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Abstract
Central poststroke pain (CPSP) is a medical complication that arises poststroke and significantly impacts the quality of life and social functioning of affected individuals. Despite ongoing research, the exact pathomechanisms of CPSP remain unclear, and practical treatments are still unavailable. Our review aims to systematically analyse current clinical and preclinical studies on CPSP, which is critical for identifying gaps in knowledge and guiding the development of effective therapies. The review will clarify the clinical characteristics, evaluation scales and contemporary therapeutic approaches for CPSP based on clinical investigations. It will particularly emphasise the CPSP model initiated by stroke, shedding light on its underlying mechanisms and evaluating treatments validated in preclinical studies. Furthermore, the review will not only highlight methodological limitations in animal trials but also offer specific recommendations to researchers to improve the quality of future investigations and guide the development of effective therapies. This review is expected to provide valuable insights into the current knowledge regarding CPSP and can serve as a guide for future research and clinical practice. The review will contribute to the scientific understanding of CPSP and help develop effective clinical interventions.
- Hemorrhage
- Brain
- Spinal Nerves
- Stroke
- Inflammation
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Introduction
Central poststroke pain (CPSP) manifests as neuropathic pain (NP) during either the acute or chronic stages after a cerebrovascular incident (ischaemic or haemorrhagic) resulting from lesions in the central somatosensory pathway.1 Following an intracerebral haemorrhage (ICH), the occurrence rate of CPSP changes between 8% and 46%, a variation attributed to the diverse brain regions impacted, with a likelihood that patients experience a thalamic stroke.2 Additionally, CPSP has been reported in young ischaemic stroke (IS) survivors, with an occurrence rate of 5.9%.3 Typical symptoms of CPSP include persistent headache, spasticity-related pain, shoulder discomfort and musculoskeletal pain.4 Spontaneous pain can manifest immediately or appear several years after a stroke.5
CPSP is often accompanied by symptoms such as anxiety, depression, fatigue and cognitive dissonance as well as physical dysfunction. These comorbidities intensify both the sensitivity and duration of pain, fostering a cyclical relationship between pain and negative emotions. Consequently, this results in limitations in daily activities and a decline in overall well-being.6 Currently, CPSP treatment is based on a combination of drug therapy and non-pharmacological interventions to alleviate pain. However, prolonged drug use often leads to various adverse effects, and the efficacy and underlying mechanisms of non-pharmacological treatments remain incompletely understood. In preclinical studies, animal models serve as tools for investigating the pathogenesis of CPSP and identifying novel therapeutic strategies. However, the animal models used for CPSP research lack comprehensive characterisation. Therefore, comparisons of different animal models, behavioural evaluation protocols and potential pathogenesis of CPSP are essential to identify suitable animal models and advance research in this field.
The increasing studies on CPSP highlight the need for a thorough and systematic analysis of existing research to enhance our understanding of CPSP and encourage novel experimental research. This review aims to provide the first comprehensive and systematic description of pain patterns and clinical manifestations among CPSP patients. This review begins with clinical studies and then moves on to animal models replicating clinical aspects, including evaluation metrics and potential pathogenesis. By summarising the features and mechanisms of CPSP from both clinical and preclinical perspectives, we suggest strategies to identify new therapeutic targets for CPSP. Furthermore, we analyse inadequacies in preclinical research design and data analysis to encourage improvements in experimental methodologies.
Search strategy and selection criteria
For detailed information on the search strategy and selection criteria, please see online supplemental material 1 and online supplemental material 2.
Supplemental material
Supplemental material
Clinical studies
CPSP is a type of NP that frequently develops following cerebrovascular damage to the somatosensory pathways connecting the cortex to the medulla. Unfortunately, a retrospective study has revealed that around 80% of patients with CPSP are not receiving adequate treatment, which affects their quality of life. Clinicians must remain vigilant, use clinical assessments to identify the development of CPSP and promptly administer appropriate treatment to patients.
