In this article, the mechanisms of central pain syndrome (CPS) are examined for the purpose of gaining insight into how a unified conscious experience arises from brain and body interaction. We provide a novel etiolog...In this article, the mechanisms of central pain syndrome (CPS) are examined for the purpose of gaining insight into how a unified conscious experience arises from brain and body interaction. We provide a novel etiology for CPS via implementation of the previously proposed 3D Default Space (3DDS) consciousness model in which consciousness and body schema arise when afferent information is processed by corticothalamic feedback loops and integrated via the thalamus. Further, we propose the mechanisms by which CPS represents deficits in dynamic interactions between afferent and efferent signaling. Modern hypotheses of CPS suggest roles for maladaptive neuroplasticity, a deafferentated somatosensory cortex and/or thalamus, and reorganization along the sensory pathways of the spinothalamic tract in the pathogenesis of the painful sensations. We propose that CPS arises when painful sensory signals originating along the maladapted and/or dysfunctional spinothalamic tract become accentuated by the dominant top down mechanisms of the brain.展开更多
Pain in Parkinson’s disease is common, with an estimated prevalence up to 85% of those with the disease. Central pain in Parkinson’s disease is poorly understood and the role of pharmacological treatment, including ...Pain in Parkinson’s disease is common, with an estimated prevalence up to 85% of those with the disease. Central pain in Parkinson’s disease is poorly understood and the role of pharmacological treatment, including the use of dopamine agonists, needs further investigation. Our objective is to discuss a case report of central pain in Parkinson’s disease in an outpatient setting. A 67-year-old-male patient with Parkinson’s disease presented with right-sided pain, which was refractory to non-steroidal anti-inflammatory drugs, acetaminophen, and opioid agonists. The initiation of dopaminergic therapy resulted in a near complete relief of pain. This case illustrates the need for a multidisciplinary approach to better care for Parkinson’s disease patients with central pain, and further study to identify the pathophysiologic mechanism.展开更多
Thalamic hemorrhage can lead to the development of central post-stroke pain.Changes in histone acetylation levels,which are regulated by histone deacetylases,affect the excitability of neurons surrounding the hemorrha...Thalamic hemorrhage can lead to the development of central post-stroke pain.Changes in histone acetylation levels,which are regulated by histone deacetylases,affect the excitability of neurons surrounding the hemorrhagic area.However,the regulato ry mechanism of histone deacetylases in central post-stroke pain remains unclea r.Here,we show that iron overload leads to an increase in histone deacetylase 2expression in damaged ventral posterolateral nucleus neurons.Inhibiting this increase restored histone H3 acetylation in the Kcna2 promoter region of the voltage-dependent potassium(Kv)channel subunit gene in a rat model of central post-stroke pain,thereby increasing Kcna2expression and relieving central pain.However,in the absence of nerve injury,increasing histone deacetylase 2 expression decreased Kcna2expression,decreased Kv current,increased the excitability of neurons in the ventral posterolateral nucleus area,and led to neuropathic pain symptoms.Moreover,treatment with the iron chelator deferiprone effectively reduced iron overload in the ventral posterolateral nucleus after intracerebral hemorrhage,reversed histone deacetylase 2 upregulation and Kv1.2 downregulation,and alleviated mechanical hypersensitivity in central post-stroke pain rats.These results suggest that histone deacetylase 2 upregulation and Kv1.2 downregulation,mediated by iron overload,are important factors in central post-stroke pain pathogenesis and co uld se rve as new to rgets for central poststroke pain treatment.展开更多
In addition to the loss of motor function,~60% of patients develop pain after spinal cord injury.The cellular-molecular mechanisms are not well understood,but the data suggests that plasticity within the rostral,epice...In addition to the loss of motor function,~60% of patients develop pain after spinal cord injury.The cellular-molecular mechanisms are not well understood,but the data suggests that plasticity within the rostral,epicenter,and caudal penumbra of the injury site initiates a cellularmolecular interplay that acts as a rewiring mechanism leading to central neuropathic pain.Sprouting can lead to the formation of new connections triggering abnormal sensory transmission.The excitatory glutamate transporters are responsible for the reuptake of extracellular glutamate which makes them a critical target to prevent neuronal