Hsi-Chien Shih

Targeting P2X7 receptor for the treatment of central post-stroke pain in a rodent model

Stroke is a leading cause of death and disability in industrialized countries. Approximately 8-14% of stroke survivors suffer from central post-stroke pain (CPSP) when hemorrhagic stroke occurs in lateral thalamic regions, which severely affects their quality of life. Because the mechanisms of CPSP are not well understood, effective treatments have not been developed. In the present study, we tested the hypothesis that persistent CPSP is caused by P(2)X(7)receptor activation after brain tissue damage and subsequent elevations in inflammatory cytokines. A thalamic hemorrhagic rat model was used, characterized by thermal and mechanical allodynia that develops in the subacute to chronic phases upon CPSP onset. We found a significant increase in P(2)X(7) expression in reactive microglia/macrophages in thalamic peri-lesion tissues at 5 weeks post-hemorrhage. Thalamic P(2)X(7) receptors were directly involved in pain transmission and hypersensitivity. The systemic targeting of P(2)X(7) receptors during the acute stage of hemorrhage rescued abnormal pain behaviors and neuronal activity in the thalamocingulate pathway by reducing reactive microglia/macrophage aggregation and associated inflammatory cytokines. After CPSP onset, the targeting of interleukin-1β reversed abnormal pain sensitivity. The aberrant spontaneous thalamocortical oscillations in rats with CPSP were modulated by blocking P(2)X(7) receptors. Taken together, our results suggest that targeting P(2)X(7) may be bi-effective in the treatment of CPSP, as both a pain blocker and immunosuppressant that inhibits inflammatory damage to brain tissue. P(2)X(7)receptors may serve as a potential target to prevent the occurrence of CPSP and may be beneficial for the recovery of patients from stroke.

Electrically and mechanically evoked nociceptive neuronal responses in the rat anterior cingulate cortex

The present study examined nociceptive properties of anterior cingulate cortical (ACC) neurons following application of peripheral noxious electrical and mechanical stimulations to anesthetized rats. Among a total of 108 recorded neurons, 59 units were excited or inhibited by noxious electrical or mechanical stimulation. Of these 59 cells, 38% were located in area 24b, another 38% were located in area 8, and the remaining cells were located in areas 24a and 25. The noxious stimulus-responsive neurons were located predominately in layers V (58%) and III (30%), and the remaining cells were located in layers II and VI. The latency of evoked unit activities was 209.75 +/- 26.62 ms and the threshold of the ACC responses was 10 times greater than that in primary somatosensory cortex (SI). Morphine treatment (5 mg/kg, i.v.) increased activity in evoked ACC neurons. This effect was reversed by naloxone (2 mg, i.v.). Nociceptive neurons in the ACC were distributed in area 24 and motor related regions. The locations and properties of evoked responses indicated that ACC neurons may play a role in avoidance behavior in the context of affective aspects of nociceptive information processing.

Effects of thalamic hemorrhagic lesions on explicit and implicit learning during the acquisition and retrieval phases in an animal model of central post-stroke pain

HighlightsVBC lesions induced thermal hyperalgesia for acquisition and retrieval phases.VBC lesions facilitated conditioned place preference in implicit memory.VBC lesions did not affect spatial learning in explicit memory.VBC lesions did not affect motor function.Our data provide some insights for CPSP and learning memory. ABSTRACT Hemorrhagic stroke has many symptoms, including central pain, learning and memory impairments, motor deficits, language problems, emotional disturbances, and social maladjustment. Lesions of the ventral basal complex (VBC) of the thalamus elicit thermal and mechanical hyperalgesia, forming an animal model of central post‐stroke pain (CPSP). However, no research has yet examined the involvement of learning and memory in CPSP using an animal model. The present study examined whether VBC lesions affect motor function, conditioned place preference (CPP; implicit memory), and spatial learning (explicit memory) in the acquisition and retrieval phases. The results showed that rats with VBC lesions exhibited thermal hyperalgesia in the acquisition and retrieval phases, indicating that these lesions can induce CPSP. During these phases, the rats with VBC lesions exhibited enhanced (morphine‐induced) CPP learning. These lesions did not affect the rats’ total distance travelled, time spent, or velocity in the spatial learning tasks. The lesions also did not affect motor function in the rotarod task. Altogether, VBC lesions resulted in CPSP and facilitated CPP (implicit memory). However, the lesions did not affect spatial learning (explicit memory) or motor function. The relationship between CPSP and learning and memory is important for patients who suffer from such central pain. The implications of the present study may provide insights into helping reduce CPSP and its associated symptoms.