Clinical features and lesion site
CPSP is a condition that typically manifests within 3–6 months after a stroke. Its cardinal symptoms comprise pain and somatosensory abnormalities. Despite being overlooked as a stroke complication, CPSP affects 36.5% of patients and diminishes their quality of life.7 8 CPSP encompasses diverse types of pain, such as persistent pain, spontaneous intermittent pain and nociceptive hypersensitivity. The pain can be severe and persist for 3 months to several decades, although interspersed with remission periods.9 Spontaneous hyperalgesia can provoke touch-induced pain with normal temperature, although with abnormal sensitivity to pinpricks and heat. Moreover, the affected side of the trunk may experience tearing, burning, freezing or squeezing sensations or pain. Clinicians use two criteria to diagnose the condition: pain that manifests within 6 months after a stroke and imaging evidence of a vascular injury in the susceptible area. For more detailed information, please refer to table 1, which presents data from recent clinical studies.
Patient demographics, clinical characteristics and treatments
The incidence rate of CPSP varies between studies and depends on the brain injury site.10 Recent advances in imaging techniques have helped physicians enhance their understanding of how specific anatomical lesions contribute to CPSP development.3 In patients with IS, CPSP has been observed in 25%–56.1% of cases.11 12 The involvement of the spinothalamic tract (STT) and the thalamic ventral posterior nucleus, situated at the thalamus/pulvinar border zone, is a prerequisite for CPSP.13 The interruption of white matter connections between the thalamus and the cerebral cortex significantly affects the development of CPSP.14 As described in the literature, the primary haemorrhage locations associated with CPSP include thalamic and brain stem/cerebellum lesions.15 16 The primary haemorrhage locations associated with CPSP include the thalamus, the thalamic capsular region, the supratentorial extrathalamic area, the lenticulocapsular region, the internal capsule, the external capsule, the pons, the lateral medulla, the putamen, the basal ganglia, the cortex, the occipital lobe, the temporal lobe, the frontal lobe, the parietal white matter and the caudate nucleus.12 17–21
CPSP often co-occurs with anxiety, depression and sleep disorders.3 Regrettably, anxiety and stress can exacerbate pain, creating a challenging cycle characterised by the mutual reinforcement of negative emotions and pain, thus complicating CPSP treatment. A neural feedback loop exists between the anterior cingulate cortex, a centre for nociceptive processing and the ventral tegmental area, an emotional centre.22 This intricate mechanism plays a role in perpetuating chronic pain and negative emotions,22 thereby complicating the treatment of CPSP. Notably, the interaction between chronic pain and negative emotions implicates diverse neurofunctional networks, including brain regions like the thalamus and primary motor cortex,23 24 both play crucial roles in this process.
Clinical assessment scales
Assessing CPSP can be challenging due to the longitudinal nature required for symptom development and the similarity of symptoms to other chronic pains. Additionally, cognitive impairments resulting from a stroke make self-assessment skills complicated.5 Physicians can use various scales to detect the severity of stroke and CPSP. The National Institutes of Health Stroke Scale assesses the severity of the stroke. At the same time, questionnaires such as the Pain Detect Questionnaire and Douleur Neuropathique 4 can aid in diagnosing NP by identifying neuropathic symptoms and signs.21 These questionnaires clarify the frequency of different pain features. Pain questionnaires or Numerical Rating Scales (using numbers 0–10) can be used for pain assessment during the clinical examination of a stroke patient.5 Quantitative sensory testing semiobjectively evaluates the central sensitivity in the somatosensory pathway in NP, allowing long-term pain tracking and disease development recording. The Visual Analogue Scale assesses spontaneous pain intensity, while the NP symptom inventory evaluates pain intensity with its psychometric properties.25 The Patient Global Impression of Change scale gauges the degree of general pain improvement.17 The tactile sensation subscale of the Nottingham Sensory Assessment can be used to evaluate the somatosensory function, with a total score of 20. These scales have been used in various ways in clinical research and trials.
Clinical treatment
CPSP poses several unanswered questions compared with other pain syndromes. Its pathophysiological mechanism remains unclear.26 Furthermore, there is no established gold-standard drug for CPSP treatment.26 Clinical research suggests pharmacological and non-pharmacological interventions help manage CPSP.10 Currently, the primary clinical treatments for CPSP include analgesics, neuromodulation technology and other potential treatments. For more detailed information, please refer to online supplemental material 3, which presents treatments used in clinical studies.