hyperexcitability and excitotoxicity.Our previous studies showed a sexually dimorphic therapeutic window for spinal cord injury after treatment with the selective estrogen receptor modulator tamoxifen.In this study,we investigated the anti-allodynic effects of tamoxifen in male and female rats with spinal cord injury.We hypothesized that tamoxifen exerts anti-allodynic effects by increasing the expression of glutamate transporters,leading to reduced hyperexcitability of the secondary neuron or by decreasing aberrant sprouting.Male and female rats received a moderate contusion to the thoracic spinal cord followed by subcutaneous slow-release treatment of tamoxifen or matrix pellets as a control(placebo).We used von Frey monofilaments and the“up-down method”to evaluate mechanical allodynia.Tamoxifen treatment decreased allodynia only in female rats with spinal cord injury revealing a sexdependent effect.The expression profile of glutamatergic transporters(excitatory amino acid transporter 1/glutamate aspartate transporter and excitatory amino acid transporter 2/glutamate transporter-1)revealed a sexual dimorphism in the rostral,epicenter,and caudal areas of the spinal cord with a pattern of expression primarily on astrocytes.Female rodents showed a significantly higher level of excitatory amino acid transporter-1 expression while male rodents showed increased excitatory amino acid transporter-2 expression compared with female rodents.Analyses of peptidergic(calcitonin gene-related peptide-α)and non-peptidergic(isolectin B4)fibers outgrowth in the dorsal horn after spinal cord injury showed an increased calcitonin gene-related peptide-α/isolectin B4 ratio in comparison with sham,suggesting increased receptive fields in the dorsal horn.Although the behavioral assay shows decreased allodynia in tamoxifen-treated female rats,this was not associated with overexpression of glutamate transporters or alterations in the dorsal horn laminae fibers at 28 days post-injury.Our findings provide new evidence of the sexually dimorphic expression of glutamate transporters in the spinal cord.The dimorphic expression revealed in this study provides a therapeutic opportunity for treating chronic pain,an area with a critical need for treatment.展开更多
Many studies using diffusion tensor tractography（DTT） have demonstrated that injury of the spinothalamic tract（STT） is the pathogenetic mechanism of central post-stroke pain（CPSP） in intracerebral hemorrhage; ho...Many studies using diffusion tensor tractography（DTT） have demonstrated that injury of the spinothalamic tract（STT） is the pathogenetic mechanism of central post-stroke pain（CPSP） in intracerebral hemorrhage; however, there is no DTT study reporting the pathogenetic mechanism of CPSP in cerebral infarction. In this study, we investigated injury of the STT in patients with CPSP following cerebral infarction, using DTT. Five patients with CPSP following cerebral infarction and eight age-and sex-matched healthy control subjects were recruited for this study. STT was examined using DTT. Among DTT parameters of the affected STT, fractional anisotropy and tract volume were decreased by more than two standard deviations in two patients（patients 1 and 2） and three patients（patients 3, 4, and 5）, respectively, compared with those of the control subjects, while mean diffusivity value was increased by more than two standard deviations in one patient（patient 2）. Regarding DTT configuration, all affected STTs passed through adjacent part of the infarct and three STTs showed narrowing. These findings suggest that injury of the STT might be a pathogenetic etiology of CPSP in patients with cerebral infarction.展开更多
BACKGROUND： Central sensitization, a state of increased excitability of nociceptive neurons in the spinal dorsal horn following peripheral tissue injury and/or inflammation, is an important mechanism underlying hyper...BACKGROUND： Central sensitization, a state of increased excitability of nociceptive neurons in the spinal dorsal horn following peripheral tissue injury and/or inflammation, is an important mechanism underlying hyperalgesia and neuropathic pain. Participation of the glutamate-glutamine cycle in central sensitization of the spinal cord remains poorly understood. OBJECTIVE： To determine whether the astrocyte-neuronal glutamate-glutamine cycle is involved in formalin-induced central sensitization in the spinal cord. DESIGN, TIME AND SETTING： A randomized, controlled, animal experiment was performed at the Institute of Orthopedics, Second Hospital, Lanzhou University, China from September 2007 to August 2008. MATERIALS： Methionine sulfoximine （MSO, 0.1 mmol/L）, glutamine （0.25 mmol/L）, and formalin were used for this study. METHODS： A total of 43 male, Sprague Dawley rats, aged 4 months, were randomly assigned to a sham operation group （n = 6） and a model group （n = 37）. Rats in the model