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.
Highlights
Spinal cord injury (SCI) is a debilitating state which causes severe motor dysfunctions, loss of bladder control and impairment of sexual function, and chronic pain, especially neuropathic pain [1,2]
Physiological State of Spinal Cord Transected Rats After full recovery from anaesthesia, spinal cord transection (SCT) rats first showed hindlimb paralysis and flabbiness
They moved in their cage without major difficulty and could access food and water as readily as before the surgery, SCT rats stopped gaining weight for the first week after surgery (26.363.8 g, mean 6 S.E.M., n = 8), in contrast to sham-operated animals (+4362 g, mean 6 S.E.M., n = 8); but, afterwards, weight gain was parallel in both SCT- and sham-operated rats (+175.4628.3 g and +171.2612.5 g from day 7 to day 30 post-surgery, respectively, means 6 S.E.M., n = 8 in each group)
Summary
Spinal cord injury (SCI) is a debilitating state which causes severe motor dysfunctions, loss of bladder control and impairment of sexual function, and chronic pain, especially neuropathic pain [1,2]. Several animal models of SCI-induced neuropathic pain have been developed (through spinal cord contusion, compression, ischemia, section; see [4]), each of them displaying different characteristics in terms of localization, duration, type of pain and even responses to drugs. Some studies did provide relevant data regarding treatment efficacy and underlying molecular mechanisms [5,6,7], they focused mostly on pain below the lesion produced by contusion or clip compression of the spinal cord. Lesion-induced neuroinflammatory processes could be highly variable among SCI rats which underwent the very same lesion procedure [10], so that characterization of actual physiopathological mechanisms underlying neuropathic pain might be a real challenge in, at least, some SCI models
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