Selective ablation of nociceptive neurons for elimination of hyperalgesia and neurogenic inflammation

2005 ◽  
Vol 102 (3) ◽  
pp. 522-525 ◽  
Author(s):  
Gabriel C. Tender ◽  
Stuart Walbridge ◽  
Zoltan Olah ◽  
Laszlo Karai ◽  
Michael Iadarola ◽  
...  
Keyword(s):  
Motor Function ◽  
High Intensity ◽  
Rhesus Monkeys ◽  
Neurogenic Inflammation ◽  
Pain Perception ◽  
Function Analysis ◽  
Immunohistochemical Analysis ◽  
Content Type ◽  
Nociceptive Neurons ◽  
Fine Print

Object. Neuropathic pain is mediated by nociceptive neurons that selectively express the vanilloid receptor 1 (VR1). Resiniferatoxin (RTX) is an excitotoxic VR1 agonist that causes destruction of VR1-positive neurons. To determine whether RTX can be used to ablate VR1-positive neurons selectively and to eliminate hyperalgesia and neurogenic inflammation without affecting tactile sensation and motor function, the authors infused it unilaterally into the trigeminal ganglia in Rhesus monkeys. Methods. Either RTX (three animals) or vehicle (one animal) was directly infused (20 µl) into the right trigeminal ganglion in Rhesus monkeys. Animals were tested postoperatively at 1, 4, and 7 weeks thereafter for touch and pain perception in the trigeminal distribution (application of saline and capsaicin to the cornea). The number of eye blinks, eye wipes, and duration of squinting were recorded. Neurogenic inflammation was tested using capsaicin cream. Animals were killed 4 (one monkey) and 12 (three monkeys) weeks postinfusion. Histological and immunohistochemical analyses were performed. Throughout the duration of the study, response to high-intensity pain stimulation (capsaicin) was selectively and significantly reduced (p < 0.001, RTX-treated compared with vehicle-treated eye [mean ± standard deviation]): blinks, 25.7 ± 4.4 compared with 106.6 ± 20.8; eye wipes, 1.4 ± 0.8 compared with 19.3 ± 2.5; and squinting, 1.4 ± 0.6 seconds compared with 11.4 ± 1.6 seconds. Normal response to sensation was maintained. Animals showed no neurological deficit or sign of toxicity. Neurogenic inflammation was blocked on the RTX-treated side. Immunohistochemical analysis of the RTX-treated ganglia showed selective elimination of VR1-positive neurons. Conclusions. Nociceptive neurons can be selectively ablated by intraganglionic RTX infusion, resulting in the elimination of high-intensity pain perception and neurogenic inflammation while maintaining normal sensation and motor function. Analysis of these findings indicated that intraganglionic RTX infusion may provide a new treatment for pain syndromes such as trigeminal neuralgia as well as others.

scholarly journals Selective ablation of nociceptive neurons for elimination of hyperalgesia and neurogenic inflammation

2005 ◽  
Vol 18 (5) ◽  
pp. 1-5
Author(s):  
Gabriel C. Tender ◽  
Stuart Walbridge ◽  
Zoltan Olah ◽  
Laszlo Karai ◽  
Michael Iadarola ◽  
...  
Keyword(s):  
Motor Function ◽  
High Intensity ◽  
Rhesus Monkeys ◽  
Neurogenic Inflammation ◽  
Pain Perception ◽  
Function Analysis ◽  
Immunohistochemical Analysis ◽  
Nociceptive Neurons ◽  
New Treatment ◽  
The Right