group received intrathecal infusion in the spinal cord. 7 days later, 37 model rats were randomly divided into PBS, MSO, glutamine, MSO ＋ glutamine and formalin subcutaneous injection alone groups. The PBS, MSO, glutamine, MSO ＋ glutamine groups were respectively intrathecally injected with PBS, MSO, glutamine, MSO ＋ glutamine （50 μL each）, and then infused with 10 μL of saline. Rats from the sham operation group were not subjected to intrathecal infusion in the spinal cord. At 15 minutes after intrathecal injection, a rat model of formalin-induced inflammatory pain was established by subcutaneous injection of 5% formalin （50 μL） in the left hindpaw. MAIN OUTCOME MEASURES： Changes in spontaneous nociceptive behavior （licking/biting or flinching） were observed following formalin injection into the rat hindpaw. RESULTS： Compared with the PBS group, duration of licking/biting was significantly shortened, and flinching frequency was significantly diminished in the MSO group （P 〈 0.05）. Compared with the MSO group, duration of licking/biting was significantly prolonged, and flinching frequency was significantly increased in the MSO ＋ glutamine group （P 〈 0.05）. There was no significant difference in inflammatory pain behaviors among the sham operation, PBS, glutamine, MSO ＋ glutamine, and formalin subcutaneous injection alone groups （P 〉 0.05）. CONCLUSION： The astrocyte-neuronal glutamate-glutamine cycle in the spinal cord was shown to be involved in central sensitization induced by formalin subcutaneous injection into the hindpaw.展开更多
Applying a stimulating current to acupoints through acupuncture needles–known as electroacupuncture–has the potential to produce analgesic effects in human subjects and experimental animals. When acupuncture was app...Applying a stimulating current to acupoints through acupuncture needles–known as electroacupuncture–has the potential to produce analgesic effects in human subjects and experimental animals. When acupuncture was applied in a rat model, adenosine 5-triphosphate disodium in the extracellular space was broken down into adenosine, which in turn inhibited pain transmission by means of an adenosine A1 receptor-dependent process. Direct injection of an adenosine A1 receptor agonist enhanced the analgesic effect of acupuncture. The analgesic effect of acupuncture appears to be mediated by activation of A1 receptors located on ascending nerves. In neuropathic pain, there is upregulation of P2X purinoceptor 3 （P2X3） receptor expression in dorsal root ganglion neurons. Conversely, the onset of mechanical hyperalgesia was diminished and established hyperalgesia was significantly reversed when P2X3 receptor expression was downregulated. The pathways upon which electroacupuncture appear to act are interwoven with pain pathways, and electroacupuncture stimuli converge with impulses originating from painful areas. Electroacupuncture may act via purinergic A1 and P2X3 receptors simultaneously to induce an analgesic effect on neuropathic pain.展开更多
文摘In this article, the mechanisms of central pain syndrome (CPS) are examined for the purpose of gaining insight into how a unified conscious experience arises from brain and body interaction. We provide a novel etiology for CPS via implementation of the previously proposed 3D Default Space (3DDS) consciousness model in which consciousness and body schema arise when afferent information is processed by corticothalamic feedback loops and integrated via the thalamus. Further, we propose the mechanisms by which CPS represents deficits in dynamic interactions between afferent and efferent signaling. Modern hypotheses of CPS suggest roles for maladaptive neuroplasticity, a deafferentated somatosensory cortex and/or thalamus, and reorganization along the sensory pathways of the spinothalamic tract in the pathogenesis of the painful sensations. We propose that CPS arises when painful sensory signals originating along the maladapted and/or dysfunctional spinothalamic tract become accentuated by the dominant top down mechanisms of the brain.
文摘Pain in Parkinson’s disease is common, with an estimated prevalence up to 85% of those with the disease. Central pain in Parkinson’s disease is poorly understood and the role of pharmacological treatment, including the use of dopamine agonists, needs further investigation. Our objective is to discuss a case report of central pain in Parkinson’s disease in an outpatient setting. A 67-year-old-male patient with Parkinson’s disease presented with right-sided pain, which was refractory to non-steroidal anti-inflammatory drugs, acetaminophen, and opioid agonists. The initiation of dopaminergic therapy resulted in a near complete relief of pain. This case illustrates the need for a multidisciplinary approach to better care for Parkinson’s disease patients with central pain, and further study to identify the pathophysiologic mechanism.
