Blockade of the 5-HT 3 receptor for days causes sustained relief from mechanical allodynia following spinal cord injury
ABSTRACT Chronic neuropathic pain is a frequent, serious outcome of spinal cord injury (SCI) that is highly refractory to treatment. Serotonin can contribute to neuropathic pain after SCI, as suggested by our previous observation that transient blockade of the 5-HT(3) receptor by intrathecal injections of the antagonist ondansetron reduces mechanical allodynia after SCI in rats. The current study determined whether intrathecal or intravenous infusion of ondansetron for 3 or 7 days, respectively, could cause sustained blockade of mechanical allodynia at and below the level of a twelfth thoracic clip compression injury in rats. Intrathecal 3-day infusion of ondansetron (2.0 microg/hr), targeted to the cord rostral to the SCI and commencing at 28 days after SCI, decreased at-level mechanical allodynia by 40% and below-level allodynia by 60% compared with saline-treated rats (controls). This reduction was sustained throughout drug delivery and for 1 day afterward. During the next 3 days, allodynia gradually returned toward the values of saline-treated rats. An initial experiment showed that bolus intravenous injections of ondansetron (20-100 microg) at 28 days after SCI decreased both at- and below-level allodynia for 90-120 min. Intravenous 7-day infusions (20 microg/hr), commencing at 28 days after SCI, significantly decreased at-level allodynia by 48% and below-level allodynia by 51% compared with controls. This reduction of allodynia lasted throughout the infusion and for 1-3 days afterward while pain responses gradually approached those of controls. These findings suggest a potential role of 5-HT(3) receptor antagonism in the relief of neuropathic pain after SCI in humans.
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ABSTRACT: 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 cm2) 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.PLoS ONE 07/2014; 9(7):e102027. DOI:10.1371/journal.pone.0102027 · 3.53 Impact Factor
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ABSTRACT: Spinal root avulsion (SRA) produces tactile and thermal hypersensitivity, neurodegeneration and microglial and astrocyte activation in both the deafferented and the adjacent intact spinal cord segments. Following avulsion of the fifth lumbar spinal root, immediate and prolonged treatment with riluzole or minocycline for two weeks altered the development of behavioural hypersensitivity. Riluzole delayed the onset of thermal and tactile hypersensitivity, and partially reversed established pain behaviour. Minocycline effectively prevented and reversed both types of behavioural change. Histological analysis revealed that both drugs reduced microglial staining in the spinal cord, with minocycline being more effective than riluzole. Astrocyte activation was ameliorated to a lesser extent. Surprisingly, neither drug provided a neuroprotective effect on avulsed motoneurons. Immediate treatment of spinal root avulsion injuries with minocycline or riluzole prevents the onset of evoked pain hypersensitivity by reducing microglial cell activation. When treatment is delayed, minocycline, but not riluzole, reverses pre-established hypersensitivity. Thus, these drugs may provide a new translational treatment option for chronic avulsion injury pain.The journal of pain: official journal of the American Pain Society 03/2014; DOI:10.1016/j.jpain.2014.03.001 · 4.22 Impact Factor
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ABSTRACT: Sulfur speciation in a comprehensive set of insoluble organic matter (IOM) samples extracted from 3 CI (Orgueil, Alais, Ivuna), 5 CM (QUE97990, Murchison, Murray, QUE99355, Cold Bokkeveld), 1 CR (Renazzo) and ungrouped C2 Tagish Lake chondrites has been studied by K-edge XANES micro-spectroscopy. Five main sulfur groups were identified: (1) sulfides, (2) aliphatic sulfur, (3) heterocyclic organic sulfur, (4) oxidized organic sulfur and (5) sulfates. The IOM of the 3 CIs and the extensively altered Cold Bokkeveld CM exhibit a higher abundance of heterocyclic versus aliphatic organic sulfur compared to the other CMs and compared to the Renazzo and Tagish Lake chondrites. This suggests greater thermal heating on the parent body of CIs, consistent with the higher temperatures experienced by these chondrites (~70°C for the most altered clasts of Cold Bokkeveld; 100–150°C for CIs). Alais may have experienced more heating than Ivuna and Orgueil. The IOM of CIs contains oxidized organic sulfur, suggesting the presence of a mild-temperature oxidation process on the parent body. Among type 2 chondrites other than Cold Bokkeveld, no significant variation of the sulfur speciation was detected. This suggests tenuous oxidation processes and a low-temperature aqueous alteration (< ~35°C) on the parent body. The global chemical variations between the CR and CM groups (e.g. H/C elemental ratio, alkyl groups concentration) reported in earlier studies appear to be more the result of chemical variations among the accreted precursors than of post-accretional processes.Earth and Planetary Science Letters 12/2010; 300(3):321-328. DOI:10.1016/j.epsl.2010.10.012 · 4.72 Impact Factor