Supplemental material
In summary, CPSP is likely to occur when patients present with pain and somatosensory abnormalities, accompanied by anxiety, depression, sleep disturbance and other brain dysfunctions due to cerebrovascular impairment impacting medulla-to-cortex somatosensory pathways. Since the exact aetiology and pathogenesis of CPSP are unclear, the diagnosis mainly relies on clinical evaluation. Various scales can help doctors evaluate the severity of pain and treatment efficacy. Additionally, based on current research evidences, drugs such as gabapentin have shown curative effects, and neurostimulation therapies are viable options for resistant cases.
Clinical studies have limitations when exploring new treatments and uncovering potential causes of CPSP. Therefore, it is necessary to conduct preclinical studies using animal experiments. Due to the high incidence of CPSP and the lack of adequate clinical treatments, preclinical studies have become important. Preclinical studies on CPSP have seen a notable rise, offering valuable insights into this condition’s mechanisms and impact.
Preclinical studies
Developing appropriate animal models and evaluation criteria is crucial to advance clinical research and identify effective therapies for CPSP. Over the years, researchers have established rodent and primate models of CPSP by inducing a focal stroke to create a lesion toward the thalamic ventral posterolateral nucleus (VPL).27 28 To monitor pain changes after CPSP induction, researchers evaluate mechanical, cold and thermal pain. They also assess the impact of CPSP by evaluating various behavioural changes in CPSP animals, including anxiety and depression-like behaviours, motor coordination and cognitive functions. The impact of these evaluations and the promising results of various therapeutic interventions tested in CPSP animal models, thanks to the advances in animal models and evaluation criteria, inspire and motivate further research. These advances contribute to furthering our understanding of CPSP and identifying effective therapies. Research on CPSP caused by IS mainly focuses on central sensitisation, neuroinflammation, neuroplasticity, brain dysfunction and neuronal damage (table 2). On the other hand, ICH-induced CPSP research focuses on central sensitisation/disinhibition, neuroinflammation, spinal cord-thalamic tract dysfunction and neurotoxicity (table 3). We will discuss the mechanisms in detail below.
The pathophysiological mechanism of CPSP caused by ischaemic stroke in rodents
The pathophysiological mechanism of CPSP caused by thalamus haemorrhage in rodents and non-human primates
Preclinical models
The CPSP model induced by IS
CPSP can manifest after an IS. Various techniques are employed to establish rodent models of CPSP, including bilateral common carotid artery occlusion, photochemically induced thrombosis and endothelin-1-induced ischaemia in the ventral basal complex (VBC) area. In DDY mice (an outbred rodent strain), a model of cerebral ischaemia is typically induced through temporary occlusion of the bilateral common carotid artery using Sugita standard aneurysm clips for 30 min, resulting in observed hyperalgesia on day 3 via mechanical stimulation testing.26 Conversely, C57BL/6 mice have been used to develop a long-lasting CPSP mouse model after photochemically induced thrombosis, exhibiting hypersensitivity to electrical stimulation on both paw sides, although without abnormal pain responses in thermal or mechanical nociception tests.29 Studies using SD rats have demonstrated that ischaemia can be induced by injecting endothelin-1 into the VBC area, targeting the right ventral posterior thalamic nuclei at specific coordinates: anteroposterior: 3.00 mm, mediolateral: −3.00 mm, dorsoventral: 6.00 mm. This injection results in transient ischaemia and cerebral infarction, leading to a reduced thermal pain threshold but no change in the mechanical pain threshold.30 The absence of increased sensitivity to touch in this model may be due to differences in lesion size, location and mechanisms. These studies indicate that while hypersensitivity is discernible in these three CPSP models induced by IS, there are variations in the induced stimulation, highlighting the intriguing diversity of responses in these models.
