Dissecting the Neural Circuitry for Pain Modulation and Chronic Pain: Insights from Optogenetics / 神经科学通报·英文版

Pain is an unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage. The processing of pain involves complicated modulation at the levels of the periphery, spinal cord, and brain. The pathogenesis of chronic pain is still not fully understood, which makes the clinical treatment challenging. Optogenetics, which combines optical and genetic technologies, can precisely intervene in the activity of specific groups of neurons and elements of the related circuits. Taking advantage of optogenetics, researchers have achieved a body of new findings that shed light on the cellular and circuit mechanisms of pain transmission, pain modulation, and chronic pain both in the periphery and the central nervous system. In this review, we summarize recent findings in pain research using optogenetic approaches and discuss their significance in understanding the pathogenesis of chronic pain.

Antiepileptic effect of low-frequency electrical stimulation is waveform-dependent in hippocampal kindled mice / 浙江大学学报·医学版

<p><b>OBJECTIVE</b>To investigate whether the waveform of electrical stimulus affects the antiepileptic effect of focal low-frequency stimulation (LFS).</p><p><b>METHODS</b>The antiepileptic effects of the LFS in sine, monophase square and biphase square waves were investigated in hippocampal kindled mice, respectively.</p><p><b>RESULTS</b>Compared to the control group, sine wave focal LFS (30 s) inhibited seizure stages (2.85 ± 0.27 vs 4.75 ± 0.12, P<0.05), lowered incidence of generalized seizures (53.6% vs 96.5%, P<0.01) and reduced afterdischarge durations [(16.2 2 ± 1.69)s vs (30.29 ± 1.12)s, P<0.01] in hippocampal kindled mice, while monophase or biphase square wave LFS (30 s) showed no antiepileptic effect. Monophase square LFS (15 min) inhibited seizure stages (3.58 ± 0.16, P<0.05) and incidence of generalized seizures (66.7%,P<0.01), but had weaker inhibitory effect on hippocampal afterdischarge durations than sine wave LFS. In addition, pre-treatment and 3 s but not 10 s post-treatment with sine wave LFS resulted in suppression of evoked seizures (P<0.05 or P<0.01).</p><p><b>CONCLUSION</b>The antiepileptic effect of LFS is dependent on its waveform. Sine wave may be optimal for closed-loop LFS treatment of epilepsy.</p>

Effects of kindling epilepsy and low frequency of epileptic focus on spontaneous neuropathic pain in rats / 浙江大学学报·医学版

<p><b>OBJECTIVE</b>To investigate the effects of epileptogenesis and low frequency stimulation at epileptic focus on spontaneous neuropathic pain in rats.</p><p><b>METHODS</b>Bipolar stimulating electrodes were implanted in the amygdala and current with constant intensity was applied to evoke kindling-induced seizures. In partial and generalized stages of seizure acquisition, neuroma model of spontaneous neuropathic pain was prepared by completely transection of the left sciatic and saphenous nerves of rats. Autotomy behavior was scored daily until d 63 postoperatively. Rats were divided into 5 groups: Control (n=7), rats with partial seizures (1-3 stages, n=5), rats with generalized seizures (4-5 stages, n=7), rats with partial seizures and low frequency stimulation(n=4), rats with generalized seizures and low frequency stimulation(n=4). Low frequency stimulation was applied to the amygdala, the epileptic focus for 21 d from the d 2 after nerve transection.</p><p><b>RESULTS</b>Autotomy level in rats with partial seizures was significantly lower than that in controls. The autotomy scores during postoperative d 40 ≊63 were significantly lower than those of controls, the area under the progression curve of autotomy behavior was decreased from 308.2 ±51.57 to 45.80 ±24.64, the onset day of autotomy was postponed by 32 d and none of the animals with partial seizures showed high autotomy, while 71.4 % of controls showed that on d 63 postoperatively. Rats with generalized seizures showed autotomy similar to controls, except that the onset day was postponed by 16 d. Autotomy behavior in rats receiving low frequency stimulation of the amygdala was not different from that in controls.</p><p><b>CONCLUSION</b>Focal seizures can lower sensitivity to spontaneous neuropathic pain in rats, while low frequency stimulation applied to the focus can abolish such effect.</p>