Cingulate seizure-like activity reveals neuronal avalanche regulated by network excitability and thalamic inputs

BackgroundCortical neurons display network-level dynamics with unique spatiotemporal patterns that construct the backbone of processing information signals and contribute to higher functions. Recent years have seen a wealth of research on the characteristics of neuronal networks that are sufficient conditions to activate or cease network functions. Local field potentials (LFPs) exhibit a scale-free and unique event size distribution (i.e., a neuronal avalanche) that has been proven in the cortex across species, including mice, rats, and humans, and may be used as an index of cortical excitability. In the present study, we induced seizure activity in the anterior cingulate cortex (ACC) with medial thalamic inputs and evaluated the impact of cortical excitability and thalamic inputs on network-level dynamics. We measured LFPs from multi-electrode recordings in mouse cortical slices and isoflurane-anesthetized rats.ResultsThe ACC activity exhibited a neuronal avalanche with regard to avalanche size distribution, and the slope of the power-law distribution of the neuronal avalanche reflected network excitability in vitro and in vivo. We found that the slope of the neuronal avalanche in seizure-like activity significantly correlated with cortical excitability induced by γ-aminobutyric acid system manipulation. The thalamic inputs desynchronized cingulate seizures and affected the level of cortical excitability, the modulation of which could be determined by the slope of the avalanche size.ConclusionsWe propose that the neuronal avalanche may be a tool for analyzing cortical activity through LFPs to determine alterations in network dynamics.

Cardioprotection induced in a mouse model of neuropathic pain via anterior nucleus of paraventricular thalamus

Myocardial infarction is the leading cause of death worldwide. Restoration of blood flow rescues myocardium but also causes ischemia-reperfusion injury. Here, we show that in a mouse model of chronic neuropathic pain, ischemia-reperfusion injury following myocardial infarction is reduced, and this cardioprotection is induced via an anterior nucleus of paraventricular thalamus (PVA)-dependent parasympathetic pathway. Pharmacological inhibition of extracellular signal-regulated kinase activation in the PVA abolishes neuropathic pain-induced cardioprotection, whereas activation of PVA neurons pharmacologically, or optogenetic stimulation, is sufficient to induce cardioprotection. Furthermore, neuropathic injury and optogenetic stimulation of PVA neurons reduce the heart rate. These results suggest that the parasympathetic nerve is responsible for this unexpected cardioprotective effect of chronic neuropathic pain in mice.Various forms of preconditioning can prevent ischemic-reperfusion injury after myocardial infarction. Here, the authors show that in mice, the presence of chronic neuropathic pain can have a cardioprotective effect, and that this is dependent on neural activation in the paraventricular thalamus.

Network dynamics in nociceptive pathways assessed by the neuronal avalanche model

BackgroundTraditional electroencephalography provides a critical assessment of pain responses. The perception of pain, however, may involve a series of signal transmission pathways in higher cortical function. Recent studies have shown that a mathematical method, the neuronal avalanche model, may be applied to evaluate higher-order network dynamics. The neuronal avalanche is a cascade of neuronal activity, the size distribution of which can be approximated by a power law relationship manifested by the slope of a straight line (i.e., the α value). We investigated whether the neuronal avalanche could be a useful index for nociceptive assessment.FindingsNeuronal activity was recorded with a 4 × 8 multichannel electrode array in the primary somatosensory cortex (S1) and anterior cingulate cortex (ACC). Under light anesthesia, peripheral pinch stimulation increased the slope of the α value in both the ACC and S1, whereas brush stimulation increased the α value only in the S1. The increase in α values was blocked in both regions under deep anesthesia. The increase in α values in the ACC induced by peripheral pinch stimulation was blocked by medial thalamic lesion, but the increase in α values in the S1 induced by brush and pinch stimulation was not affected.ConclusionsThe neuronal avalanche model shows a critical state in the cortical network for noxious-related signal processing. The α value may provide an index of brain network activity that distinguishes the responses to somatic stimuli from the control state. These network dynamics may be valuable for the evaluation of acute nociceptive processes and may be applied to chronic pathological pain conditions.

Involvement of P2X7 Receptors and BDNF in the Pathogenesis of Central Poststroke Pain

Central pain is commonly found in patients with neurological complications that are associated with central nervous system insult, such as stroke. It can result directly from central nervous system injury. Impairments in sensory discrimination can make it challenging to differentiate central neuropathic pain from other types of pain or spasticity. Central neuropathic pain may also begin months to years after the injury, further obscuring the recognition of its association with past neurologic injury. This chapter focuses on the involvement of P2X7 receptor and brain-derived neurotrophic factor (BDNF) in central poststroke pain (CPSP). An experimental animal model is introduced that assesses the pathogenesis of central neuropathic pain, and pharmacological approaches and neuromodulatory treatments of this difficult-to-treat pain syndrome are discussed.

Author Correction: Cardioprotection induced in a mouse model of neuropathic pain via anterior nucleus of paraventricular thalamus

The original version of this Article contained an error in the affiliation of the second author, Ya-Ting Chang. The correct affiliations for Ya-Ting Chang are Institute of Biomedical Sciences, Academia Sinica, Taipei, 115, Taiwan and International Graduate Program in Molecular Medicine, National Yang-Ming University and Academia Sinica, Taipei 115, Taiwan.