isobolographic analysis showed that the morphine+noci/OFQ association (i.t.) suppressed mechanical hyperalgesia in a superadditive manner. In summary, the present findings reveal that spinal noci/OFQ produces a differential antinociception in diabetic and traumatic neuropathic pain according to the etiology of neuropathy, an effect possibly mediated by opioid receptors. Moreover, noci/OFQ combined with morphine produces antinociceptive synergy in experimental neuropathy, opening new opportunities in the treatment of neuropathic pain.

Animals↗
PubMed2004

Venlafaxine-induced depression of wind-up activity in mononeuropathic rats is potentiated by inhibition of brain 5-HT1A receptor expression in vivo.

Antinociceptive effects of inhibiting 5-HT1A receptor expression by intracerebroventricular administration of an antisense oligodeoxynucleotide were studied in mononeuropathic rats. A 7-day period of treatment with the antisense produced: (i) reduction of mechanical hyperalgesia in the neuropathic hindlimb starting from day 5 of treatment, (ii) decrease of the hypothermic effect of 8-OH-DPAT challenge on day 6 of treatment, and (iii) potentiation of the inhibitory effect of velafaxine on spinal wind-up activity on day 7 of treatment. Results suggest a counteracting role of somatodendritic 5-HT1A receptors of raphe nuclei neurons in the antinociceptive efficacy of antidepressants with serotonergic spectrum in neuropathic pain.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed2003

Evidence for an antihyperalgesic effect of venlafaxine in vincristine-induced neuropathy in rat.

Venlafaxine, a new antidepressant with fewer side effects, could be of interest to reduce neuropathic pain following antineoplasic drug treatment. In the present study, we demonstrated that venlafaxine inhibits hyperalgesia in a new rat model of neuropathy induced by the antineoplasic drug vincristine, and exerts its effect preferentially via supraspinal and spinal mechanisms.

Analgesics↗
PubMed2003

Antihyperalgesic effect of levetiracetam in neuropathic pain models in rats.

The purpose of this study was to assess, in rats, the antinociceptive effects of levetiracetam (i.p.), a novel antiepileptic drug, in acute pain tests and in two models of human neuropathic pain. Levetiracetam and carbamazepine contrasted morphine by an absence of effect in the tail flick and hot plate tests. In normal rats, carbamazepine failed to modify the vocalisation thresholds to paw pressure whereas levetiracetam slightly increased this threshold only at the highest dose (540 mg/kg) for 30 min. In the sciatic nerve with chronic constriction injury model, the highest dose of levetiracetam (540 mg/kg) and carbamazepine (30 mg/kg) reversed the hyperalgesia. In streptozocin-induced diabetic rats, levetiracetam dose-dependently increased the vocalization threshold from 17 to 120 mg/kg reaching a similar effect as 10 mg/kg of carbamazepine. These results indicate that levetiracetam induces an antihyperalgesic effect in two models of human neuropathic pain, suggesting a therapeutic potential in neuropathic pain patients.

Acute Disease↗
PubMed2003

Does Mg2+ deficiency induce a long-term sensitization of the central nociceptive pathways?

In rats, a Mg(2+)-deficient diet, which in a few days dramatically decreased the Mg(2+) concentration in plasma, cerebrospinal fluid (CSF) and spinal cord, was accompanied by a significant lowering of the nociceptive threshold. After reloading, the Mg(2+) concentration was rapidly normalized in both spinal cord and CSF. In parallel, the neurological disturbances induced by Mg(2+) deficiency vanished in less that 24 h, but the reversal of the hyperalgesia was delayed for up to 11 to 20 days. In this model, repeated doses of dizocilpine (MK-801), a non-competitive NMDA receptor antagonist, given at start of the Mg(2+)-depleted diet, prevented hyperalgesia, suggesting the involvement of NMDA receptor channels. The delayed recovery of a normal pain threshold argues for long-term sensitization of the nociceptive pathways.

Animals↗
PubMed2003

The antihyperalgesic effect of venlafaxine in diabetic rats does not involve the opioid system.

