Article Figures & Data
- Figure 1
The pathophysiological mechanism of CPSP caused by ischaemic stroke. (A) Central sensitisation: It is a phenomenon that may give rise to hypersensitivity, resulting from functional changes in Aβ, Aδ and C fibres. These nerve fibres express specific calcium and voltage-gated sodium channels, such as Caα2δ−1 and Nav1.3, facilitating signal transmission to the thalamus-cerebral cortex. Furthermore, hyperalgesia can occur as a result of inflammatory cytokines. (B) Neuroinflammation: It is a biological process that involves glial cells and signalling pathways, such as HMGB1/TLR4/NOS and HMGB1/RAGE/NOS, which all play a crucial role in the induction of CPSP. A decrease in Orexin A expression also influences the occurrence of CPSP, which reduces the binding of Orexin A and OX1R and a corresponding reduction in the production and release of NE and 5-HT, both essential for CPSP. Microglial activation can also contribute to mechanical allodynia by upregulating DDAH1 and increasing NOS. Furthermore, ischaemic stroke can damage neurons, contributing to the induction of CPSP. CPSP, Central poststroke pain; DDAH1, N(G), N(G)-Dimethylarginine dimethylaminohydrolase 1; ERK, extracellular signal-regulated kinase; 5-HT, 5-hydroxytryptamine; HMGB1, high-mobility group box-1; NE, norepinephrine; NF-κB, nuclear factor kappa-B; NOS, nitric oxide synthase; LC, locus coeruleus; LH, lateral hypothalamus; RAGE, receptor for the advanced glycation end products; RVM, rostral ventromedial medulla; TLR4, Toll-like receptor 4; OX1R, orexin one receptor; VPL, ventral posterolateral nucleus; VPM, ventral posteromedial nucleus.
- Figure 2
The pathophysiological mechanism of CPSP resulting from thalamic haemorrhage. (A) Neuroinflammation: When cells in the thalamus get damaged, ATP is released outside the cell, which triggers the activation of P2X7 receptors in microglia. This process leads to an increase in the levels of BDNF and IL-1β, as well as glutamate signalling. As a result, more neurons start firing frequently along the thalamocingulate pathway, causing abnormal excitability of the surviving neurons in VPL. Additionally, the interactions between microglia, astrocytes and neurons contribute to the development of CPSP through HIF-1α/SDF1/CXCR4 signalling and astrocyte-related mediators, which increases the transmission of pain-related signals. (B) Central sensitisation: It is a phenomenon where the normal inhibitory function of the thalamus is reversed due to reduced levels of 14,15-EET after a thalamic haemorrhage in VPL. This process is mediated by the StAR/AP/δGABAAR signalling, resulting in altered pain perception through Ca2+ influx into thalamic neurons. This process is facilitated by the activation and production of NO by the NMDA receptor, along with the presence of PSD-95/nNOS/NMDA subunits. Furthermore, overexpression of the α2δ−1 subunit increases Ca2+ influx and neurotransmitter release. Damage to the medial lemniscus system or partial damage to the spinothalamic tract can lead to neuropathic pain or bilateral mechanical hypersensitivity through central sensitisation/inhibition.AP, allopregnanolone; BDNF, brain-derived neurotrophic factor; CXCR4, C-X-C chemokine receptor type 4; CPSP, Central poststroke pain; HIF-1α, hypoxia-inducible factor 1α; KCC2, potassium/chloride cotransporter 2; IL-1β, interleukin-1β; MT, middle temporal area; SDF1, stromal cell-derived factor 1; StAR, acute regulatory protein steroidogenic; Po, posterior thalamic nucleus; PSD-95, postsynaptic density protein 95; TIF1, Transcriptional intermediary factor 1; TrkB, tyrosine kinase receptor B; 14,15-EET, 14,15-epoxyeicosatrienoic acids; δGABAAR, δ-subunit gamma-aminobutyric acid A receptor; nNOS, neuronal nitric oxide synthase; NO, Nitric oxide; VPL, ventral posterolateral nucleus; VPM, ventral posteromedial nucleus.
