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  • 1
    Language: English
    In: European Journal of Pain, 2011, Vol.15(5), pp.451-458
    Description: Previous studies showed that triptans and other 5-HT -receptor agonists attenuate hyper-responsiveness to mechanical stimulation of the face in a rat model of trigeminal neuropathic pain, probably by activating 5-HT -receptors on primary afferent nociceptive fibers. We now tested whether blockade of post-synaptic receptors for the excitatory amino acid glutamate released by these fibers would increase this action. We thus evaluated whether (±)1-hydroxy-3-aminopyrrolidine-2-one (HA-966), an antagonist at the glycine/ -serine site of N-methyl- -aspartate (NMDA)-receptors, would potentiate the anti-allodynic action of dihydroergotamine and zolmitriptan in rats with chronic constriction injury to the infraorbital nerve (CCI-ION). Complementary studies were performed with other NMDA-receptor ligands and in rats with chronic constriction injury to the sciatic nerve (CCI-SN) for comparison. Injury was produced by loose ligatures of the nerves. Responsiveness to mechanical stimulation (vibrissae or hindpaw territories) with von Frey filaments was used to evaluate allodynia 2 weeks after nerve ligature. Rats received NMDA-receptor ligands or saline 20 min before dihydroergotamine (25–100 μg/kg, i.v.) or zolmitriptan (25–100 μg/kg, s.c.). HA-966 (2.5 mg/kg, s.c.), inactive on its own, enhanced the anti-allodynic effects of dihydroergotamine (eightfold increase) and zolmitriptan (threefold increase) in CCI-ION rats, but these drugs exerted no effects in allodynic CCI-SN rats. NMDA-receptor blockade by memantine (5 mg/kg, i.p.) also enhanced, whereas activation at glycine/NMDA site by -cycloserine (3 mg/kg, i.p.) reduced the anti-allodynic properties of zolmitriptan in CCI-ION rats. Combined administration of NMDA-receptor antagonist and 5-HT -receptor agonist may be a promising approach for alleviating trigeminal neuropathic pain.
    Keywords: Trigeminal Neuropathic Pain ; 5-Ht 1b/1d Receptor ; Nmda-Receptor ; Dihydroergotamine ; Zolmitriptan ; Medicine
    ISSN: 1090-3801
    E-ISSN: 1532-2149
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  • 2
    In: PLoS ONE, 2014, Vol.9(7)
    Description: In humans, spinal cord lesions induce not only major motor and neurovegetative deficits but also severe neuropathic pain which is mostly resistant to classical analgesics. Better treatments can be expected from precise characterization of underlying physiopathological mechanisms. This led us to thoroughly investigate (i) mechanical and thermal sensory alterations, (ii) responses to acute treatments with drugs having patent or potential anti-allodynic properties and (iii) the spinal/ganglion expression of transcripts encoding markers of neuronal injury, microglia and astrocyte activation in rats that underwent complete spinal cord transection (SCT). SCT was performed at thoracic T8–T9 level under deep isoflurane anaesthesia, and SCT rats were examined for up to two months post surgery. SCT induced a marked hyper-reflexia at hindpaws and strong mechanical and cold allodynia in a limited (6 cm 2 ) cutaneous territory just rostral to the lesion site. At this level, pressure threshold value to trigger nocifensive reactions to locally applied von Frey filaments was 100-fold lower in SCT- versus sham-operated rats. A marked up-regulation of mRNAs encoding ATF3 (neuronal injury) and glial activation markers (OX-42, GFAP, P2×4, P2×7, TLR4) was observed in spinal cord and/or dorsal root ganglia at T6-T11 levels from day 2 up to day 60 post surgery. Transcripts encoding the proinflammatory cytokines IL-1β, IL-6 and TNF-α were also markedly but differentially up-regulated at T6–T11 levels in SCT rats. Acute treatment with ketamine (50 mg/kg i.p.), morphine (3–10 mg/kg s.c.) and tapentadol (10–20 mg/kg i.p.) significantly increased pressure threshold to trigger nocifensive reaction in the von Frey filaments test, whereas amitriptyline, pregabalin, gabapentin and clonazepam were ineffective. Because all SCT rats developed long lasting, reproducible and stable allodynia, which could be alleviated by drugs effective in humans, thoracic cord transection might be a reliable model for testing innovative therapies aimed at reducing spinal cord lesion-induced central neuropathic pain.