Venlafaxine (VFX) is a structurally novel antidepressant that inhibits reuptake of serotonin and norepinephrine but, unlike tricyclic antidepressants, has few side effects. The present work studies the antihyperalgesic effect of repeated administrations of VFX (five successive injections of 2.5, 5 or 10 mg/kg, s.c., every half-life) in diabetic rats with the paw pressure test and the effect of the opioid receptor antagonist naloxone (1 mg/kg, i.v.) because an opioidergic mechanism is usually considered to be involved in the analgesic effect of antidepressants. VFX induced a significant dose-dependent increase in vocalization thresholds. This effect was not reversed by naloxone. Thus, we demonstrate a clear antinociceptive effect of VFX which, unlike that of most mixed tricyclic antidepressants, does not involve the endogenous opioid system.

Analgesics↗
PubMed2003

An animal model of nociceptive peripheral neuropathy following repeated cisplatin injections.

We report the assessment of motor and sensory behaviors using an electrophysiologic and an histologic approach, in a rat model of cisplatin peripheral neuropathy. Cisplatin was injected intraperitoneally one (3 mg/ kg), two (2 mg/kg), or three (1 mg/kg) times a week up to a cumulative dose of 15 or 20 mg/kg. With regard to nociceptive signs, we observed mechanical and thermal (cold stimuli) hyperalgesia and allodynia associated with minor motor disorders for the 3 mg/kg dose. Peripheral nerve conduction velocities were decreased in the cisplatin-(3 mg/kg) treated group. In addition, the histologic approach revealed that large axons were more frequently affected than the small ones, and nonmyelinated axons were unaffected. However, even in the most severe cases, myelin sheaths remained within normal limits. This animal model of nociceptive neuropathy would be suitable to study the pathophysiologic mechanisms of neuropathic pain and to test potential neuroprotective agents.

Animals↗
PubMed2003

A new animal model of vincristine-induced nociceptive peripheral neuropathy.

Using doses close to those used clinically, we have developed an animal model of vincristine-induced nociceptive sensory neuropathy after repeated intravenous injection in male Sprague-Dawley rats. In order to validate the model, three different doses (50, 100 and 150 microg/kg) of vincristine were injected every 2nd day until five injections had been given. The sensory behavioural assessment revealed mechanical hyperalgesia and allodynia associated with cold thermal hyperalgesia and allodynia. With regard to electrophysiological evaluation, we observed a decrease in the nerve conduction velocity in the highest dose group. Morphological studies revealed few degenerated fibers in the sciatic nerve and many degenerated myelinated axons in the fine nerve fibers of the subcutaneous paw tissue. Finally, to develop an animal model, we chose the 150 microg/kg dose because of the good general clinical status of the rats without motor function changes associated with severe sensation disorders like hyperalgesia and allodynia. This model of vincristine-induced painful neuropathy will be used to explore physiopathological mechanisms implied in the genesis of neuropathic pain and also to test new analgesic and neuroprotective drugs.

Animals↗
PubMed2003

Role of nerve growth factor in the trinitrobenzene sulfonic acid-induced colonic hypersensitivity.

The majority of patients with digestive disorders display visceral pain. In these troubles, visceral pain threshold is decreased, demonstrating visceral hypersensitivity. There is growing evidence that nerve growth factor (NGF) may function as a mediator of persistent pain states. This hypothesis was tested in a model of colonic hypersensitivity measured by isobaric distension in conscious rats. This study was designed to evaluate (1) the effect of exogenous NGF on colonic pain threshold, (2) the involvement of NGF in trinitrobenzene sulfonic acid (TNBS)-induced colonic hypersensitivity, by testing an anti-NGF antibody, and (3) finally the involvement of sensory nerves on NGF and TNBS effects using rats treated neonatally with capsaicin. Intra-peritoneal injection of NGF (0.1-100 ng/rat) decreased in a dose-related manner colonic pain threshold in naive rats. This effect was reversed by anti-NGF antibody (1/2000; 2 ml/kg). TNBS-induced colonic hypersensitivity was also reversed by anti-NGF antibody (1/2000; 2 ml/kg): 37.7 +/- 1.7 and 17.6 +/- 0.7 mmHg (p<0.01) for anti-NGF antibody- and vehicle-treated group, respectively. Neonatal capsaicin pre-treatment inhibited NGF- and TNBS-induced decrease in colonic pain threshold: 49.4 +/- 5.3 versus 22.3 +/- 1.6 mmHg (p<0.01) for capsaicin versus vehicle in NGF-treated rats and 39.6 +/- 3.3 versus 18.0 +/- 1.0 mm Hg (p<0.001) for capsaicin versus vehicle in TNBS-treated rats. These data suggest that the action of NGF on sensory neurons contributes to the development of visceral hypersensitivity and that anti-NGF strategy may be of some therapeutic benefits in digestive sensory disorders.