The CPSP model induced by thalamic haemorrhage
When simulating pain after thalamic haemorrhage, researchers usually target the right VPL or VBC region. However, the location of these regions in the brain varies between species. For rat CPSP models, the stereotaxic coordinates usually range from anterior to 2.4–3.8 mm, left to 2.8–3.6 mm and ventral to 5.5–6.4 mm.31 32 Meanwhile, stereotaxic coordinates for establishing the mouse CPSP model are anterior: −0.82 to 2.30 mm; left: −1.30 to 1.95 mm; ventral: −3.01 to 4.25 mm.33 The stereotaxic location of VPL in non-human primates is determined based on MRI.28 34 In these models, collagenase VII-s, IV (0.025 U/0.25 µL) or autologous blood (25 µL) is injected into these precise locations to induce CPSP.27 32 SD rats usually weigh between 200 and 400 g, while CD1 or C57BL/6 mice are typically 7–8 weeks old. Researchers evaluate mechanical, thermal and cold pain to assess the model’s success.
Evaluation metrics
Allodynia, hyperalgesia and spontaneous pain manifest in patients with CPSP after a stroke. While the CPSP rodent model can replicate human conditions to a certain extent, direct evaluation of rodent pain sensation is challenging. As a result, indirect assessments using mechanical, cold and heat pain modalities are employed to represent pain manifestations, including allodynia and hyperalgesia, characterised by abnormal pain responses to normal or mildly painful stimuli.
Different protocols exist to detect mechanical, cold and thermal pain in rodents with CPSP. Each pain measurement protocol has pros and cons, and we will analyse them individually to help identify the most suitable option. Furthermore, tests are available to evaluate common complications of CPSP, such as mood disorders and cognitive dysfunction. We will also compare these tests and provide a comprehensive assessment.
Mechanical pain
Mechanical pain assessment is a widely used method to evaluate the behaviour of rodents with CPSP. Typically, the assessment lasts between 7 and 28 days. Pain is present bilaterally,35–37 starting on day 1, peaking between 2 and 7 days, and persisting for 4 weeks.36 38 There have been reported cases of contralateral pain.38–40 In primates with CPSP, mechanical and thermal withdrawal tests detected hind limb paralysis on the opposite side of the body within 2–3 days.39 41 To determine paw withdrawal mechanical threshold (PWMT) in SD rats, researchers often use Von Frey filaments ranging from 2 to 26 g. The threshold is calculated as the average of three minimal forces in consecutive trials, each separated by 5 min.31 37 40 42–44 In CD1 mice, calibrated von Frey filaments (0.07 and 0.4 g) are employed, and calculating paw withdrawal frequency involves using the formula: response frequency=(number of paw withdrawals/10 trials)×100%.33 38
Cold pain
After the induction of CPSP, there is a reduction in the threshold for cold pain in animals.31 Cold allodynia was assessed by quantifying hind paw withdrawal latency in response to acetone or a cold stimulus.45 This can be achieved by applying a single drop of cold acetone to the plantar skin of the hind paw of mice without direct skin contact and scoring their response using a 4-point scale as per the established protocol. Alternatively, cold pain evaluation involves placing the animals on a low-temperature (4°C) aluminium plate and recording the duration before lifting their feet. Most studies reported significant changes in cold pain in the contralateral limbs of mice after a stroke.38
Thermal pain
Regarding research on thermal pain, please refer to online supplemental material 3 for more information.
Anxiety-like and depression-like behaviour
Please refer to online supplemental material 4 for research on anxiety-like and depression-like behaviour.
Supplemental material
Motor coordination and cognitive functions
Please refer to online supplemental material 5 for research on motor coordination and cognitive functions.