Object Neuropathic pain is mediated by nociceptive neurons that selectively express the vanilloid receptor 1 (VR1). Resiniferatoxin (RTX) is an excitotoxic VR1 agonist that causes destruction of VR1-positive neurons. To determine whether RTX can be used to ablate VR1-positive neurons selectively and to eliminate hyperalgesia and neurogenic inflammation without affecting tactile sensation and motor function, the authors infused it unilaterally into the trigeminal ganglia in Rhesus monkeys. Methods Either RTX (three animals) or vehicle (one animal) was directly infused (20 μl) into the right trigeminal ganglion in Rhesus monkeys. Animals were tested postoperatively at 1, 4, and 7 weeks thereafter for touch and pain perception in the trigeminal distribution (application of saline and capsaicin to the cornea). The number of eye blinks, eye wipes, and duration of squinting were recorded. Neurogenic inflammation was tested using capsaicin cream. Animals were killed 4 (one monkey) and 12 (three monkeys) weeks postinfusion. Histological and immunohistochemical analyses were performed. Throughout the duration of the study, response to high-intensity pain stimulation (capsaicin) was selectively and significantly reduced (p < 0.001, RTX-treated compared with vehicle-treated eye [mean ± standard deviation]): blinks, 25.7 ± 4.4 compared with 106.6 ± 20.8; eye wipes, 1.4 ± 0.8 compared with 19.3 ± 2.5; and squinting, 1.4 ± 0.6 seconds compared with 11.4 ± 1.6 seconds. Normal response to sensation was maintained. Animals showed no neurological deficit or sign of toxicity. Neurogenic inflammation was blocked on the RTX-treated side. Immunohistochemical analysis of the RTX-treated ganglia showed selective elimination of VR1-positive neurons. Conclusions Nociceptive neurons can be selectively ablated by intraganglionic RTX infusion, resulting in the elimination of high-intensity pain perception and neurogenic inflammation while maintaining normal sensation and motor function. Analysis of these findings indicated that intraganglionic RTX infusion may provide a new treatment for pain syndromes such as trigeminal neuralgia as well as others.

Craniocerebral missile injuries in the monkey: an experimental physiological model

1972 ◽  
Vol 36 (1) ◽  
pp. 43-49 ◽  
Author(s):  
Arthur M. Gerber ◽  
Robert A. Moody
Keyword(s):  
Rhesus Monkeys ◽  
Common Factor ◽  
Blood Gases ◽  
Physiological Model ◽  
Content Type ◽  
Epidural Compression ◽  
The Brain ◽  
Strong Suspicion ◽  
Fine Print ◽  
Carotid Flow

✓ Experiments were carried out on rhesus monkeys to determine what physiological parameters were most closely correlated with death due to craniocerebral missile injuries. Observations of intracranial pressure, blood pressure, carotid flow, blood gases, respiratory rate, depth and volume, and electroencephalograms were made. These parameters were compared in survivors and nonsurvivors as were the pathological injuries. The most important single parameter that correlated with death was the drop in carotid flow. As this same correlation has been observed in epidural compression experiments in the monkey, there is a strong suspicion that reduced blood flow to the brain as measured by carotid flow is a common factor in craniocerebral missile injuries and epidural compression injuries.

Distribution of activity in spinal pathways evoked by experimental dorsal column stimulation

1975 ◽  
Vol 42 (3) ◽  
pp. 290-295 ◽  
Author(s):  
Heinrich Bantli ◽  
James R. Bloedel ◽  
Donlin M. Long ◽  
Phudhiphorn Thienprasit
Keyword(s):  
Rhesus Monkeys ◽  
Dorsal Column ◽  
Electrode Position ◽  
Content Type ◽  
Spinal Pathways ◽  
Therapeutic Value ◽  
Stimulus Parameters ◽  
Different Characteristics ◽  
Dorsal Column Stimulation ◽  
Fine Print

✓ Experiments were performed in rhesus monkeys to determine the distribution of activity evoked in spinal pathways by dorsal column stimulation. It was shown that many pathways in both the dorsal and ventral quadrants of the cord can be activated either directly or transsynaptically by stimulation with electrodes of the type implanted clinically. Moreover, the transsynaptically evoked responses recorded in each quadrant had somewhat different characteristics. Therefore, since the activation of each group of pathways may have differing effects in modifying the perception of noxious stimuli, the authors believe that changes in electrode position and stimulus parameters may be important in obtaining the therapeutic value of spinal cord stimulation for relief of pain.

Interleukin-6 overexpression as a marker of malignancy in human gliomas

2001 ◽  
Vol 94 (1) ◽  
pp. 97-101 ◽  
Author(s):  
Christine Rolhion ◽  
Frédérique Penault-Llorca ◽  
Jean-Louis Kémény ◽  
Jean-Jacques Lemaire ◽  
Christiane Jullien ◽  
...  
Keyword(s):  
Gene Expression ◽  
Interleukin 6 ◽  
Vascular Endothelial Cells ◽  
Immunohistochemical Analysis ◽  
Vascular Endothelial ◽  
Content Type ◽  
Major Interest ◽  
Polymerase Chain ◽  
The Relationship ◽  
Fine Print