基金supported by the National Natural Science Foundation of China,Nos.U2004106 (to WY),81971061 (to JC)the Key Scientific Research Project of Colleges and Universities in Henan Province,No.21A320039 (to WY)。
文摘Thalamic hemorrhage can lead to the development of central post-stroke pain.Changes in histone acetylation levels,which are regulated by histone deacetylases,affect the excitability of neurons surrounding the hemorrhagic area.However,the regulato ry mechanism of histone deacetylases in central post-stroke pain remains unclea r.Here,we show that iron overload leads to an increase in histone deacetylase 2expression in damaged ventral posterolateral nucleus neurons.Inhibiting this increase restored histone H3 acetylation in the Kcna2 promoter region of the voltage-dependent potassium(Kv)channel subunit gene in a rat model of central post-stroke pain,thereby increasing Kcna2expression and relieving central pain.However,in the absence of nerve injury,increasing histone deacetylase 2 expression decreased Kcna2expression,decreased Kv current,increased the excitability of neurons in the ventral posterolateral nucleus area,and led to neuropathic pain symptoms.Moreover,treatment with the iron chelator deferiprone effectively reduced iron overload in the ventral posterolateral nucleus after intracerebral hemorrhage,reversed histone deacetylase 2 upregulation and Kv1.2 downregulation,and alleviated mechanical hypersensitivity in central post-stroke pain rats.These results suggest that histone deacetylase 2 upregulation and Kv1.2 downregulation,mediated by iron overload,are important factors in central post-stroke pain pathogenesis and co uld se rve as new to rgets for central poststroke pain treatment.
基金supported by COBRE(P30GM149367)the Puerto Rico Science&Technology Trust(2022-00125)+1 种基金MBRS-RISE Program(R25 GM061838)SC1GM144032 program(all to JDM)。
文摘In addition to the loss of motor function,~60% of patients develop pain after spinal cord injury.The cellular-molecular mechanisms are not well understood,but the data suggests that plasticity within the rostral,epicenter,and caudal penumbra of the injury site initiates a cellularmolecular interplay that acts as a rewiring mechanism leading to central neuropathic pain.Sprouting can lead to the formation of new connections triggering abnormal sensory transmission.The excitatory glutamate transporters are responsible for the reuptake of extracellular glutamate which makes them a critical target to prevent neuronal hyperexcitability and excitotoxicity.Our previous studies showed a sexually dimorphic therapeutic window for spinal cord injury after treatment with the selective estrogen receptor modulator tamoxifen.In this study,we investigated the anti-allodynic effects of tamoxifen in male and female rats with spinal cord injury.We hypothesized that tamoxifen exerts anti-allodynic effects by increasing the expression of glutamate transporters,leading to reduced hyperexcitability of the secondary neuron or by decreasing aberrant sprouting.Male and female rats received a moderate contusion to the thoracic spinal cord followed by subcutaneous slow-release treatment of tamoxifen or matrix pellets as a control(placebo).We used von Frey monofilaments and the“up-down method”to evaluate mechanical allodynia.Tamoxifen treatment decreased allodynia only in female rats with spinal cord injury revealing a sexdependent effect.The expression profile of glutamatergic transporters(excitatory amino acid transporter 1/glutamate aspartate transporter and excitatory amino acid transporter 2/glutamate transporter-1)revealed a sexual dimorphism in the rostral,epicenter,and caudal areas of the spinal cord with a pattern of expression primarily on astrocytes.Female rodents showed a significantly higher level of excitatory amino acid transporter-1 expression while male rodents showed increased excitatory amino acid transporter-2 expression compared with female rodents.Analyses of peptidergic(calcitonin gene-related peptide-α)and non-peptidergic(isolectin B4)fibers outgrowth in the dorsal horn after spinal cord injury showed an increased calcitonin gene-related peptide-α/isolectin B4 ratio in comparison with sham,suggesting increased receptive fields in the dorsal horn.Although the behavioral assay shows decreased allodynia in tamoxifen-treated female rats,this was not associated with overexpression of glutamate transporters or alterations in the dorsal horn laminae fibers at 28 days post-injury.Our findings provide new evidence of the sexually dimorphic expression of glutamate transporters in the spinal cord.The dimorphic expression revealed in this study provides a therapeutic opportunity for treating chronic pain,an area with a critical need for treatment.