Supplemental material
Promising strategies that have been tested in an animal model of CPSP
Researchers have explored effective therapies for CPSP in animal models. One such therapy is the stellate ganglion block, which involves enhancing cerebral blood flow and suppressing HIF-1α/NLR pyrin domain containing 3 (NLRP3) inflammatory signalling, effectively reducing anxiety and depression in CPSP rats.2 New drugs and compounds have also emerged as potential treatments for CPSP. For instance, pretreatment with ZL006 has been found to attenuate haemorrhage-induced thalamic pain.38 At the same time, exogenous 14,15-EET has demonstrated the ability to alleviate mechanical pain by restoring the normal thalamic inhibition state and exhibiting anti-inflammatory effects.27 46 Antidepressants and selective serotonin reuptake inhibitors have also shown positive effects on pain associated with depression and comorbid anxiety in CPSP.47 Regulating genes and proteins have observed positive effects on pain after CPSP. Injection of the tyrosine kinase receptor B -Fc, a brain-derived neurotrophic factor receptor blocker, has been shown to inhibit the nociceptive responses of the medial thalamus.43 Notably, a remarkable reduction in NP has been observed in rats with knocked-out P2X4 receptors.32
Moreover, the signal mediated by the CXC factor one chemokine receptor (CXCR4), derived from stromal cells, is responsible for the interaction between glial-glial and glial-neuronal cells. This signal represents a potential new target for CPSP therapy.35 Additionally, low-frequency electroacupuncture can reduce the haematoma size, inhibit neuronal apoptosis, and alleviate CPSP-induced pain abnormalities. On the one hand, high-frequency electroacupuncture relieves the pain by inhibiting abnormal activation of astrocytes.44 Furthermore, electroacupuncture can effectively relieve CPSP by inhibiting autophagy in the hippocampus.35 Lastly, repetitive transcranial magnetic stimulation therapy can restore altered connectivity between the mediodorsal nucleus and the amygdala in primates with CPSP.34
Several research studies have been conducted to identify the causes and development of CPSP. These studies have used animal models induced by IS or ICH, including rodents and primates, to help clinicians address the treatment challenges associated with CPSP. Various behavioural tests assessing mechanical pain, thermal pain, cold pain, motor coordination and cognitive functions have helped understand the pathophysiology of CPSP. These studies suggest that CPSP may arise due to central sensitisation theory, neuroinflammation, changes in the spinal cord and thalamic tract function, central imbalance and other factors. The findings from these studies and the effective therapies observed in animal models provide the potential for a breakthrough in the clinical treatment of CPSP.
Probable mechanisms of CPSP
CPSP is a commonly occurring NP syndrome that can develop after a stroke. The condition is characterised by allodynia, hyperpathia and sharp, stabbing or burning pain.48 These symptoms result from the pain-related network associated with maladaptive plasticity of the central nervous system (CNS).49 Animal research has indicated that the mechanisms underlying CPSP include central sensitisation theory, neuroinflammation, spinal cord and thalamic tract function changes and central imbalance. A better understanding of the underlying pathophysiological mechanisms of CPSP through research can help physicians identify better treatments for patients.
Central sensitisation theory
Patients suffering from CPSP do not experience pain due to spontaneous generation by their CNS. Instead, neurons’ excessive excitation or spontaneous discharge may generate pain in the thalamus or cortex. Additionally, the functional imbalance between the excitatory and inhibitory systems in the pain pathways can contribute to central sensitisation.1
After the bilateral carotid artery occlusion, abnormal burst firing activity in the thalamic nucleus was reported.50 This injury also affects the primary nociceptive afferent neurons Aβ and C. When the primary afferent neurons are stimulated by nociceptive signals, they transmit pain signals to the secondary afferent neurons via the dorsal horn. These signals are then processed by specific brain regions like the cerebral cortex, leading to bilateral hyperalgesia.51 Additionally, increased inflammatory cytokines within the brain during cerebral ischaemia can cause hyperalgesia through the blood circulation in the hind paw. Please refer to figure 1A for a better understanding.
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.
In models of CPSP with a haematoma in the VPL, increased cortical activity contributes to CPSP.41 Epoxyeicosatrienoic acids play a role in neuronal survival by reducing perithalamic lesions after CPSP in rats. This reduction leads to a decrease in acute steroidogenic regulatory proteins and the production of neurosteroids, which blocks the activation of extrasynaptic δ-subunit gamma-aminobutyric acid A receptors. The output of neurosteroids blocks the disinhibition of hyperexcitability of medial thalamus relay neurons caused by injury.37
During the early stage of CPSP induced by thalamus haemorrhage, in the thalamus and neurons of the lumbar spinal cord dorsal horn (L3–L5), the expression of the voltage-gated Ca2+ channel’s α2δ−1 subunit is upregulated. This leads to an increase in presynaptic Ca2+ flow.52 ICH can also activate excitatory N-methyl-D-aspartate (NMDA) receptors on the postsynaptic membrane, causing an excessive influx of Ca2+ into neurons. This results in an abnormal NO production increase, which activates neuronal nitric oxide synthase (NOS). The influx of Ca2+ and NO ultimately leads to neurotoxicity and brain injury38 or damage to the VPL/ventral posteromedial nucleus/posterior thalamic nucleus system within the dorsal column-medial lemniscus (figure 2A).