Immunophenotypic analysis of leukemia promyelocytes in 71 patients with acute promyelocytic leukemia / 中国实验血液学杂志

This study was purpose to investigate the immunophenotype of leukemia promyelocytes (LP) and its significance through retrospective analysis of LP immunophenotype and data in new diagnosis of patients with acute promyelocytic leukemia (APL). The immunophenotype of leukemia cells in 71 APL patients was analyzed by means of 6 color immunotyping. The results indicated that MPO, CD33 and CD13 were consistently expressed in leukemia cells of all APL cases with highest average percentages (> 88%) of positive cells among all studied markers. CD117 was found to be positive in 50.7%, and its average percentage of positive cells was 52.5%. Leukemia cells in about 10% cases expressed CD15 weakly, and its average percentage of positive cells was 42.5%. CD34 and HLA-DR showed decreased expressions in a small number of cases and were negative in the others. CD2 and CD56 were weakly expressed in nearly 25% APL cases, and the average percentage of positive cells were 39.3% and 42.3%, respectively. Thereby, it is of the opinion that the typical immunophenotype is characterized by MPO(+)CD13(+)CD33(+)CD117(±)CD15(±)CD34(-)HLA-DR(-) in APL. CD2 and CD56 were expressed significantly higher in CD34(+) or HLA-DR(+) group (including CD34(+) HLA-DR(+), CD34(+) HLA-DR(-) and CD34(-)HLA-DR(+)) than in CD34(-) and HLA-DR(-) group. Significant differences were also found in WBC and platelet counts, percentage of peripheral blood leukemic promyelocytes and the expression of CD13 among CD15 < 10%, 10% < CD15 < 20% and CD15 > 20% groups. It is concluded that the APL has a characteristic immunophenotypic profile, flow cytometric immunophenotyping may be considered as a useful tool for rapid recognition of APL and also may be considered to have an important significance for analysing origin of leukemic cells and clinical outcome of patients.

Role of voltage-sodium channels in neuropathic pain / 浙江大学学报·医学版

Voltage-gated sodium channels are critical for the generation and conduction of nerve impulses. Recent studies show that in primary sensory neurons, the expression and dynamic regulation of several sodium channel subtypes play important roles in neuropathic pain. A number of SCN9A (encoding Nav1.7) gene point mutations are related with human genetic pain disorders. Transgenic and specific knockout techniques have revealed that Nav1.3, Nav1.8, Nav1.9 are important for the development and maintenance of neuropathic pain condition. Specific blockers of these sodium channels have been demonstrated to be effective in alleviating allodynia and hyperalgesia. Here we reviewed the roles of sodium channels in neuropathic pain, which may be applicable for the development of new drugs with enhanced efficacy for neuropathic pain treatment.

Advances in application of deep brain stimulation in treatment of neuropsychological diseases / 浙江大学学报·医学版

Deep brain stimulation has drawn more and more concerns as a method to treat neuropsychological diseases. Compared with surgery and other methods using electrical stimulation, deep brain stimulation has advantages of clear targets, high selectivity, reversibility, titratability and non-ablation. A large body of clinical trials has shown that deep brain stimulation targeting various brain structures is able to alleviate the symptoms of Parkinson's disease, epilepsy, chronic pain and depression that are intractable with medicines and other methods, with few complications or side effects. Deep brain stimulation is now emerging as a promising approach for the treatment of resistant neuropsychological diseases.