Object. Glioblastomas multiforme (GBMs) grow rapidly and are highly resistant to treatment compared with other glioma types and grades. Consequently, it is of major interest to identify markers of aggressiveness in these tumors that could represent new therapeutic targets. Interleukin (IL)—6 is frequently produced in gliomas and, given its manifold properties, could be considered as a candidate marker. Expression of IL-6 may be involved in cell growth, resistance to chemotherapy and radiotherapy (via an antiapoptotic pathway), and angiogenesis. This study was conducted to test this hypotheses and to evaluate the suitability of IL-6 as a target in the treatment of GBMs. Methods. The authors studied the relationship between the level of IL-6 gene expression as assessed using semiquantitative reverse transcription—polymerase chain reaction and by determining various histological types and grades in a series of 59 gliomas. It was found that GBMs displayed a significantly higher level of IL-6 expression than other types of glioma (p < 0.001). Immunohistochemical analysis revealed that IL-6 was produced mainly by malignant cells and a few vascular endothelial cells. Conclusions. It can be inferred from these findings that IL-6 gene expression is related to glioma aggressiveness and that IL-6 may play a central role in GBM behavior. Interleukin-6, therefore, could be considered as a new potential target in the treatment of GBMs.

Intracranial bone marrow transplantation after traumatic brain injury improving functional outcome in adult rats

2001 ◽  
Vol 94 (4) ◽  
pp. 589-595 ◽  
Author(s):  
Asim Mahmood ◽  
Dunyue Lu ◽  
Yi Li ◽  
Jae Li Chen ◽  
Michael Chopp
Keyword(s):  
Traumatic Brain Injury ◽  
Bone Marrow ◽  
Brain Injury ◽  
Motor Function ◽  
Glial Fibrillary Acid Protein ◽  
Protein Markers ◽  
Adult Rats ◽  
Content Type ◽  
The Impact ◽  
Fine Print

Object. The authors tested the hypothesis that intracranial bone marrow (BM) transplantation after traumatic brain injury (TBI) in rats provides therapeutic benefit. Methods. Sixty-six adult Wistar rats, weighing 275 to 350 g each, were used for the experiment. Bone marrow prelabeled with bromodeoxyuridine (BrdU) was harvested from tibias and femurs of healthy adult rats. Other animals were subjected to controlled cortical impact, and BM was injected adjacent to the contusion 24 hours after the impact. The animals were killed at 4, 7, 14, or 28 days after transplantation. Motor function was evaluated both before and after the injury by using the rotarod test. After the animals had been killed, brain sections were examined using hemotoxylin and eosin and immunohistochemical staining methods. Histological examination revealed that, after transplantation, BM cells survived, proliferated, and migrated toward the injury site. Some of the BrdU-labeled BM cells were reactive, with astrocytic (glial fibrillary acid protein) and neuronal (NeuN and microtubule-associated protein) markers. Transplanted BM expressed proteins phenotypical of intrinsic brain cells, that is, neurons and astrocytes. A statistically significant improvement in motor function in rats that underwent BM transplantation, compared with control rats, was detected at 14 and 28 days posttransplantation. Conclusions. On the basis of their findings, the authors assert that BM transplantation improves neurological outcome and that BM cells survive and express nerve cell proteins after TBI.

Deep brain stimulation in Parkinson disease: a metaanalysis of patient outcomes

2005 ◽  
Vol 103 (6) ◽  
pp. 956-967 ◽  
Author(s):  
Frances Weaver ◽  
Kenneth Follett ◽  
Kwan Hur ◽  
Dolores Ippolito ◽  
Matthew Stern
Keyword(s):  
Deep Brain Stimulation ◽  
Parkinson Disease ◽  
Patient Outcomes ◽  
Motor Function ◽  
Brain Stimulation ◽  
Multiple Time ◽  
Content Type ◽  
Study Characteristics ◽  
Fine Print ◽  
Deep Brain

Object. Deep brain stimulation (DBS) to treat advanced Parkinson disease (PD) has been focused on one of two anatomical targets: the subthalamic nucleus (STN) and the globus pallidus internus (GPI). Authors of more than 65 articles have reported on bilateral DBS outcomes. With one exception, these studies involved pre- and postintervention comparisons of a single target. Despite the paucity of data directly comparing STN and GPI DBS, many clinicians already consider the STN to be the preferred target site. In this study the authors conducted a metaanalysis of the existing literature on patient outcomes following DBS of the STN and the GPI. Methods. This metaanalysis includes 31 STN and 14 GPI studies. Motor function improved significantly following stimulation (54% in patients whose STN was targeted and 40% in those whose GPI was stimulated), with effect sizes (ESs) of 2.59 and 2.04, respectively. After controlling for participant and study characteristics, patients who had undergone either STN or GPI DBS experienced comparable improved motor function following surgery (p = 0.094). The performance of activities of daily living improved significantly in patients with either target (40%). Medication requirements were significantly reduced following stimulation of the STN (ES = 1.51) but did not change when the GPI was stimulated (ES = −0.02). Conclusions. In this analysis the authors highlight the need for uniform, detailed reporting of comprehensive motor and nonmotor DBS outcomes at multiple time points and for a randomized trial of bilateral STN and GPI DBS.

