Late-Onset Thermal Hypersensitivity after Focal Ischemic Thalamic Infarcts as a Model for Central Post-Stroke Pain in Rats

Abstract

Central post-stroke pain (CPSP) is a neuropathic pain syndrome that often develops in a delayed manner after thalamic stroke. Here, we describe a new model of CPSP by stereotaxic thalamic injection of endothelin-1. Stroke rats (n = 12), but not saline-injected controls (n = 12), developed a progressive, contralateral cutaneous thermal hyperalgesia over 4 weeks, without motor deficits. Lesions were highly focal and mainly affected the ventral posterior thalamic complex. Tchis model reproduces the infarct location and delayed hypersensitivity typical of CPSP, and may be useful to investigate its pathophysiology and test therapies targeting recovery and pain after thalamic stroke. INTRODUCTIONCentral post-stroke pain (CPSP) is a neuropathic pain syndrome characterized by constant or recurrent pain after central nervous system injury. 1 Central post-stroke pain can be triggered by either an ischemic or hemorrhagic infarct at any level of the spinothalamic pathway and its cortical projections often involving the thalamus. 2 Central post-stroke pain is frequently overlooked, and can be misdiagnosed as musculoskeletal pain resulting from paresis and/or muscle tone abnormalities. 3 Epidemiological data are scarce, probably because of the difficulty in interpreting the clinical signs and the variable symptom onset. Thus, CPSP is often perceived as a rare event. 4 However, the true incidence in stroke patients is as high as 8% to 11%. 5 The pathophysiology of CPSP is still poorly understood, and therapeutic options are limited in part owing to a lack of clinically relevant animal models. 6 For example, experimental CPSP models involving thalamic hemorrhage all show acute onset of the pain symptoms, 7,8 in contrast to the delayed onset of CPSP several weeks later in patients. 4 To address these shortcomings, we aimed to develop a new experimental model that better mimics the lateonset hypersensitivity seen in CPSP patients. Recently, two clinical reports linked CPSP to more posterior, inferior, and lateral thalamic infarcts, clustering at the ventral posterior thalamic nuclei. 9,10 These relay nuclei receive inputs from medial lemniscus, spinothalamic, and trigeminothalamic tracts, and project to the somatosensory cortex where noxious and non-painful, thermal, and mechanical stimuli are processed. We, therefore, targeted the ventral posterior thalamic complex by using stereotaxic microinjections of endothelin-1 to create highly focal ischemic lesions in rats.

Late-onset hypersensitivity after a lesion in the ventral posterolateral nucleus of the thalamus: A macaque model of central post-stroke pain

“…In a majority of patients with CPSP, however, the onset of abnormal pain often occurs several weeks after a cerebrovascular accident 2 . A similar delay in the onset of CPSP was recently reported in rats in which a focal ischemic lesion in the thalamus was induced by injection of endothelin-1 34 . Unfortunately, this animal model exhibited thermal hyperalgesia but not mechanical allodynia, which is one of the most common symptoms of CPSP 35 , 36 .…”

“…The different behavioral changes in rodent CPSP models depending on the methods for lesion induction may reflect the different effects of hemorrhagic and ischemic strokes on the development of central pain. However, variations in lesion size might also contribute to the differences in behavioral changes, because lesions in the ischemic model were smaller than in the hemorrhagic models 17 , 18 , 20 , 34 .…”

Botulinum Toxin for Central Neuropathic Pain

“…These results have also been demonstrated in animal model experiments. Thermal hypersensitivity was observed in a rat model of the ventral posterior thalamic infarction [ 36 ], with thermal and mechanical hyperalgesia developing in rats with a thalamic hemorrhagic lesion [ 37 ].…”

Electroacupuncture Treatment Alleviates Central Poststroke Pain by Inhibiting Brain Neuronal Apoptosis and Aberrant Astrocyte Activation

“…As a type of the neuropathic pain, central poststroke pain (CPSP) is one of the most troublesome sequelae of stroke, which can be caused by a primary lesion that affects the central somatosensory system following intracerebral hemorrhagic stroke [ 1 ]. In the clinic, patients exhibit thermal and mechanical hyperalgesia, which produces a low quality of life.…”