Pathological Activity in Mediodorsal Thalamus of Rats with Spinal Cord Injury Pain

Whitt, Jessica L.; Masri, Radi; Pulimood, Nisha S.; Keller, Asaf

doi:10.1523/jneurosci.2639-12.2013

Cited by 56 publications

(45 citation statements)

References 76 publications

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“…We obtained single-unit, electrophysiological recordings from urethane-anesthetized rats, as previously described [24,50,61]. Consistent with our previous findings after electrolytic lesions of the spinothalamic tract [13], SCI significantly increased both spontaneous and sensory-evoked responses of PO neurons, as evidenced by comparing peri-stimulus time histograms (Fig.…”

Section: Administration Of Cdk Inhibitor Cr8 Reduces Sci-induced Hypesupporting

confidence: 81%

Cell Cycle Activation Contributes to Increased Neuronal Activity in the Posterior Thalamic Nucleus and Associated Chronic Hyperesthesia after Rat Spinal Cord Contusion

Raver

Piao

et al. 2013

Neurotherapeutics

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Spinal cord injury (SCI) causes not only sensorimotor and cognitive deficits, but frequently also severe chronic pain that is difficult to treat (SCI pain). We previously showed that hyperesthesia, as well as spontaneous pain induced by electrolytic lesions in the rat spinothalamic tract, is associated with increased spontaneous and sensory-evoked activity in the posterior thalamic nucleus (PO). We have also demonstrated that rodent impact SCI increases cell cycle activation (CCA) in the injury region and that post-traumatic treatment with cyclin dependent kinase inhibitors reduces lesion volume and motor dysfunction. Here we examined whether CCA contributes to neuronal hyperexcitability of PO and hyperpathia after rat contusion SCI, as well as to microglial and astroglial activation (gliopathy) that has been implicated in delayed SCI pain. Trauma caused enhanced pain sensitivity, which developed weeks after injury and was correlated with increased PO neuronal activity. Increased CCA was found at the thoracic spinal lesion site, the lumbar dorsal horn, and the PO. Increased microglial activation and cysteine-cysteine chemokine ligand 21 expression was also observed in the PO after SCI. In vitro, neurons co-cultured with activated microglia showed up-regulation of cyclin D1 and cysteine-cysteine chemokine ligand 21 expression. In vivo, post-injury treatment with a selective cyclin dependent kinase inhibitor (CR8) significantly reduced cell cycle protein induction, microglial activation, and neuronal activity in the PO nucleus, as well as limiting chronic SCI-induced hyperpathia. These results suggest a mechanistic role for CCA in the development of SCI pain, through effects mediated in part by the PO nucleus. Moreover, cell cycle modulation may provide an effective therapeutic strategy to improve reduce both hyperpathia and motor dysfunction after SCI.

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Section: Administration Of Cdk Inhibitor Cr8 Reduces Sci-induced Hypesupporting

confidence: 81%

Cell Cycle Activation Contributes to Increased Neuronal Activity in the Posterior Thalamic Nucleus and Associated Chronic Hyperesthesia after Rat Spinal Cord Contusion

Raver

Piao

et al. 2013

Neurotherapeutics

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“…21,67 In experi mental spinothalamic tract lesions in rodents, and in patients with neuropathic pain, extracellular recordings from the ventro posterolateral and central lateral thalamic nuclei show abnormal spontaneous activity. [68][69][70][71] Together, these findings suggest that in patients with CNS diseases, ongoing burning pain might arise from abnormal spontaneous activity in denervated thalamic nuclei.…”

Section: Anatomical Denervationmentioning

confidence: 99%

“…72,73 In diseases that cause loss of connections between primary afferents and second-order neurons, such as ganglionopathy and root avulsion, ongoing burning pain is presumably related to spontaneous hyperactivity in denervated second-order neurons, whereas in lesions of ascending spinothalamic tracts, abnormal bursting activity develops in the thalamus. [68][69][70][71] In these pathological conditions, patients usually manifest a severe thermal-pain sensory deficit.…”