- Table 1
Patient demographics, clinical characteristics and treatments
Stroke type Sex Aged
(years)Lesion site Type of pain Treatment Clinical trials Reference Ischaemic (I) 1 male 60 Dorsal thalamic region: pulvinar, sensory nuclei Pronounced allodynia and burning paresthesia, sharp Motor cortex stimulation (MCS) in the epidural brain Visual Analogue Scale (VAS) 50 I 1 female 32 Right posteroinferior, thalamus (T), occipital cortex, parahippocampal Acute onset of pain and paresthesia Repetitive transcranial magnetic stimulation (TMS) Repetitive TMS 70 Haemorrhagic (H) 1 female 57 T Continuous, tingling and cold sensational – Diffusion tensor tractography 71 H, I 8 males
8 females48–73 T, pons, insula in I, external capsule, lenticulocapsular Burning, pricking, squeezing, aching, hypoesthesia, allodynia Repetitive TMS MCS 12 H, I 17 males
15 females57.7±8.2 Cortex, T, basal ganglia, brainstem Light touching painful, cold or thermal painful, slight pressure painful – Pain Detect Questionnaire, the Leeds Assessment of Neuropathic Symptoms and Signs, douleur neuropathique questionnaire-4 (DN-4) 21 H, I 12 males
2 females58.5±8.9 T, pons, lateral medulla, posterior limb of the internal capsule, putamen Persistent numbness and pain – TMS, contact heat evoked potentials, somatosensory evoked potentials, quantitative sensory testing 20 H, I 16 male
21 female58.9±12.1 – 30 mg duloxetine (once a day) Use duloxetine 72 H, I 39 patients 59.4±11.9 Cortical, subcortical, brain stem/cerebellum, Tactile, mechanical and cold hypoesthesia – Short-form McGill pain questionnaire, brief pain inventory, DN-4, neuropathic pain symptoms inventory 7 H, I, H/I 4 males
4 females37–62 T, basal ganglia, frontal lobe, internal capsule, occipital lobe – Peripheral nerve block Block peripheral nerve 19 H, I, H/I 6 males
4 females41–60 T, middle cerebral artery territory, medulla, brainstem, temporal stem, parietal white matter, basal ganglia – Bilateral deep brain stimulation (DBS) targeting ventral striatum/anterior limb of the internal capsule DBS 18 H, I, H/I 109 male 54 female 63.4±7.9 T, putamen, pons, medulla Moderate sensory disturbance, allodynia and hyperpathia Spinal cord stimulation VAS, Patient global impression of changes 17 H/I 82 patients ≥18 Unilateral brain lesion – Flexible-dose placebo (1–2 tablets a day) or (1–2 tablets of 30 mg/day) Short-form McGill Pain Questionnaire-2, Numerical Rating Scale, Pain Disability Index 73 – 17 patients – DBS or MCS DBS, MCS 74 5 males
4 females57–76 Unilateral thalamic, putaminal, spinal cord Compressing, lancinating,
stinging, burning sensations or twitchingElectrical stimulation the ventral posterolateral nucleus Stereotactic thalamic ventral posterolateral nucleus stimulation 75 – 4 patients – DBS of internal capsule VAS 76 – 42 males, 40 females >50 Use acetaminophen, heat and ice packs Pain assessment survey 77 – 5 patients – DBS targeting ventral striatum/anterior limb of the internal Functional MRI 78 – 1 female 45 Constant burning pain Transcranial direct current stimulation VAS, DN-4, Beck Depression Inventory 79 – 23 patients Contralesionally extensive ongoing pain at the lower extremity Explicit sensory discrimination retraining VAS 11 1 male 68 Left hemisphere Slowly progressive, intense Directional DBS targeting the thalamic left ventrocaudal nucleus DBS 80 – 5 patients 41–67 Intermittent tingling, burning and lancinating sensations. Stellate ganglion block Numerical Rating Scale 81 22 patients ver 19 M1; C3, C4-Anode, over the contralateral supraorbital region-cathode – Transcranial direct current stimulation for 20 min, 5 times weekly, for 2 weeks Brief pain inventory, Beck Depression Inventory, the patient’s quality of life, Euro Quality of Life-5 Dimensions 82 DBS, Deep brain stimulation; DN-4, Douleur neuropathique questionnaire-4; H, Hemorrhagic; I, Ischemic; MCS, Motor cortex stimulation; T, thalamus; TMS, transcranial magnetic stimulation; VAS, Visual analogue scale.