A prospective study of stroke recurrence and the risk factors / 南方医科大学学报

<p><b>OBJECTIVE</b>To evaluate prognosis of stroke and identify the risk factors for stroke recurrence.</p><p><b>METHODS</b>Based on the West China Hospital stroke register database, we conducted a prospective follow-up study of stroke patients to record the potential risk factors of stroke recurrence and investigate stroke recurrence at 1 year. Analysis of the risk factors was performed using a logistic regression model.</p><p><b>RESULTS</b>A total of 1913 stroke consecutive patients admitted to our department were prospectively registered. Of these patients, 599 (31.3%) were identified to have intracerebral hemorrhage (ICH), and 1314 (68.7%) had ischemic stroke. The total recurrence rate at 1 year was 11.2%, and was 10.5% in ischemic patients and 12.7% in ICH patients. Multivariate analysis adjusted for age and gender identified atrial fibrillation, hypertension, hyperlipemia, family history of stroke, and smoking as the risk factors of stroke recurrence at 1 year.</p><p><b>CONCLUSION</b>The 1 year recurrent rate is about 11%, and monitoring the factors of atrial fibrillation, hyperlipemia, hypertension, and smoking may help reduce the recurrence of stroke.</p>

Incomplete protective effects of minocycline on traumatic brain injury in rats and mice / 浙江大学学报·医学版

<p><b>OBJECTIVE</b>To evaluate protective effect of minocycline,a semisynthetic tetracycline derivative on different traumatic brain injuries in rats and mice.</p><p><b>METHODS</b>The opened brain trauma was induced in rats and the closed head injury and cold brain injury were induced in mice. In 3 brain trauma models, minocycline (45 mg/kg, ip) was administered twice daily for 2 d before the operation, at 30 min before and 1 h after the operation, and once daily for 2 d following the operation (totally 8 doses in 5 d). After the operation, the behavioral alteration was observed daily, lesion area and survival neuron density were measured at the end of the experiments (14 d after the injuries).</p><p><b>RESULT</b>For rat opened traumatic injury, minocycline promoted the recovery of hindlimb motor activity (inclined board angle), but did not alter other indexes. For mouse closed head traumatic injury, minocycline reduced the neuron loss, but did not improve behavioral dysfunction. For mouse cold injury-induced trauma, minocycline reduced death rate and lesion area, but did not remarkably improve behavior and neuron loss.</p><p><b>CONCLUSION</b>Minocycline only has an incomplete neuroprotective effect on different brain traumatic injuries in rats and mice.</p>

Photomacrography of brain surface for evaluating blood-brain barrier disruption within 24 h after focal cerebral ischemia in mice / 浙江大学学报·医学版

<p><b>OBJECTIVE</b>To establish a new photomacrographic analysis of morphological changes on brain surface to evaluate blood-brain barrier (BBB) disruption.</p><p><b>METHODS</b>Permanent focal cerebral ischemia was induced by middle cerebral artery occlusion (MCAO) in mice. Brains were removed 10 min, 0.5, 1, 3, 6, 12 and 24 h after MCAO. The whole brains and brain slices were photographed by a digital camera. BBB disruption was evaluated by hemorrhage and traced Evans blue (EB) on the brain surface. Fluoremetric quantitation of EB and water content in the brains were also performed at various time points.</p><p><b>RESULT</b>Photomacrographic morphological analysis showed that hemorrhage and traced EB on the surface of the brains significantly increased from 3 h after focal cerebral ischemia,which were correlated to the results in the brain slices. EB content in the ischemic hemispheres was significantly increased from 0.5 h after MCAO, and water content was increased from 1 h after MCAO.</p><p><b>CONCLUSION</b>Photomacrographic measurement is a simple and useful method for evaluating BBB disruption semi-quantitatively, and can detect BBB disruption earlier after focal cerebral ischemia in mice.</p>

Increased expression of aquaporin-4 in human traumatic brain injury and brain tumors / 浙江大学学报（英文版）（B辑：生物医学和生物技术）