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.
The pathogenesis of CPSP could be closely associated with the glial activation and neuronal hyperexcitability that occur in response to thalamic haemorrhage in rats. Specifically, spinal monocyte chemoattractant protein-1 is released, which results in the effects above.53 At present, the treatment of CPSP involves the use of drugs that decrease neuronal excitability,37 indirectly supporting the central axis sensitisation mechanism. However, relative blockers in these pathways should be developed to relieve symptoms in preclinical and clinical trials. Such drugs would be instrumental in targeting the underlying mechanisms of CPSP, thereby providing significant therapeutic benefits to patients.
Neuroinflammation
Neuroinflammation is considered a significant factor in developing chronic pain.40 Apoptosis and inflammation in the VPL also contribute to CPSP.27 Moreover, neuroinflammation can interact with endoplasmic reticulum stress, leading to central sensitisation.42 A review suggests that factors, for instance, inflammasome with the NLR pyrin domain-containing 3 (NLRP3),54 an increased microglial inflammatory response, alteration of GABAergic pathways in thalamic reticular neurons and inhibition of ventral basal interneurons may contribute to CPSP.55 For detailed research on neuroinflammation, please see online supplemental material 6.
Supplemental material
It is essential to recognise that neuroinflammation is a complex process that involves activating various immune cells56 and the secretion of proinflammatory cytokines.57–59 The resulting inflammation reaction can profoundly impact the CNS, leading to hyperexcitability and hyperalgesia.60–62 Given the significant contribution of neuroinflammation to CPSP pathogenesis, it is imperative to develop effective strategies to mitigate this response. Enhancing researchers’ comprehension of neuroinflammation’s basic mechanisms and its impact on CPSP will undoubtedly lead to the development of novel therapeutic interventions and improve the stroke survivors’ quality of life
Changes in the spinal cord and thalamic tract function
The STT is a group of nerve fibres responsible for transmitting pain, temperature, touch and pressure sensations from the trunk and limbs to the thalamus. The continuous activation of the STT can result in central pain, also known as CPSP.1 CPSP implies dysfunction of the pain matrix of the brain and the thalamocortical pathway of the spinal cord and damage to the VBC in the spinal thalamocortical pathway can result in mechanical and thermal hyperalgesia,56 contributing to the development of CPSP. Activating the NLRP3 inflammasome in the cerebral cortex can cause CPSP by decreasing descending projection fibres to the thalamus, reducing GABAergic release and increasing ventral basal neuron excitability.55 Sensory input from the afflicted region is vital in perpetuating spontaneous and elicited pain in CPSP.19 Peripheral nerve blocks in the painful area have been found to halt ongoing pain in CPSP, indicating that it results from maladaptive changes that cause CNS neurons to become sensitised to input from peripheral nerves. Retrograde axonal degeneration within the STT projecting system, triggered by thalamic haemorrhage, underlies subsidiary neuroinflammation and neuronal loss in the spinal dorsal horn.63
The other potential mechanisms
According to the proposed dynamic reverberation theory, an imbalance in the oscillatory pattern of a sensory corticothalamocortical reverberatory loop can result in central pain.38 The STT and the thalamic cingulate gyrus pathways regulate CPSP. Please refer to online supplemental material 7 for the latest findings.
Supplemental material
Discussion and future perspectives
CPSP is a painful condition that occurs following primary brain injury after a stroke. It is characterised by various anatomical, neurochemical and neurophysiological alterations to the CNS, including nerve excitability, neurotoxicity, nerve conduction pathways and neuroinflammation.51 This debilitating complication often leads to somatosensory abnormalities and pain experienced by patients, impairing their quality of life.8 Over the years, comprehensive researchs have been conducted, including clinical and preclinical studies, to advance the understanding of CPSP. These studies have focused on epidemiology, treatments, animal models and underlying mechanisms.