- Table 2
The pathophysiological mechanism of CPSP caused by ischaemic stroke in rodents
Experimental animals Model Behavioural testing Mechanism and lesion site Experimental design Reference DDY mice Bilateral common carotid artery occlusion Paw-withdrawal mechanical threshold (PWMT) (frequency right pain (FRP), 3 days, n=6) Orexin-A/orexin 1 receptor signaling injuries lateral hypothalamus to locus coeruleus and rostral ventromedial medulla B 26 PWMT (FRP, 3 days, n=6) N(G),N(G)-Dimethylarginine dimethylaminohydrolase 1↑- nitric oxide synthetase (NOS)↑ B 65 PWMT (FRP, 3 days, n=6) The association of spinal glial cells with HMGB1/RAGE/NOS or HMGB1/TLR4/NOS B 64 PWMT (FRP, 3 days, n=4) Decreased pain thresholds: ischaemic neuronal damage Not clarified 69 PWMT (FRP, 3 days, n=6) A decrease in hypothalamic orexin A B 83 SD rats Distal middle cerebral artery occlusion Body asymmetry test (neurological deficits (ND), 3–28 days, n=9), Modified Bederson’s score (ND, 3–14 days, n=9), PWL/PWT (no changes) Cortex B, randomisation 84 Endothelin-1 PWL (contralateral pain, 28 days), PWT (no changes), cylinder test (no changes), adhesive removal test (no changes), open field test (no changes), ANY-MAZE test (no changes) Ventral posterolateral nucleus and ventral posteromedial nucleus B, randomisation 30 Wistar rats Left common carotid artery occlusion Neurological assessment (ND, 1–23 days), current perception threshold (right nociception: 5/250/2000 Hz, 3–15 days; left nociception: 5 Hz, 6–7 days/13–15 days, 250/2000 Hz, 3–15 days) Hypersensitisation caused by functional changes in nociceptive primary afferent A fibres↑ B 51 C57BL/6J Photochemically induced thrombosis Electrical stimulation-induced paw withdrawal (250/2000 Hz bilateral nociception, 4–19 days), PWL (bilateral pain, 3–17 days), PMT (up and down bilateral pain, 4–18 days) Lysophosphatidic acid receptor 1 and lysophosphatidic acid receptor three signalling; cortex and striatum B 29 B, Blind; CPSP, central poststroke pain; HMGB1, high-mobility group box-1; ND, neurological deficits; PWL, paw-withdrawal latency; PWT, paw-withdrawal threshold; RAGE, receptor for advanced glycation end products; TLR4, Toll-like receptor 4.
- Table 3
The pathophysiological mechanism of CPSP caused by thalamus haemorrhage in rodents and non-human primates
Animals Model of CPSP Behavioural testing Mechanism and lesion site Experimental design Ref SD rats Right VPL
Collagenase (Coll) IV (0.025U)PWMT (FBP, 7–28 days, n=8)
OFT, novelty-suppressed feeding test, elevated plus maze test, FSTHIF-1α/NLRP3↑ Blind (B), Randomisation (R) 2 PWMT (FBP, 28 days, n=14) Endoplasmic reticulum stress/ inflammation interactions/ central sensitisation B, R 42 PWMT (FBP, 28 days, n=10), PWTL (no changes) 14,15-EET↓/StAR/allopregnanolone/δGABAAR signaling-reversed normal thalamic inhibition B, R 37 PWMT (FBP, 7–28 days, n=10) HIF-1α/SDF1/CXCR4 signalling-microglia-astrocytes-neurons interactions. B, R 35 PWMT (FBP, 7–28 days, n=8) Spinal neuronal MCP-1 as a distant trigger for central sensitisation B, R 53 PWMT (FBP, 7–28 days, n=7) Inflammation and apoptosis B, R 27 PWMT\PWTL (FBP,7, 14 days, n=5), Chronic melatonin administrations↓ stimulating complex I and IV activities B, R 85 Right VPL