<p><b>OBJECTIVE</b>To characterize the expression of aquaporin-4 (AQP4), one of the aquaporins (AQPs), in human brain specimens from patients with traumatic brain injury or brain tumors.</p><p><b>METHODS</b>Nineteen human brain specimens were obtained from the patients with traumatic brain injury, brain tumors, benign meningioma or early stage hemorrhagic stroke. MRI or CT imaging was used to assess brain edema. Hematoxylin and eosin staining were used to evaluate cell damage. Immunohistochemistry was used to detect the AQP4 expression.</p><p><b>RESULTS</b>AQP4 expression was increased from 15 h to at least 8 d after injury. AQP4 immunoreactivity was strong around astrocytomas, ganglioglioma and metastatic adenocarcinoma. However, AQP4 immunoreactivity was only found in the centers of astrocytomas and ganglioglioma, but not in metastatic adenocarcinoma derived from lung.</p><p><b>CONCLUSION</b>AQP4 expression increases in human brains after traumatic brain injury, within brain-derived tumors, and around brain tumors.</p>

A novel method for continuously assessing the spatio-temporal properties of locomotor activity in mice / 浙江大学学报·医学版

<p><b>OBJECTIVE</b>To develop a novel method for continuously assessing the spatio-temporal properties of locomotor activity of mice in an open field using a video-tracking system.</p><p><b>METHODS</b>The locomotor tracks in the open field were recorded by video camera within 22 h, and analyzed by AnalyPower1.1 system that we developed recently. Total distance, distances traveled in different zones and their ratios to total distance; total time,times spent in different zones and their ratios to total time were used as indicators to assess the properties of locomotor activity.</p><p><b>RESULTS</b>In free and wakeful state, the locomotor activity of mice presented obvious regional and temporal properties. Mice preferred to stay in home base (food and water zones), and frequently visited the peripheral zones but seldom the center zones within 22 h. On the other hand, mice were most active within the first 1 h, and then their activity obviously decreased. After their activity became stable, the mice showed the obvious circadian variation of the activity as they were more active in the night.</p><p><b>CONCLUSION</b>The novel method we developed in this study can continuously assess the spatio-temporal properties of locomotor activity quantitatively and objectively.</p>

Protective effect of ONO-1078, a leukotriene receptor antagonist, on focal cerebral ischemia induced by endothelin-1 in rats / 药学学报

<p><b>AIM</b>To determine the protective effect of ONO-1078, a leukotriene receptor antagonist, on focal cerebral ischemia induced by endothelin-1 in rats.</p><p><b>METHODS</b>Slow microinjection of endothelin-1 (120 pmol in 6 microL, for > 6 min) into the region near the middle cerebral artery was used to induce focal cerebral ischemia. ONO-1078 (0.1 mg.kg-1) was i.p. injected 1 h before endothelin-1 injection. Neurological symptoms, brain edema, brain infarction size, and the survival neurons in cortex and striatum were observed 24 h after ischemia.</p><p><b>RESULTS</b>Intracerebral microinjection of endothelin-1 induced remarkable neurological symptoms, brain infarction, brain edema, and decrease of survival neurons in the cortex and striatum. In rats pretreated with ONO-1078, endothelin-1-induced brain edema and brain infarction size were decreased. The numbers of survival neurons in striatum and cortex were increased significantly. The neurological symptoms were improved but not significantly.</p><p><b>CONCLUSION</b>ONO-1078 possesses neuroprotective effect against cerebral ischemic injury induced by endothelin-1, therefore, leukotrienes may play a role in the injury of cerebral ischemia.</p>

Macrophotographic measurement of brain surface area for evaluating brain edema after focal cerebral ischemia in mice / 浙江大学学报·医学版

<p><b>OBJECTIVE</b>To establish a new macrophotographic measurement of brain surface area to evaluate brain edema after focal cerebral ischemia in mice.</p><p><b>METHODS</b>Permanent focal cerebral ischemia was induced by middle cerebral artery occlusion (MCAO) in mice. The brains were removed 10,30 min,1,3,6,12 and 24 h after MCAO, and photographed in dorsal and lateral views by a digital camera. Then, 6 coronal slices of 1 mm thick were cut and photographed. Finally, the water content of brain tissue was measured by heating at 110 degrees C for 24 h. The left and right hemisphere areas of the brains and the brain slices were analyzed and calculated by MedBrain 2 imaging analyzer to evaluate brain edema.</p><p><b>RESULT</b>The macrophotographic measurement showed that the ischemic hemisphere areas significantly increased from 1 h after focal cerebral ischmia, which was similar to the measurement of water content. This measurement for brain edema correlated well with those of water content and brain slice volume.</p><p><b>CONCLUSION</b>The macrophotographic measurement is an objective and quantitative method for evaluating brain edema after focal cerebral ischemia.</p>