The incidence rate of CPSP varies significantly across different studies and lesion sites.10 In clinical settings, pain management interventions such as the use of analgesics (eg, gabapentin, NMDA inhibitors, lamotrigine), neuromodulation technology (motor cortex stimulation, transcranial magnetic stimulation, deep brain stimulation) and other treatments, like acupuncture and mirror therapy, have been applied. Preclinical models have also been used to understand the underlying mechanisms of CPSP induction. These models include IS and ICH, which have been used to explore various potential mechanisms of CPSP, including central sensitisation theory, neuroinflammation, spinal cord and thalamic tract function alterations, central imbalance and other modifications.
In IS models, alterations in the functioning of Aβ, Aδ and C fibres can lead to hypersensitisation, which in turn causes mechanical changes that activate Caα2δ−1 or Nav1.3. These changes then transmit pain signals to the thalamus, subsequently sending them to the cerebral cortex. CPSP can be triggered by neuroinflammation, often activated by pathways such as toll-like receptor 4/NOS or box-1 high-mobility group/receptor for advanced glycation end products/NOS signalling due to activated glial cells and box-1 high-mobility group.64 The binding of orexin-A and orexin 1 receptors can reduce norepinephrine and 5-hydroxytryptamine signalling, thereby decreasing microglial activation.26 Additionally, increased NOS activity and upregulated enzymes–N(G), N(G)-dimethylarginine dimethylaminohydrolase-1 can contribute to mechanical allodynia.65
The central sensitisation theory in models of ICH posits that injury to the VPL nucleus decreases in 14,15-EET.37 Acute steroidogenic regulatory proteins modulate allopregnanolone, influencing extrasynaptic δ-subunit gamma-aminobutyric acid A receptors and reversing normal thalamic inhibition signalling.37 The interaction between PSD-95/neuronal NOS and NMDA subunits triggers NMDA receptor activation, producing NO and the influx of Ca2+ into thalamic neurons, ultimately influencing pain sensation.38 Neuroinflammation occurs due to damage to the thalamic cell, which releases ATP into the extracellular space. This activates the P2X7 receptors in microglia, releasing brain-derived neurotrophic factor and interleukin-1β, further enhancing glutamate signalling.43 Neuron bursting occurs due to interactions between microglia, astrocytes and neurons initiated by hypoxia-inducible factor 1α/stromal cell-derived factor 1/CXCR4 signalling.35
CPSP pathogenesis may include central sensitisati on, neuroinflammation and other contributory factors. Various models postulate the following underlying mechanisms: alterations in the function of the spinal cord and thalamic tract, NLRP3 activation leading to injury of the cerebral cortex, resulting in a decline in descending projection fibres to the thalamus. This decrease leads to reduced GABAergic releases and an increase in the excitability of ventral neurons. Furthermore, an imbalance occurs integrating the lateral spinal thalamic system, which comprises the lateral thalamic nucleus and the insular lobe, and the medial thalamic system, which includes the anterior cingulate gyrus. Further investigation into these mechanisms and developing effective treatments using animal models could lead to significant advancements in clinical practice.
Table 3 shows the occurrence of mechanical pain on both sides in previous studies. It is worth noting that in the studies where bilateral pain was present, the threshold for pain in the hind paw on the opposite side was lower. This difference could be due to the animal model, injury progression or location. Genotype, microglial state or oestrogen can also affect pain research outcomes. It is essential to mention that all the experimental animals used in the studies were male. Still, there are significant differences between males and females regarding pain perception. Therefore, it is essential to consider sex as a biological variable in preclinical research.35 42 66
Studies have not established the examination of neural circuits in animal models of CPSP. However, the thalamus has played a role in investigating neural circuits in pain. Specifically, a projection from glutamatergic neurons in the posterior thalamic nucleus to glutamatergic neurons in the primary somatosensory cortex is responsible for allodynia induced by tissue injury. In contrast, the parafascicular thalamic nucleus mediates allodynia in a depression-like state.23 These circuits could also be related to CPSP.