Section: Anatomical Denervationmentioning

confidence: 99%

“…113 The reticularis nucleus and zona incerta are major sources of inhibition of spinothalamic relay nuclei in rodents and primates, and loss of their inhibitory action has been proposed to sustain exaggerated responses to afferent sensory input. 71,139,140 In addition to increased activity in pain-related brain regions, cortical responses during allodynia in humans show changes in their interhemispheric balance, whereby insular responses may predominate in the hemisphere ipsilateral to the site of the allodynic stimulus. 138,141 This paradox has been attributed to disinhibition of ipsilateral spinothalamic pathways, which represent up to 17% of spinothalamic axons in primates 142 and are tonically inhibited when both spinothalamic pathways are intact.…”

Section: Anatomical Denervationmentioning

confidence: 99%

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Reappraising neuropathic pain in humans—how symptoms help disclose mechanisms

2013

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Neuropathic pain--that is, pain arising directly from a lesion or disease that affects the somatosensory system--is a common clinical problem, and typically causes patients intense distress. Patients with neuropathic pain have sensory abnormalities on clinical examination and experience pain of diverse types, some spontaneous and others provoked. Spontaneous pain typically manifests as ongoing burning pain or paroxysmal electric shock-like sensations. Provoked pain includes pain induced by various stimuli or even gentle brushing (dynamic mechanical allodynia). Recent clinical and neurophysiological studies suggest that the various pain types arise through distinct pathophysiological mechanisms. Ongoing burning pain primarily reflects spontaneous hyperactivity in nociceptive-fibre pathways, originating from 'irritable' nociceptors, regenerating nerve sprouts or denervated central neurons. Paroxysmal sensations can be caused by several mechanisms; for example, electric shock-like sensations probably arise from high-frequency bursts generated in demyelinated non-nociceptive Aβ fibres. Most human and animal findings suggest that brush-evoked allodynia originates from Aβ fibres projecting onto previously sensitized nociceptive neurons in the dorsal horn, with additional contributions from plastic changes in the brainstem and thalamus. Here, we propose that the emerging mechanism-based approach to the study of neuropathic pain might aid the tailoring of therapy to the individual patient, and could be useful for drug development.

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“…In addition, there are many unanswered questions regarding the pathophysiology. One model hypothesizes that some NP conditions are the results of thalamic dysregulation, which inhibit the natural pain modulatory system thalamus [7,8].…”

Section: Introductionmentioning

confidence: 99%

Transcranial Direct Current Stimulation in Neuropathic Pain

Ngernyam¹

2014

J Pain Relief

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Neuropathic pain (NP) is one of the most common problems contributing to suffering and disability worldwide. Unfortunately, NP is also largely refractory to treatments, with a large number of patients continuing to report significant pain even when they are receiving recommended medications and physical therapy. Thus, there remains an urgent need for additional effective treatments. In recent years, nonpharmacologic brain stimulation techniques have emerged as potential therapeutic options. Many of these techniques and procedures -such as transcranial magnetic stimulation, spinal cord stimulation, deep brain stimulation, and motor cortical stimulation -have very limited availability, particularly in developing countries. Transcranial direct current stimulation (tDCS) is a noninvasive brain stimulation procedure that has shown promise for effectively treating NP, and also has the potential to be widely available. This review describes tDCS and the tDCS procedures and principles that may be helpful for treating NP. The findings indicate that the analgesic benefits of tDCS can occur both during stimulation and beyond the time of stimulation. The mechanisms of cortical modulation by tDCS may involve various activities in neuronal networks such as increasing glutamine and glutamate under the stimulating electrode, effects on the μ-opioid receptor, and restoration of the defective intracortical inhibition. Additional research is needed to determine (1) the factors that may moderate the efficacy of tDCS, (2) the dose (e.g. number and frequency of treatment sessions) that results in the largest benefits and (3) the long-term effects of tDCS treatment.

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Pathological Activity in Mediodorsal Thalamus of Rats with Spinal Cord Injury Pain

Cited by 56 publications

References 76 publications

Cell Cycle Activation Contributes to Increased Neuronal Activity in the Posterior Thalamic Nucleus and Associated Chronic Hyperesthesia after Rat Spinal Cord Contusion

Cell Cycle Activation Contributes to Increased Neuronal Activity in the Posterior Thalamic Nucleus and Associated Chronic Hyperesthesia after Rat Spinal Cord Contusion

Reappraising neuropathic pain in humans—how symptoms help disclose mechanisms

Transcranial Direct Current Stimulation in Neuropathic Pain

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