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
Intractable central post-stroke pain（CPSP） is one of the most common sequelae of stroke, but has been inadequately studied to date. In this study, we first determined the relationship between the lesion site and cha...Intractable central post-stroke pain（CPSP） is one of the most common sequelae of stroke, but has been inadequately studied to date. In this study, we first determined the relationship between the lesion site and changes in mechanical or thermal pain sensitivity in a rat CPSP model with experimental thalamic hemorrhage produced by unilateral intra-thalamic collagenase IV（ITC） injection. Then, we evaluated the efficacy of gabapentin（GBP）, an anticonvulsant that binds the voltage-gated Ca2＋ channel α2δ and a commonly used anti-neuropathic pain medication. Histological case-by-case analysis showed that only lesions confined to the medial lemniscus and the ventroposterior lateral/medial nuclei of the thalamus and/or the posterior thalamic nucleus resulted in bilateral mechanical pain hypersensitivity. All of the animals displaying CPSP also had impaired motor coordination, while control rats with intra-thalamic saline developed no central pain or motor deficits. GBP had a dose-related anti-allodynic effect after a single administration（1, 10, or 100 mg/kg） on day 7 post-ITC, with significant effects lasting at least 5 hfor the higher doses. However, repeated treatment, once a day for two weeks, resulted in complete loss of effectiveness（drug tolerance） at 10 mg/kg, while effectiveness remained at 100 mg/kg, although the time period of efficacious analgesia was reduced. In addition, GBP did not change the basal pain sensitivity and the motor impairment caused by the ITC lesion, suggesting selective action of GBP on the somatosensory system.展开更多
The α2δ-1 subunit of the voltage-gated Ca2＋ channel （VGCC） is a molecular target of gabapentin （GBP）, which has been used as a first-line drug for the relief of neuropathic pain. GBP exerts its anti-nociceptive...The α2δ-1 subunit of the voltage-gated Ca2＋ channel （VGCC） is a molecular target of gabapentin （GBP）, which has been used as a first-line drug for the relief of neuropathic pain. GBP exerts its anti-nociceptive effects by disrupting trafficking of the α2δ-1 subunit to the presynaptic membrane, resulting in decreased neurotrans- mitter release. We previously showed that GBP has an anti- allodynic effect in the first two weeks; but this is followed by insensitivity in the later stage after repeated adminis- tration in a rat model of central post-stroke pain （CPSP） hypersensitivity induced by intra-thalamic hemorrhage. To explore the mechanisms underlying GBP insensitivity, the cellular localization and time-course of expression of the α2δ-1 subunit in both the thalamus and spinal dorsal horn were studied in the same model. We found that the α2δ-1 subunit was mostly localized in neurons, but not astrocytes and microglia. The level of α2δ-1 protein increased in the first two weeks after injury but then decreased in the third week, when GBP insensitivity occurred. Furthermore, the c^2g-1 down-regulation was likely caused by later neuronal loss in the injured thalamus through a mechanism other than apoptosis. In summary, the present results suggest that the GBP receptor ~2^-1 is mainly expressed in thalamic neurons in which it is up-regulated in the early stage of CPSP but this is followed by dramatic down-regulation, which is likely associated with GBP insensitivity after long-term use.展开更多
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supported by grants from the National Natural Science Foundation of China (81171049)the National Basic Research Development Program of China (2011CB504100,2013CB835100 and 2013BAI04B04)
文摘Intractable central post-stroke pain（CPSP） is one of the most common sequelae of stroke, but has been inadequately studied to date. In this study, we first determined the relationship between the lesion site and changes in mechanical or thermal pain sensitivity in a rat CPSP model with experimental thalamic hemorrhage produced by unilateral intra-thalamic collagenase IV（ITC） injection. Then, we evaluated the efficacy of gabapentin（GBP）, an anticonvulsant that binds the voltage-gated Ca2＋ channel α2δ and a commonly used anti-neuropathic pain medication. Histological case-by-case analysis showed that only lesions confined to the medial lemniscus and the ventroposterior lateral/medial nuclei of the thalamus and/or the posterior thalamic nucleus resulted in bilateral mechanical pain hypersensitivity. All of the animals displaying CPSP also had impaired motor coordination, while control rats with intra-thalamic saline developed no central pain or motor deficits. GBP had a dose-related anti-allodynic effect after a single administration（1, 10, or 100 mg/kg） on day 7 post-ITC, with significant effects lasting at least 5 hfor the higher doses. However, repeated treatment, once a day for two weeks, resulted in complete loss of effectiveness（drug tolerance） at 10 mg/kg, while effectiveness remained at 100 mg/kg, although the time period of efficacious analgesia was reduced. In addition, GBP did not change the basal pain sensitivity and the motor impairment caused by the ITC lesion, suggesting selective action of GBP on the somatosensory system.
基金supported by the National Natural Science Foundation of China(81171049)the National Basic Research Development Program of China(2011CB504100 and2013CB835100)+1 种基金the National Key Technology R&D Program of China(2013BAI04B04)the Twelfth Five-Year Project of China(AWS12J004)
文摘The α2δ-1 subunit of the voltage-gated Ca2＋ channel （VGCC） is a molecular target of gabapentin （GBP）, which has been used as a first-line drug for the relief of neuropathic pain. GBP exerts its anti-nociceptive effects by disrupting trafficking of the α2δ-1 subunit to the presynaptic membrane, resulting in decreased neurotrans- mitter release. We previously showed that GBP has an anti- allodynic effect in the first two weeks; but this is followed by insensitivity in the later stage after repeated adminis- tration in a rat model of central post-stroke pain （CPSP） hypersensitivity induced by intra-thalamic hemorrhage. To explore the mechanisms underlying GBP insensitivity, the cellular localization and time-course of expression of the α2δ-1 subunit in both the thalamus and spinal dorsal horn were studied in the same model. We found that the α2δ-1 subunit was mostly localized in neurons, but not astrocytes and microglia. The level of α2δ-1 protein increased in the first two weeks after injury but then decreased in the third week, when GBP insensitivity occurred. Furthermore, the c^2g-1 down-regulation was likely caused by later neuronal loss in the injured thalamus through a mechanism other than apoptosis. In summary, the present results suggest that the GBP receptor ~2^-1 is mainly expressed in thalamic neurons in which it is up-regulated in the early stage of CPSP but this is followed by dramatic down-regulation, which is likely associated with GBP insensitivity after long-term use.