Animals↗
PubMed2003

Orally administered paracetamol does not act locally in the rat formalin test: evidence for a supraspinal, serotonin-dependent antinociceptive mechanism.

BACKGROUND: The mechanism of action of paracetamol (acetaminophen) remains elusive because it is still under discussion as to whether it acts locally and/or centrally. The primary aim of this study was to clarify its site(s) of action (central and/or local) using the rat formalin test. METHODS: Spontaneous biting and licking of the injected paw following intraplantar injection of formalin 2.5% was monitored during the two phases of nociceptive behavior (0-5 and 20-40 min after injection), and the authors examined the antinociceptive activity of paracetamol following oral, intravenous, intraplantar, and intrathecal administrations as well as the reversion of this effect by an intrathecal injection of WAY 100,635, a selective 5-HT1A receptor antagonist. RESULTS: The oral administration of paracetamol (300, 400 mg/kg) reduced nociceptive behavior in both phases (400 mg/kg: 36.9 +/- 4.6% and 61.5 +/- 5.2% of inhibition in phases I and II, respectively, P <0.05), whereas lower doses reduced primarily the score of the second phase of the test. Only high doses of 10 to 20 mg/kg intraplantarly administered paracetamol, which were ineffective when administered subcutaneously, produced a significant but limited reduction in the early phase of the test and had no effect on the second phase or any antiinflammatory activity. Thus, this local effect did not seem to participate in the antinociceptive action of 400 mg/kg orally given paracetamol, which was totally blocked in both phases by an intrathecal injection of 40 microg WAY 100,635 per rat. Such an inhibition was not observed when paracetamol (200 microg per rat) was intrathecally coinjected with WAY 100,635, whereas the antinociceptive action of 5-HT (50 microg per rat, intrathecally) during both phases of pain was inhibited by WAY 100,635 (intrathecally). CONCLUSIONS: Orally administered paracetamol does not seem to exert any relevant local action in the formalin model of tonic pain in rats, but it might activate the serotonergic bulbospinal pathways via a supraspinal site of action that remains to be elucidated.

Acetaminophen↗
PubMed2003

[Antinociceptive mechanism of action of paracetamol].

The mechanism of action of paracetamol (acetaminophen) is still not clearly understood. Unlike morphine, for example, paracetamol has no known endogenous high-affinity binding sites. In addition, paracetamol does not appear to share with nonsteroidal anti-inflammatory drugs (NSAIDs) the capacity to inhibit peripheral cyclo-oxygenase (COX) activity. There is currently considerable evidence to support the hypothesis of a central antinociceptive effect. Although various biochemical studies point to inhibition of central COX-2 activity, the existence of a COX activity that is selectively susceptible to paracetamol (COX-3?) is an alternative hypothesis. Modulation of the serotoninergic system has also been suggested on the basis of biochemical and behavioural studies supporting an indirect serotoninergic (5-HT) effect. Paracetamol may stimulate the activity of descending 5-HT pathways that inhibit nociceptive signal transmission in the spinal cord. Support for this possibility has come from evidence that spinally administered antagonists of several 5-HT receptor subtypes abolish the antinociceptive activity of paracetamol. These hypotheses have yet to be confirmed by further studies. Until then, the primary pharmacological mechanism underlying the analgesic effect of paracetamol has still to be clearly defined.

Acetaminophen↗