Spinal-, brainstem- and cerebrally mediated responses at- and below-level of a spinal cord contusion in rats: Evaluation of pain-like behavior

Abstract

Pain is a frequent consequence of spinal cord injury (SCI) which may profoundly impair the patients' quality of life. Valid experimental models and methods are therefore desirable in the search for better treatments. Usually, experimental pain assays depend on stimulus-evoked withdrawal responses; however, this spinal-mediated reflex response may be particularly problematic when evaluating below-level SCI pain due to the development of hyperactive reflex circuitries. In this study, we applied and compared assays measuring cold (acetone), static (von Frey filaments), and dynamic mechanical (soft brush) hypersensitivity at different levels of the neuroaxis at and below the level of injury in a rat model of SCI. We induced an experimental SCI (MASCIS 25 mm weight-drop) and evaluated the development of spinal reflexes (withdrawal), spinal-brainstem-spinal reflexes (licking, guarding, struggling, vocalizing, jumping, and biting) and cerebral-dependent behavior (place escape/avoidance paradigm (PEAP)). We demonstrated increased brainstem reflexes and cerebrally mediated aversive reactions to stimuli applied at the level of SCI, suggesting development of at-level evoked pain behavior. Furthermore, stimulation below-level increased innate reflex responses without increasing brainstem reflexes or aversive behavior in the PEAP, suggesting development of the spasticity syndrome rather than pain-like behavior. While spinal reflex measures are acceptable for studying changes in the spinal reflex pathways and spinal cord, they are not suited as nociceptive behavioral measures. Measuring brainstem organized responses eliminates the bias associated with the spastic syndrome, but pain requires cortical involvement. Methods depending on cortical structures, as the PEAP, are therefore optimal endpoints in animal models of central pain.

Translation of the rat thoracic contusion model; part 1—supraspinally versus spinally mediated pain-like responses and spasticity

“…3 This spastic syndrome does not occur as it does in human patients, in whom often the most evident feature of the spastic syndrome is increased muscle resistance/activity (that is, spasticity). However, spasticity in its most common and narrow definition, is defined as a velocity-dependent increase in muscle activity after tonic passive stretch (stretch hyperreflexia).…”

“…1 Both types are difficult to model in animal models, with below-level pain probably being the most challenging. 2, 3 In animal SCI pain models, pain is often investigated by determining hypersensitivity, as is mostly done in dermatomes below the level of injury. [4][5][6] Changes in below-level responses occur almost immediately after rodent SCI and remain for months.…”

“…Indeed, a landmark study on SCI pain in thoracic contused rats was able to show that a reduction in the threshold for BL-WRs can present itself without escape/avoidance behavior to those same stimuli. 3 Thus, reduced paw withdrawal thresholds do not necessarily implicate an increased aversion to the stimulus. Furthermore, a significantly reduced brain activity, which was evoked by electrical stimulation of skin corresponding to belowlevel dermatomes, in similar (but anesthetized) SCI rats has been reported, which actually implicates a state of hypoesthesia, not hyperesthesia.…”

“…Therefore, in the first part of this study we tested a combination of existing paradigms in which sensitivity thresholds for below-level evoked thermal and mechanical stimuli are not assessed with BL-WRs, but with supraspinally mediated above-level escape responses (AL-ERs), 3,[13][14][15][16][17] to see how they relate to the development of BL-WRs. AL-ER thresholds or latencies are defined as force (mechanical) or time (heat) required to elicit (1) escape or struggling behavior or (2) vocalization.…”

Estratégia terapêutica após contusão da medula espinhal: recuperação funcional e estabilidade cortical sensório-motora

“…Dentre as várias alterações decorrentes da lesão medular, a perda de peso tem sido relatada como uma alteração de rápida instalação (Erschbamer et al, 2006;Baastrup et al, 2010;Ramsey et al, 2010).…”