Long-term functional outcome after selective posterior rhizotomy

2002 ◽  
Vol 97 (2) ◽  
pp. 315-325 ◽  
Author(s):  
Sandeep Mittal ◽  
Jean-Pierre Farmer ◽  
Borhan Al-Atassi ◽  
Joanne Gibis ◽  
Eileen Kennedy ◽  
...  
Keyword(s):  
Muscle Strength ◽  
Functional Outcome ◽  
Motor Function ◽  
Lower Limb ◽  
Content Type ◽  
Limb Spasticity ◽  
Lower Limb Spasticity ◽  
Selective Posterior Rhizotomy ◽  
Fine Print

Object. Selective posterior rhizotomy (SPR) is a well-recognized treatment for children with spastic cerebral palsy (CP). Few investigators have used quantitative outcome measures to assess the surgical results beyond 3 years. The authors analyzed data obtained from the McGill Rhizotomy Database to determine the long-term functional outcome of children who had undergone selective dorsal rhizotomy accompanied by intraoperative electrophysiological monitoring. Methods. The study population was composed of children with spastic CP who underwent SPR and were evaluated by a multidisciplinary team preoperatively, and at 6 months and 1 year postoperatively. Quantitative standardized assessments of lower-limb spasticity, passive range of motion, muscle strength, and ambulatory function were obtained. Of the 93 patients who met the entry criteria for the study, 71 completed the 3-year and 50 completed the 5-year assessments, respectively. Statistical analysis demonstrated significant improvements in spasticity, range of motion, and functional muscle strength at 1 year after SPR. The preoperative, 1-, 3-, and 5-year values for the global score of the Gross Motor Function Measure were 64.6, 70.8, 80, and 85.6, respectively. The greatest improvement occurred in the dimensions reflecting lower-extremity motor function, where the mean change was 10.1% at 1 year, 19.9% at 3 years, and 34.4% at the 5-year follow-up review in comparison with the baseline value. This was associated with a lasting improvement in alignment and postural stability during developmental positions, as well as increased ability to perform difficult transitional movements. Conclusions. The results of this study support the presence of significant improvements in lower-limb functional motor outcome 1 year after SPR, and the improvements persist at 3 and 5 years. The authors conclude that SPR in conjunction with intraoperative stimulation is valuable for permanently alleviating lower-limb spasticity while augmenting motor function.

Intraoperative validation of functional magnetic resonance imaging and cortical reorganization patterns in patients with brain tumors involving the primary motor cortex

1999 ◽  
Vol 91 (2) ◽  
pp. 238-250 ◽  
Author(s):  
Javier Fandino ◽  
Spyros S. Kollias ◽  
Heinz G. Wieser ◽  
Anton Valavanis ◽  
Yasuhiro Yonekawa
Keyword(s):  
Motor Cortex ◽  
Motor Function ◽  
Primary Motor Cortex ◽  
Objective Evaluation ◽  
Cortical Stimulation ◽  
Cortical Reorganization ◽  
Motor Area ◽  
Primary Motor Area ◽  
Content Type ◽  
Fine Print

Object. The purpose of the present study was to compare the results of functional magnetic resonance (fMR) imaging with those of intraoperative cortical stimulation in patients who harbored tumors close to or involving the primary motor area and to assess the usefulness of fMR imaging in the objective evaluation of motor function as part of the surgical strategy in the treatment of these patients.Methods. A total of 11 consecutive patients, whose tumors were close to or involving the central region, underwent presurgical blood oxygen level—dependent fMR imaging while performing a motor paradigm that required them to clench and spread their hands contra- and ipsilateral to the tumor. Statistical cross-correlation functional maps covering the primary and secondary motor cortical areas were generated and overlaid onto high-resolution anatomical MR images. Intraoperative electrical cortical stimulation was performed to validate the presurgical fMR imaging findings. In nine (82%) of 11 patients, the anatomical fMR imaging localization of motor areas could be verified by intraoperative electrical cortical stimulation. In seven patients two or more activation sites were demonstrated on fMR imaging, which were considered a consequence of reorganization phenomena of the motor cortex: contralateral primary motor area (nine patients), contralateral premotor area (four patients), ipsilateral primary motor area (two patients), and ipsilateral premotor area (four patients).Conclusions. Functional MR imaging can be used to perform objective evaluation of motor function and surgical planning in patients who harbor lesions near or involving the primary motor cortex. Correlation between fMR imaging findings and the results of direct electrical brain stimulation is high, although not 100%. Based on their study, the authors believe that cortical reorganization patterns of motor areas might explain the differences in motor function and the diversity of postoperative motor function among patients with central tumors.