    Keywords: Research Article ; Biology And Life Sciences ; Medicine And Health Sciences ; Research And Analysis Methods
    E-ISSN: 1932-6203
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  • 3
    Language: English
    In: Pain, September 2012, Vol.153(9), pp.1939-1948
    Description: receptor blockade by olcegepant reduced mechanical allodynia induced by infraorbital nerve ligation but not that caused by sciatic nerve ligation in rats. Previous studies showed that 5-hydroxytryptamine (5-HT) receptor stimulation by triptans alleviates neuropathic pain caused by chronic constriction injury to the infraorbital nerve (CCI-ION) but not the sciatic nerve (CCI-SN) in rats. To assess whether such differential effects in the cephalic vs extracephalic territories is a property shared by other antimigraine drugs, we used the same models to investigate the effects of olcegepant, which has an antimigraine action mediated through ( ) receptor blockade. Adult male rats underwent unilateral CCI to the ION or the SN, and subsequent allodynia and/or hyperalgesia were assessed in ipsilateral vibrissal territory or hindpaw, respectively, using von Frey filaments and validated nociceptive tests. c-Fos expression was quantified by immunohistochemistry and interleukin 6 and activating transcription factor 3 (ATF3) mRNAs by real-time quantitative reverse transcriptase-polymerase chain reaction. Like naratriptan (0.1 to 0.3 mg/kg, subcutaneously), olcegepant (0.3 to 0.9 mg/kg, intravenously) markedly reduced mechanical allodynia in CCI-ION rats. In contrast, in CCI-SN rats, mechanical allodynia was completely unaffected and hyperalgesia was only marginally reduced by these drugs. A supra-additive antiallodynic effect was observed in CCI-ION rats treated with olcegepant (0.3 mg/kg intravenously) plus naratriptan (0.1 mg/kg subcutaneously), whereas this drug combination remained inactive in CCI-SN rats. Olcegepant (0.6 mg/kg, intravenously) significantly reduced the number of c-Fos immunolabeled cells in spinal nucleus of the trigeminal nerve and upregulation of ATF3 transcript (a marker of neuron injury) but not that of interleukin-6 in trigeminal ganglion of CCI-ION rats. These findings suggest that CGRP receptor blockade might be of potential interest to alleviate trigeminal neuropathic pain.
