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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.

The present study provides an account of a sensitive and rapid experimental approach for MRI visualization and analysis of spinal cord (SC) laminar activity in normal and injured animals. This approach is based upon neuronal activity-dependant manganese (Mn) uptake after focal SC injection of MnCl2, and subsequent ex-vivo magnetic resonance imaging (MRI) of activated SC pathways. The method was designed as an alternative to time-intensive histochemical and behavioral approaches typically used for analysis of spinal cord injury (SCI) and our results provide both anatomical and functional insights. We show that ex vivo imaging can determine layer-specific activity over an extended region of the rat SC. In addition, we demonstrate that the Mn concentration profile along the SC axis accurately reflects the type of SC injury. The approach is flexible since MRI analysis can be done immediately after animal sacrifice, or alternatively several days later, without a loss of sensitivity. Moreover, the integrity and functional state of SC circuitry can be analyzed in less than 1 h whereas several days and weeks are necessary to perform classical histochemical and behavioral analysis. Thus our method can be used for precise assessment of the extent of dysfunction or change in SC disorders and may facilitate the screening of molecules with therapeutic potential after SC injury.