To gain a deeper understanding of CPSP, research methods related to neural loops, such as optogenetics and chemogenetics, should be employed in future CPSP studies. Optogenetics, for instance, involves targeting the expression of opsins in specific cell types using viral vectors. The light of particular wavelengths is then used to modulate neuronal excitability.67 On the other hand, chemogenetic technology employs viral vectors to deliver designer receptors activated exclusively by designer drugs, which are activated by clozapine N-oxide.68 Optometry and chemotherapy focus on experimental interventions performed with genetic, anatomical and temporal precision.
The use of optogenetics and chemogenetics in CPSP research represents a novel and exciting approach to exploring the neural circuits involved in pain processing. These cutting-edge research methods have the potential to significantly advance our understanding of CPSP, thereby paving the way for innovative therapeutic interventions for this challenging condition.
Considering specific issues identified in prior studies, we would like to present five points regarding suggested prospectives for future research:
To diagnose CPSP, physicians use a patient’s history, symptoms, signs and lesion location, which require comprehensive clinical assessment scales and specific guidelines. Unfortunately, there is a lack of effective treatment for CPSP, and there is a pressing need to develop drugs and novel non-pharmacological therapies for clinical trials based on the elucidated pathomechanism of CPSP.
Emerging pain research methods such as optogenetics, chemogenetics and neurocircuitry present promising avenues for future investigation, but they have not yet been applied in CPSP research.
Animal models frequently assess mechanical pain, yet establishing an objective measurement protocol remains elusive. Consideration should be given to exploring bilateral hind paw measurements as an alternative to unilateral focus. Although hypersensitivity is observable across CPSP models, variations in the induced stimulation exist. Notably, comprehensive studies on allodynia and spontaneous pain responses are lacking in the literature. Furthermore, employing well-trained researchers is imperative to minimise observer bias in results.
Stimulation hypersensitivity tests may yield similar reactions in decerebrated animals. To enhance the credibility of the findings, it is suggested that tests incorporate effective supraliminal inhibition.
Blinding or randomisation principles are commonly employed in preclinical studies to bolster the credibility of experimental results. However, researchers must elucidate the application of these principles during the experiments.27 28 32 34 36 41 43 69 Therefore, rigorously designed preclinical research must be conducted to enhance understanding of the pathomechanism of CPSP.
Conclusions
The study of CPSP has been subject to continuous research, which has led to progress in understanding its pathogenesis, diagnosis and treatment. A comprehensive analysis of behavioural changes, pathogenic mechanisms and drug interventions in patients and animals has identified therapeutic targets for CPSP, along with the effectiveness of several drugs. These findings provide a foundation for future CPSP treatments, which could involve a combination of pharmacological and non-pharmacological interventions to achieve optimal results. Such an approach could lead to enhanced efficacy and a more comprehensive treatment of CPSP, thereby improving the quality of life for those impacted by this condition.
In conclusion, CPSP requires a thorough comprehension of its underlying mechanisms to facilitate effective pain management. The latest advances in clinical and preclinical research have provided valuable information, including epidemiology, treatment, animal models and mechanisms. These insights offer the potential for more effective pain management strategies for patients, significantly improving their quality of life.
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Acknowledgments
The authors would like to express their gratitude to team members, Ruoqi Ding, Houlian Zhang, Mengyuan Li, Mengke Zhao, Jiaxin Li, Ruoyu Zhang, Xueping Li and Qidi Liu for their contributions.
References
Footnotes
XY, SH, XF and CJ contributed equally.
Contributors XY and SH: writing–original draft, writing–review and editing. XF and CJ: conceptualisation, writing–review and editing. YX, RH, YY, YR-K: writing–original draft. ZX: visualisation. QW, FW, SS, TJW, LH and LW, JianW, MW, YTK and UKB: writing–review and editing. JunyangW, XC and JunminW: conceptualisation, funding acquisition, resources, writing–review and editing.
Funding This work was supported by the National Natural Science Foundation of China (82371339 and U1704166) and the Key Scientific Research Projects of Higher Education Institutions in Henan Province (24A320029).
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
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