25 µL autologous bloodPWMT (FBP 1–21 days, n=7), PWTL (no changes) MiR-133b-3p/purinergic P2X4 receptors↓ in VPL Not clarified 32 PWMT (FBP, 1–21 days, n=8–14), PWTL (no changes) P2X4 receptor↑ in microglia of thalamic perilesional tissues R 36 Right VPM/VPL
Coll IV (0.125U)PWMT (FCP, 7–35 days, n=25), PWTL (7–35 days, n=25) Activation of P2X7 receptors on microglia and BDNF and IL1β-glutamate. Not clarified 43 Right VBC
Coll IV (0.125U)PWMT (FBP, 7–35 days, n=8),
PWTL (FBP, 21–49 days, n=8), Rotarod tests (no changes)The noxious response in the medial thalamus and the alteration of the oscillation pattern of the thalamocortical pathway B, R 40 PWMT/ PWTL (FBP, 7–35 days, n=6–10) The brain’s pain matrix and spinothalamocortical pathway R 86 Right VBC and posterior thalamic nucleus
Coll IV (0.025U)PWMT (FBP, 7–21 days, n=6–8) α2δ−1 subunit↑ in the thalamus and the dorsal horn R 52 CD1 mice Right VPL
Coll IV (0.07U)PWMT (FCP, 3 days, n=8), tail suspension test (21–28 days, n=8) Mediator complex subunit 1/BDNF/TrkB pathway B, R 87 Right VPM and VPL
Coll IV (0.01U/10 µL saline)PWMT (FBP, 1–14 days, n=8), PWTL/cold pain (1–14 days, n=8) TLR4/NF-κB/ERK1/2 in microglia B 33 PWMT/PWTL/cold pain (FCP, 1–28 days, n=10) The protein–protein collaboration between neuronal nitric oxide synthase and postsynaptic density protein 95 in the thalamus B 38 C57BL/6J mice VPM and VPL (right/left)
Coll IV (0.075 U)Bederson score, von Frey test, thermal plate test Inhibition of Panx1 attenuated proinflammatory factors transcription and neurite disassembly R 88 Rhesus macaques VPL (right/left)
Coll IV (200 U/mL saline)PWMT (FCP, 56 days, n=6) Neuronal morphology alteration, including ipsilateral—PIC/SII synaptic loss B 28 PWMT (FCP, 56–84 days, n=4), PWTL (FCP, 28–84 days, n=4) Microglia-astrocyte interaction-abnormal excitability of surviving neurons B 39 Japanese monkeys Left VPL
Coll IV (0.8U/site)PWMT (FCP, 43 days/98–119 days), PWTL (FCP, 98–119 days), cold pain (FCP) (n=2) Functional connectivity↑ between mediodorsal nucleus of the thalamus and amygdala B 34 Macaca mulatta VPL (right/left)
Coll IVPWMT (FCP, 63–273 days, n=5) Cortical activity↑ B 41 BDNF, brain-derived neurotrophic factor; Coll, collagenase; Contra, hind paw contralateral; CPSP, central poststroke pain; CXCR4, C-X-C chemokine receptor type 4; 14,15-EET, 14,15-Epoxyeicosatrienoic acid; ERK, extracellular signal-regulated kinase; FBP, frequency bilateral pain; FCP, frequency contralateral pain; HIF-1α, hypoxia inducible factor 1α; MCP-1, Monocyte Chemoattractant Protein-1; NLRP3, NOD-like receptor family, pyrin domain containing 3; OFT, Open field test; PIC, posterior insular cortex; PWMT, paw-withdrawal mechanical threshold; PWTL, paw-withdrawal thermal latency; SDF1, stromal cell-derived factor 1; SII, secondary somatosensory cortex; StAR, steroidogenic acute regulatory protein; TLR4, Toll-like receptor 4; TrkB, neurotrophic receptor tyrosine kinase 2; VBC, ventral basal complex; VPL, ventral posterolateral nucleus; VPM, ventral posteromedial nucleus; δGABAAR, δ-subunit gamma-aminobutyric acid A receptor.
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