    Keywords: 5-Ht1b/1d Receptor Activation ; Atf3 ; C-Fos Immunoreactive Labeling ; Cgrp Receptor Blockade ; Il-6 ; Neuropathic Pain ; Nociceptive Tests ; Medicine
    ISSN: 0304-3959
    E-ISSN: 1872-6623
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  • 4
    Language: English
    In: PLoS ONE, July 14, 2014, Vol.9(7)
    Description: In humans, spinal cord lesions induce not only major motor and neurovegetative deficits but also severe neuropathic pain which is mostly resistant to classical analgesics. Better treatments can be expected from precise characterization of underlying physiopathological mechanisms. This led us to thoroughly investigate (i) mechanical and thermal sensory alterations, (ii) responses to acute treatments with drugs having patent or potential anti-allodynic properties and (iii) the spinal/ganglion expression of transcripts encoding markers of neuronal injury, microglia and astrocyte activation in rats that underwent complete spinal cord transection (SCT). SCT was performed at thoracic T8-T9 level under deep isoflurane anaesthesia, and SCT rats were examined for up to two months post surgery. SCT induced a marked hyper-reflexia at hindpaws and strong mechanical and cold allodynia in a limited (6 cm.sup.2) cutaneous territory just rostral to the lesion site. At this level, pressure threshold value to trigger nocifensive reactions to locally applied von Frey filaments was 100-fold lower in SCT- versus sham-operated rats. A marked up-regulation of mRNAs encoding ATF3 (neuronal injury) and glial activation markers (OX-42, GFAP, P2x4, P2x7, TLR4) was observed in spinal cord and/or dorsal root ganglia at T6-T11 levels from day 2 up to day 60 post surgery. Transcripts encoding the proinflammatory cytokines IL-1[beta], IL-6 and TNF-[alpha] were also markedly but differentially up-regulated at T6-T11 levels in SCT rats. Acute treatment with ketamine (50 mg/kg i.p.), morphine (3-10 mg/kg s.c.) and tapentadol (10-20 mg/kg i.p.) significantly increased pressure threshold to trigger nocifensive reaction in the von Frey filaments test, whereas amitriptyline, pregabalin, gabapentin and clonazepam were ineffective. Because all SCT rats developed long lasting, reproducible and stable allodynia, which could be alleviated by drugs effective in humans, thoracic cord transection might be a reliable model for testing innovative therapies aimed at reducing spinal cord lesion-induced central neuropathic pain.
    Keywords: Intermediate Filament Proteins ; Analgesics
    ISSN: 1932-6203
    Source: Cengage Learning, Inc.
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  • 5
    Language: English
    In: Neuropharmacology, April, 2014, Vol.79, p.432(12)
    Description: To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.neuropharm.2013.12.011 Byline: Benoit Michot, Valerie Kayser, Gerard Bastian, Sylvie Bourgoin, Michel Hamon Abstract: Previous data showed that neuropathic pain induced by mechanical lesion of peripheral nerves responds differently to alleviating drugs at cephalic versus extracephalic level. Because neuropathic pain evoked by anti-cancer drugs differs from that triggered by mechanical nerve lesion, we investigated whether differences between cephalic and extracephalic levels could also be characterized in rodents rendered neuropathic by treatment with the anti-cancer platinum derivative oxaliplatin. C57BL/6J mice received two injections and Sprague-Dawley rats three injections of oxaliplatin (10 mg/kg, i.p.) or its vehicle, with three days intervals. Supersensitivity to mechanical (von Frey filaments), cold (acetone drop) and chemical/inflammatory (formalin) stimulations was assessed in vibrissae and hindpaw territories. Transcripts of neuroinflammatory markers were quantified by real-time RT-qPCR in rat ganglia and central tissues. Oxaliplatin induced mechanical allodynia, cold hyperalgesia and chemical/inflammatory supersensitivity at both hindpaw and vibrissal levels in mice and rats. Acute treatment with gabapentin (30 mg/kg i.p.), morphine (3 mg/kg s.c.) or the 5-HT.sub.1A receptor agonist 8-OH-DPAT (0.16 mg/kg s.c.) significantly reduced oxaliplatin-induced supersensitivity in hindpaw but not vibrissal territory. In contrast, the antimigraine drugs naratriptan (0.1 mg/kg s.c.) and olcegepant (0.6 mg/kg i.v.) decreased oxaliplatin-induced supersensitivity in vibrissal territory only. Among the various markers investigated, only TRPA1 transcript was upregulated in ganglia of oxaliplatin-treated rats. These data showed that oxaliplatin induced supersensitivity to various stimuli in both cephalic and extra-cephalic territories in rodents. Regional differences in the efficacy of drugs to alleviate oxaliplatin-induced allodynia/hyperalgesia further support the idea that mechanisms underlying neuropathic pain have peculiarities at cephalic versus extra-cephalic level. Author Affiliation: (a) INSERM U894 - CPN, Universite Pierre et Marie Curie - Paris 6, Faculte de Medecine Pierre et Marie Curie, Site Pitie-Salpetriere, UMR S677, 91, Boulevard de l'Hopital, Paris F-75013, France (b) Departement de Pharmacologie, Universite Pierre et Marie Curie - Paris 6, Faculte de Medecine Pierre et Marie Curie, Site Pitie-Salpetriere, 91, Boulevard de l'Hopital, Paris F-75013, France Article History: Received 7 August 2013; Revised 6 December 2013; Accepted 9 December 2013
    Keywords: Rodents ; Gabapentin ; Antineoplastic Agents ; Formaldehyde
    ISSN: 0028-3908
    Source: Cengage Learning, Inc.