基金supported by the National Research Foundation(NRF)of Korea Grant funded by the Korean Government(MSIP),No.NRF-2015R1D1A1A01060314
文摘Many studies using diffusion tensor tractography（DTT） have demonstrated that injury of the spinothalamic tract（STT） is the pathogenetic mechanism of central post-stroke pain（CPSP） in intracerebral hemorrhage; however, there is no DTT study reporting the pathogenetic mechanism of CPSP in cerebral infarction. In this study, we investigated injury of the STT in patients with CPSP following cerebral infarction, using DTT. Five patients with CPSP following cerebral infarction and eight age-and sex-matched healthy control subjects were recruited for this study. STT was examined using DTT. Among DTT parameters of the affected STT, fractional anisotropy and tract volume were decreased by more than two standard deviations in two patients（patients 1 and 2） and three patients（patients 3, 4, and 5）, respectively, compared with those of the control subjects, while mean diffusivity value was increased by more than two standard deviations in one patient（patient 2）. Regarding DTT configuration, all affected STTs passed through adjacent part of the infarct and three STTs showed narrowing. These findings suggest that injury of the STT might be a pathogenetic etiology of CPSP in patients with cerebral infarction.
基金the National Science Foundation of China,No.30800333
文摘BACKGROUND： Central sensitization, a state of increased excitability of nociceptive neurons in the spinal dorsal horn following peripheral tissue injury and/or inflammation, is an important mechanism underlying hyperalgesia and neuropathic pain. Participation of the glutamate-glutamine cycle in central sensitization of the spinal cord remains poorly understood. OBJECTIVE： To determine whether the astrocyte-neuronal glutamate-glutamine cycle is involved in formalin-induced central sensitization in the spinal cord. DESIGN, TIME AND SETTING： A randomized, controlled, animal experiment was performed at the Institute of Orthopedics, Second Hospital, Lanzhou University, China from September 2007 to August 2008. MATERIALS： Methionine sulfoximine （MSO, 0.1 mmol/L）, glutamine （0.25 mmol/L）, and formalin were used for this study. METHODS： A total of 43 male, Sprague Dawley rats, aged 4 months, were randomly assigned to a sham operation group （n = 6） and a model group （n = 37）. Rats in the model group received intrathecal infusion in the spinal cord. 7 days later, 37 model rats were randomly divided into PBS, MSO, glutamine, MSO ＋ glutamine and formalin subcutaneous injection alone groups. The PBS, MSO, glutamine, MSO ＋ glutamine groups were respectively intrathecally injected with PBS, MSO, glutamine, MSO ＋ glutamine （50 μL each）, and then infused with 10 μL of saline. Rats from the sham operation group were not subjected to intrathecal infusion in the spinal cord. At 15 minutes after intrathecal injection, a rat model of formalin-induced inflammatory pain was established by subcutaneous injection of 5% formalin （50 μL） in the left hindpaw. MAIN OUTCOME MEASURES： Changes in spontaneous nociceptive behavior （licking/biting or flinching） were observed following formalin injection into the rat hindpaw. RESULTS： Compared with the PBS group, duration of licking/biting was significantly shortened, and flinching frequency was significantly diminished in the MSO group （P 〈 0.05）. Compared with the MSO group, duration of licking/biting was significantly prolonged, and flinching frequency was significantly increased in the MSO ＋ glutamine group （P 〈 0.05）. There was no significant difference in inflammatory pain behaviors among the sham operation, PBS, glutamine, MSO ＋ glutamine, and formalin subcutaneous injection alone groups （P 〉 0.05）. CONCLUSION： The astrocyte-neuronal glutamate-glutamine cycle in the spinal cord was shown to be involved in central sensitization induced by formalin subcutaneous injection into the hindpaw.
文摘Applying a stimulating current to acupoints through acupuncture needles–known as electroacupuncture–has the potential to produce analgesic effects in human subjects and experimental animals. When acupuncture was applied in a rat model, adenosine 5-triphosphate disodium in the extracellular space was broken down into adenosine, which in turn inhibited pain transmission by means of an adenosine A1 receptor-dependent process. Direct injection of an adenosine A1 receptor agonist enhanced the analgesic effect of acupuncture. The analgesic effect of acupuncture appears to be mediated by activation of A1 receptors located on ascending nerves. In neuropathic pain, there is upregulation of P2X purinoceptor 3 （P2X3） receptor expression in dorsal root ganglion neurons. Conversely, the onset of mechanical hyperalgesia was diminished and established hyperalgesia was significantly reversed when P2X3 receptor expression was downregulated. The pathways upon which electroacupuncture appear to act are interwoven with pain pathways, and electroacupuncture stimuli converge with impulses originating from painful areas. Electroacupuncture may act via purinergic A1 and P2X3 receptors simultaneously to induce an analgesic effect on neuropathic pain.