Long-term benefits in quality of life provided by bilateral subthalamic stimulation in patients with Parkinson disease

2005 ◽  
Vol 103 (2) ◽  
pp. 252-255 ◽  
Author(s):  
Kelly E. Lyons ◽  
Rajesh Pahwa
Keyword(s):  
Quality Of Life ◽  
Parkinson Disease ◽  
Motor Function ◽  
Well Being ◽  
Strongly Correlated ◽  
Content Type ◽  
Fine Print

Object. The goals of this study were to evaluate long-term benefits in quality of life in patients with Parkinson disease (PD) after bilateral deep brain stimulation (DBS) of the subthalamic nucleus (STN) and to evaluate the relationship between improvements in motor function and quality of life. Methods. Seventy-one patients who received bilateral STN stimulation implants and participated in follow-up review for at least 12 months were included in the study. Fifty-nine patients participated in a 12-month follow-up review and 43 patients in a follow-up review lasting at least 24 months. Patients' symptoms were assessed preoperatively by using the Unified PD Rating Scale (UPDRS) in the “medication-on” and “medication-off” conditions and quality of life was examined using the 39-item PD Questionnaire (PDQ-39). Patient evaluations were repeated postoperatively during periods of stimulation. The UPDRS activities of daily living (ADL) and motor scores as well as the PDQ-39 total, mobility, ADL, emotional well-being, stigma, and bodily discomfort scores were significantly improved at 12 months compared with baseline scores; the UPDRS ADL and motor scores as well as the PDQ-39 total, mobility, ADL, stigma, and bodily discomfort scores were significantly improved at the longest follow-up examination compared with baseline scores. There was a strong correlation between UPDRS motor and ADL scores and the PDQ-39 total, mobility, and ADL scores. Further analyses indicated that improvements in tremor were only correlated with PDQ-39 ADL subscale scores and rigidity was not correlated with any aspect of quality of life. Nevertheless, bradykinesia was strongly correlated with improvements in the PDQ-39 total, mobility, and ADL scores. Conclusions. Improvements in quality of life following bilateral DBS of the STN are maintained in the long term. These improvements are strongly correlated with improvements in motor function, primarily with regard to bradykinesia.

Graded cryohypophysectomy in the rhesus monkey

1972 ◽  
Vol 36 (2) ◽  
pp. 169-177 ◽  
Author(s):  
Suleyman Saglam ◽  
Clifford L. Kragt ◽  
Charles B. Wilson ◽  
Selna L. Kaplan ◽  
Marvin Barker
Keyword(s):  
Growth Hormone ◽  
Rhesus Monkey ◽  
Pituitary Gland ◽  
Rhesus Monkeys ◽  
Endocrine Function ◽  
Posterior Lobe ◽  
Content Type ◽  
Predetermined Time ◽  
Fine Print ◽  
Damaging Effects

✓ Histopathology and endocrine function of the pituitary gland of rhesus monkeys subjected to graded cryohypophysectomy were compared with the histopathology and endocrine function in hypophysectomized and sham-operated monkeys. Freezing at −50°, −100°, and −150°C destroyed 72.3%, 78.3%, and 93.1% of the pituitary respectively. The posterior lobe was more resistant to the damaging effects of cold. A nearly complete (96.3%) histological hypophysectomy was accomplished at −190°C; nearly all remaining viable tissue was in the posterior lobe. Freezing at −150°C appears to result in a complete functional hypophysectomy. Of the adenohypophyseal cells, the gonadotropin-secreting cells were the most susceptible to cold, with the growth-hormone-producing cells next in susceptibility. Adrenocorticotropin-secreting cells were more resistant. Cells producing thyroid-stimulating hormones were not susceptible, and the pituitary stalk was quite resistant to the damaging effects of freezing at these temperatures. Thus, a predictable partial hypophysectomy by means of cryosurgery seems feasible, and, with a predetermined time, it is evident that the degree of cold is critical in achieving a complete cryohypophysectomy.

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