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  • 6
    Language: English
    In: Neuropharmacology, November 2012, Vol.63(6), pp.1093-1106
    Description: Among receptors mediating serotonin actions in pain control, the 5-HT R is of special interest because it is expressed by primary afferent fibers and intrinsic GABAergic and opioidergic interneurons within the spinal dorsal horn. Herein, we investigated whether GABA and/or opioids contribute to 5-HT R-mediated control of neuropathic pain caused by nerve ligation. Acute administration of 5-HT R agonists (AS-19, MSD-5a, E-55888) was found to markedly reduce mechanical and thermal hyperalgesia in rats with unilateral constriction injury to the sciatic nerve (CCI-SN). In contrast, mechanical hypersensitivity caused by unilateral constriction injury to the infraorbital nerve was essentially unaffected by these ligands. Further characterization of the anti-hyperalgesic effect of 5-HT R activation by the selective agonist E-55888 showed that it was associated with a decrease in IL-1ß mRNA overexpression in ipsilateral L4–L6 dorsal root ganglia and lumbar dorsal horn in CCI-SN rats. In addition, E-55888 diminished CCI-SN-associated increase in c-Fos immunolabeling in superficial laminae of the lumbar dorsal horn and the locus coeruleus, but increased c-Fos immunolabeling in the nucleus tractus solitarius and the parabrachial area in both control and CCI-SN rats. When injected intrathecally (i.t.), bicuculline (3 μg i.t.), but neither phaclofen (5 μg i.t.) nor naloxone (10 μg i.t.), significantly reduced the anti-hyperalgesic effects of 5-HT R activation (E-55888, 10 mg/kg s.c.) in CCI-SN rats. These data support the idea that 5-HT R-mediated inhibitory control of neuropathic pain is underlain by excitation of GABAergic interneurons within the dorsal horn. In addition, 5-HT R activation-induced c-Fos increase in the nucleus tractus solitarius and the parabrachial area suggests that supraspinal mechanisms might also be involved. ► 5-HT receptor agonists reduced mechanical hyperalgesia in sciatic nerve-ligated rats. ► Intrathecal bicuculline blocked 5-HT R-mediated antihyperalgesia in neuropathic rats. ► 5-HT R-mediated antihyperalgesia is unaffected by spinal opioid receptors blockade. ► Both spinal and supraspinal processes contributed to 5-HT R-mediated antihyperalgesia.
