Spinal Cord Transection-Induced Allodynia in Rats – Behavioral, Physiopathological and Pharmacological Characterization

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.

Interactive Effects Between Exercise and Serotonergic Pharmacotherapy on Cortical Reorganization After Spinal Cord Injury

“…contributing to neuropathic pain [37]. In fact, allodynia was recently reported in the same rat model of spinal cord transection [38], which encourages further work to clarify the behavioral impact of therapies and the role of cortical reorganization in this model.…”

Analysis of the behavioral, cellular and molecular characteristics of pain in severe rodent spinal cord injury

“…It is likely that pain in the forelimbs of our rats after T3 severe lesions reflects "atlevel" pain, because 3 spinal levels in humans (~30mm) exceed the 5-6 mm distance from T3 to C7-C8 spinal segments in rats. Likewise, evaluation of torso allodynia following T9 complete transection showed spread of sensitivity over a 6 cm 2 region above the level of injury [41], making it reasonable that "at-level" pain following T3 complete transection would encompass the dermatomes innervating the forepaws. We chose to focus our studies on the development of "above-level" in rodents pain due to clinical relevance; "at-level" pain is persistent, disruptive to quality of life and frequently rated categorized as the most disturbing pain experienced by patients with SCI [10; 23;…”

“…Moreover, previous studies have revealed no alterations in "above-level" simple reflex responses and have successfully modeled "at-level" pain using ischemic, excitotoxic and contusive lesions [19; 33; 56; 60]. Few studies have evaluated "at-level" pain in models of severe SCI [41]. Additionally, we confirmed that rats with T3 complete 20 transection were capable of perceiving forelimb stimuli as being aversively painful using the PEAP, which demonstrated that injured rats spent significantly more time in the light chamber when the dark chamber was paired with intermittent stimulation (6g von Frey filament).…”

“…Because spinal cord levels (C7/C8) mediating forelimb sensation in rats are anatomically adjacent (within 3-5mm) to cervical or upper thoracic spinal cord injuries, pain outcomes in the forelimbs likely reflect "at-level" pain, a clinically relevant type of pain experience for SCI patients [24]. Furthermore, there are few studies of "atand above-level" pain behaviors and outcomes in rodent models of the most common form of human injury, severe injury [41].…”

Giving priority to preclinical pain measures resistant to existing drugs for developing innovative analgesics

“…Pregabalin or amitriptyline did not alleviate this allodynia, although opioid analgesics significantly increased the threshold. As the SCT‐induced allodynia was long lasting and reproducible, it would be a reliable preclinical pain measure for selecting analgesic candidates which reduce spinal cord lesion‐associated neuropathic pain (M'Dahoma et al, ). Importantly, anti‐epileptics including pregabalin were ineffective in SCT‐induced allodynia.…”