An improved imaging analysis for quantitative measurement of brain slice volume / 浙江大学学报·医学版

<p><b>OBJECTIVE</b>To improve computer-assisted imaging analysis for quantitatively measuring brain slice volume of rats and mice in comparison with conventional measuring methods,and to evaluate its usefulness in assessment of focal cerebral ischemia.</p><p><b>METHODS</b>The accurate volumes of rat and mouse brain slices were measured by weight and special gravity measuring. The areas of brain slices were measured by imaging analysis, then the slice volumes of right and left hemispheres were calculated by multiplying the adjusted thickness of the slices. In addition, the brain slice volumes of right and left hemispheres from focal cerebral ischemic mice were compared to assess ischemic injury using the imaging analysis.</p><p><b>RESULT</b>Area measurement by computer-assisted imaging analysis was linear with different accurate areas (r=1.000). Slice volumes measured by imaging analysis correlated well with the accurate volumes measured by special gravity method, r=0.809 (n=45, P<0.001) in rats, and r=0.844 (n=74, P<0.001) in mice. The brain volumes in ischemic hemispheres were larger than in non-ischemic hemispheres in ischemic mice.</p><p><b>CONCLUSION</b>Computer-assisted imaging analysis can measure the brain slice volumes accurately and compare right and left hemisphere volumes quantitatively.</p>

Changes in mechano-receptive properties of Abeta-fiber induced by antidromical electrical stimulation of the cutaneous nerve from adjacent spinal segment / 生理学报

The purpose of the present study was to observe whether primary afferent Abeta-fiber is involved in the information transmission between peripheral terminals of adjacent dermatomes. The dorsal cutaneous nerve branches of spinal nerves from T(8) to T(12) segments were cut proximally. One peripheral stump end of the cut nerves was dissected into a few filaments for the examination of mechanoreceptive properties of single Abeta-fibers and their discharges were observed while the other end was stimulated antidromically. Fifty Abeta-units were recorded in forty-two intact rats. After an electrical stimulation (0.45 mA, 0.1 ms, 20 Hz, for 10 s) was delivered to the stimulated nerve, the size of the receptive field of 60.6% (n=33) Abeta-fibers extended. The mean area of receptive fields of all examined units enlarged from 8.94+/-6.51 mm(2) to 20.34+/-16.17 mm(2) (P<0.01) and the shapes of the receptive fields of 81.8% (n=20) units changed from a dot, round or ellipse with its long axis in parallel with the longitudinal axis of the body to an oblique ellipse with the longitudinal axis of the body. The mechanoreceptive threshold of 68.0% (n=50) units decreased with a reduction in mean threshold from 2.37+/-1.24 to 2.29+/-1.24 mN (P<0.05). The duration of these changes in mechano-receptive properties increased from 52.23+/-9.27 to 56.93+/-15.76 min. Meanwhile, increasing discharge was found in 50.0% (n=50) units but lasted only for 1.52+/-0.46 min. The changes in mechanoreceptive properties appeared simultaneously with discharge changes but had longer duration than that of discharge change (P<0.01). Discharges changes usually appeared in those units with the changes in mechanoreceptive properties following an antidromical electrical stimulation of adjacent spinal segment. These results suggest that low-threshold mechanoreceptive Abeta-fibers are affected by antidromical electrical stimulation of the cutaneous nerve from an adjacent spinal segment, indicating that information transmission occurs between the two endings of peripheral afferent nerves from adjacent spinal segments without any involvement of the central nervous system, and that Abeta-fibers are involved in the process of information transmission between peripheral terminals from adjacent spinal segments.