    Keywords: Chronic Constriction Injury ; Hyperalgesia ; 5-Ht7 Receptor ; Gaba and Opioid Receptors ; C-Fos ; Spinal Cord ; Pharmacy, Therapeutics, & Pharmacology
    ISSN: 0028-3908
    E-ISSN: 1873-7064
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  • 7
    Language: English
    In: Pain, 2002, Vol.99(3), pp.537-545
    Description: Systemic opioid dosing until adequate analgesia in neuropathic pain may involve intolerable and untreatable side effects. Peripheral opioid receptor mechanisms may participate in the antinociceptive effect of systemic morphine. We evaluated the effect of peripherally injected morphine alone, and the ability of the functional antagonist at the glycine site of the N-methyl-D-aspartate (NMDA) receptor complex (+)-HA966 to modulate the antinociceptive effect of peripheral morphine in a rat model of neuropathic pain. Mononeuropathy was induced by placing four ligatures around the common sciatic nerve. Experiments were performed 2 weeks after the nerve ligature, when the pain-related behavior reached a stable maximum. Rats received injections of either subcutaneous (+)-HA966 (2.5mg/kg) or saline administered 20 min before morphine (50-150 microg injected into the nerve-injured hindpaw). The antinociceptive effect was tested against mechanical (vocalization threshold to hindpaw pressure) or thermal (struggle latency to hindpaw immersion into a 46 degrees C hot water bath) stimuli. In both tests, morphine alone (100-150 microg) produced antinociception. Pretreatment with (+)-HA966 did not potentiate the analgesic effectiveness of the two highest doses of morphine, but it did produce analgesia when combined with a low dose of morphine (50 microg), which did not produce analgesia by itself. These effects were reversed by intraplantar naloxone methiodide (50 microg injected into the nerve-injured hindpaw) indicating a peripherally opioid-mediated mechanism of action. The present studies suggested that combined administration of glycine/NMDA receptor antagonists, and peripherally acting morphine may be an interesting approach in the treatment of neuropathic pain.
    Keywords: Antinociception ; Neuropathic Pain ; Chronic Constriction Injury ; Periphery ; Opioids ; Medicine
    ISSN: 0304-3959
    E-ISSN: 1872-6623
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  • 8
    Language: English
    In: Neuropharmacology, April 2014, Vol.79, pp.432-443
    Description: Previous data showed that neuropathic pain induced by mechanical lesion of peripheral nerves responds differently to alleviating drugs at cephalic versus extracephalic level. Because neuropathic pain evoked by anti-cancer drugs differs from that triggered by mechanical nerve lesion, we investigated whether differences between cephalic and extracephalic levels could also be characterized in rodents rendered neuropathic by treatment with the anti-cancer platinum derivative oxaliplatin. C57BL/6J mice received two injections and Sprague-Dawley rats three injections of oxaliplatin (10 mg/kg, i.p.) or its vehicle, with three days intervals. Supersensitivity to mechanical (von Frey filaments), cold (acetone drop) and chemical/inflammatory (formalin) stimulations was assessed in vibrissae and hindpaw territories. Transcripts of neuroinflammatory markers were quantified by real-time RT-qPCR in rat ganglia and central tissues. Oxaliplatin induced mechanical allodynia, cold hyperalgesia and chemical/inflammatory supersensitivity at both hindpaw and vibrissal levels in mice and rats. Acute treatment with gabapentin (30 mg/kg i.p.), morphine (3 mg/kg s.c.) or the 5-HT receptor agonist 8-OH-DPAT (0.16 mg/kg s.c.) significantly reduced oxaliplatin-induced supersensitivity in hindpaw but not vibrissal territory. In contrast, the antimigraine drugs naratriptan (0.1 mg/kg s.c.) and olcegepant (0.6 mg/kg i.v.) decreased oxaliplatin-induced supersensitivity in vibrissal territory only. Among the various markers investigated, only TRPA1 transcript was upregulated in ganglia of oxaliplatin-treated rats. These data showed that oxaliplatin induced supersensitivity to various stimuli in both cephalic and extra-cephalic territories in rodents. Regional differences in the efficacy of drugs to alleviate oxaliplatin-induced allodynia/hyperalgesia further support the idea that mechanisms underlying neuropathic pain have peculiarities at cephalic versus extra-cephalic level.
    Keywords: Oxaliplatin ; Neuropathic Pain ; Mechanical Allodynia ; Cold Hyperalgesia ; Inflammatory Pain ; Rodents ; Pharmacy, Therapeutics, & Pharmacology
    ISSN: 0028-3908
    E-ISSN: 1873-7064
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  • 9
    Language: English
    In: Pain, 01 October 2000, Vol.88(1), pp.53-60
    Description: The anticonvulsant gabapentin is effective against neuropathic pain, but the primary site(s) and mechanism(s) of action are unknown. In order to explore the relative contribution of spinal versus supra-spinal mechanisms to the antinociceptive effect of gabapentin, this study used two differentially integrated nociceptive tests. We systematically compared the effects of various doses of gabapentin on the paw withdrawal to pressure (PWTP), a spinally coordinated reflex and the vocalization threshold to paw pressure (VTPP), a supra-spinal integrated test in the sciatic nerve constriction rat model of neuropathic pain. In addition, we evaluated the effect of gabapentin on the struggle latency to paw immersion into a non-noxious cold (10 degrees C) water bath. Similar lower doses (1-30 mg/kg) of gabapentin produced potent antinociception in the VTPP test but were devoid of effects on the PWTP. The effect was observed not only on the nerve-injured side, but also, although less pronounced, on the contralateral side. Only the highest dose (100 mg/kg) of the anticonvulsant was able to induce an increase in the nerve-injured paw threshold in both tests. In the thermal test, gabapentin (3, 10 and 30 mg/kg i.p.) dose-dependently increased the response time to the 10 degrees C stimulus. Gabapentin at 100 mg/kg but not at 30 mg/kg produced motor deficits in animals using the rotarod test. Taken together, our findings suggest that low doses of gabapentin have a preferential action on the more integrated pain-related behaviour in neuropathic rats. The present results confirm that gabapentin may be a useful approach for the clinical management of several aspects of neuropathic pain.
    Keywords: Neuropathic Pain ; Gabapentin ; Antinociception ; Paw Withdrawal Threshold ; Vocalization Threshold ; Struggle Latency ; Rat ; Medicine
    ISSN: 0304-3959
    E-ISSN: 1872-6623
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  • 10
    Language: English
    In: Pain, 2000, Vol.88(3), pp.231-238
    Description: The inability of opioids to control pain over time may be influenced by different factors such as drug tolerance, hyperalgesia due to repeated morphine administration or progression of the original disease. In addition, chronic pain may alter morphine tolerance development. This study examined whether chronic morphine exposure differently affects mechanical and thermal stimulus evoked pain-related behaviour in non-operated, nerve-injured and sham-operated rats. Further, we studied the effect of nerve injury and sham surgery on the development of tolerance to the analgesic effect of morphine. Vocalization thresholds to paw pressure and struggle latencies to hindpaw immersion into a 46 degrees C hot-water bath were determined in groups of non-operated rats, nerve-injured (chronic constriction of the sciatic nerve) and sham-operated rats. Immediately thereafter, pretreatment regimens with s.c. injections of either saline or morphine (10 mg/kg) were started. Injections were given twice daily on post-operative days 12-15, when the abnormal pain behaviour in nerve-injured rats is at a stable maximum. On day 16, the effect of an acute dose of i.v. morphine (1 mg/kg) was tested. On day 12 the baseline vocalization threshold and struggle latency were decreased in nerve-injured but not in non- and sham-operated rats. Morphine pretreatment further decreased the vocalization threshold in nerve-injured rats and induced threshold reductions in non- and sham-operated rats. In the thermal test, morphine pretreatment produced no change in baseline latencies in any of the groups. Following morphine pretreatment, acute i.v. morphine on day 16 remained effective against both mechanical and thermal stimuli in non-operated rats, but was strongly reduced in nerve-injured rats. Sham-operated rats displayed a tendency towards a reduced effect of i.v. morphine after morphine pretreatment in the mechanical but not in the thermal test. The results suggest that mechanical afferent systems may be more sensitive to hyperalgesia associated with repetitive morphine injections than thermal systems and that nerve injury facilitates the development of tolerance to morphine analgesia.
    Keywords: Neuropathic Pain ; Antinociception ; Rat ; Test ; Tolerance ; Medicine
    ISSN: 0304-3959
    E-ISSN: 1872-6623
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