Browsing by Subject "Neuropathic pain"
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Item An adolescent rat model of vincristine-induced peripheral neuropathy(Elsevier, 2021-11-11) Li, Ai-Ling; Crystal, Jonathon D.; Lai, Yvonne Y.; Sajdyk, Tammy J.; Renbarger, Jamie L.; Hohmann, Andrea G.; Pediatrics, School of MedicineChildhood acute lymphoblastic leukemia (ALL) is a significant clinical problem that can be effectively treated with vincristine, a vinca alkaloid-based chemotherapeutic agent. However, nearly all children receiving vincristine treatment develop vincristine-induced peripheral neuropathy (VIPN). The impact of adolescent vincristine treatment across the lifespan remains poorly understood. We, consequently, developed an adolescent rodent model of VIPN which can be utilized to study possible long term consequences of vincristine treatment in the developing rat. We also evaluated the therapeutic efficacy of voluntary exercise and potential impact of obesity as a genetic risk factor in this model on the development and maintenance of VIPN. Out of all the dosing regimens we evaluated, the most potent VIPN was produced by fifteen consecutive daily intraperitoneal (i.p.) vincristine injections at 100 µg/kg/day, throughout the critical period of adolescence from postnatal day 35 to 49. With this treatment, vincristine-treated animals developed hypersensitivity to mechanical and cold stimulation of the plantar hind paw surface, which outlasted the period of vincristine treatment and resolved within two weeks following the cessation of vincristine injection. By contrast, impairment in grip strength gain was delayed by vincristine treatment, emerging shortly following the termination of vincristine dosing, and persisted into early adulthood without diminishing. Interestingly, voluntary wheel running exercise prevented the development of vincristine-induced hypersensitivities to mechanical and cold stimulation. However, Zucker fa/fa obese animals did not exhibit higher risk of developing VIPN compared to lean rats. Our studies identify sensory and motor impairments produced by vincristine in adolescent animals and support the therapeutic efficacy of voluntary exercise for suppressing VIPN in developing rats.Item Capturing the Perceived Phantom Limb through Virtual Reality(Hindawi, 2016-09-05) Rogers, Christian; Lau, Jonathan; Huynh, Denver; Albertson, Steven; Beem, James; Qian, Enlin; Department of Computer Information and Graphics, School of Engineering and TechnologyPhantom limb is the sensation amputees may feel when the missing limb is still attached to the body and is still moving as it would if it still existed. Despite there being between 50 and 80% of amputees who report neuropathic pain, also known as phantom limb pain (PLP), there is still little understanding of why PLP occurs. There are no fully effective long-term treatments available. One of the struggles with PLP is the difficulty for amputees to describe the sensations of their phantom limbs. The sensations may be of a limb that is in a position that is impossible for a normal limb to attain. The goal of this project was to treat those with PLP by developing a system to communicate the sensations those with PLP were experiencing accurately and easily through various hand positions using a model arm with a user friendly interface. The system was developed with Maya 3D animation software, the Leap Motion input device, and the Unity game engine. The 3D modeled arm was designed to mimic the phantom sensation being able to go beyond normal joint extensions of regular arms. The purpose in doing so was to obtain a true 3D visualization of the phantom limb.Item Case Report: Novel Anchoring Technique and Surgical Nuances for Trigeminal Ganglion Stimulation in the Treatment of Post-Herpetic Trigeminal Neuropathic Facial Pain(Frontiers Media, 2022-03-17) Gupta, Kunal; Neurological Surgery, School of MedicineIntroduction: Trigeminal ganglion stimulation is a neuromodulatory surgical procedure utilized to treat trigeminal neuropathic pain. This technique involves the placement of a stimulating electrode adjacent to the trigeminal ganglion and can be trialed before permanent implantation. Wider adoption by surgical practitioners is currently limited by complications such as lead migration from the trigeminal ganglion, which can result in loss of therapy and cannot be rectified without repeat surgery. We describe a novel surgical modification that successfully anchors the trigeminal ganglion electrode long-term. Objective: To describe a novel surgical technique for the anchoring of trigeminal ganglion stimulation electrodes and a case report of a patient with post-herpetic trigeminal neuropathic pain treated with this approach. Methods: An electrode was inserted percutaneously through the foramen ovale into Meckel's cave, adjacent to the trigeminal ganglion. The lead was anchored using a modification of an existing anchoring device, which was inserted into the buccal incision. The lead was connected to a generator for therapeutic stimulation. The location of the lead was followed radiographically using serial lateral skull radiographs. Results: A 74-year-old male with post-herpetic trigeminal neuropathic pain, who had failed prior surgical therapies, underwent trigeminal ganglion stimulation. The trial lead was anchored using standard techniques and migrated outward within 7 days, rendering the trial electrode ineffective. The permanent lead was anchored using the described novel technique and remained in position without clinically significant outward migration nor loss in targeted stimulation until the last follow-up at 6 months. Conclusion: Trigeminal ganglion stimulation is an effective therapeutic option for medically refractory trigeminal neuropathic pain. The novel surgical adaptation described prevents the outward migration of the lead and enables stable long-term lead placement.Item Characterizing mechanism-based pain phenotypes in patients with chronic pancreatitis: a cross-sectional analysis of the PROspective Evaluation of Chronic Pancreatitis for EpidEmiologic and Translational StuDies(Wolters Kluwer, 2023) Saloman, Jami L.; Conwell, Darwin L.; Fogel, Evan; Vege, Santhi Swaroop; Li, Liang; Li, Shuang; Andersen, Dana K.; Fisher, William E.; Forsmark, Christopher E.; Hart, Phil A.; Pandol, Stephen J.; Park, Walter G.; Evans Phillips, Anna; Topazian, Mark; Van Den Eeden, Stephen K.; Serrano, Jose; Yadav, Dhiraj; Consortium for the Study of Chronic Pancreatitis, Diabetes and Pancreatic Cancer; Medicine, School of MedicinePain is common in chronic pancreatitis (CP) and profoundly reduces quality of life (QoL). Multiple underlying mechanisms contribute to a heterogenous pain experience and reduce efficacy of pain management. This study was designed to characterize the distribution of mechanism-based pain phenotypes in painful CP. The data analyzed were collected as part of the PROspective Evaluation of Chronic Pancreatitis for EpidEmiologic and Translational StuDies, an NCI/NIDDK-funded longitudinal study of the natural history of CP. The PROspective Evaluation of Chronic pancreatitis for EpidEmiologic and translational stuDies includes patient-reported outcome (PRO) measures of pain, medication use, global health, and QoL. Of subjects (N = 681) with CP, 80% experienced abdominal pain within the year before enrollment. Subjects who experienced pain in the week before enrollment (N = 391) completed PROMIS Neuropathic and Nociceptive Pain Quality instruments which were then used to classify them by pain type: 40% had nociceptive, 5% had neuropathic-like, and 32% had both types of pain. The prevalence of having both types of pain was higher among women and subjects with diabetes mellitus, whereas nociceptive-only pain was more prevalent among men and those with pancreatic duct stricture. Other factors, including pain medication use and healthcare utilization, did not differ between groups based on pain type. Subjects in the Both group had significantly worse health and QoL scores relative to those with nociceptive-only pain, suggesting that using psychosocial pain surveys may be useful for understanding pain subtypes in patients with CP. Additional research is needed to identify biochemical and biophysical signatures that may associate with and predict responses to mechanism-specific interventions.Item Cortical stimulation for treatment of neurological disorders of hyperexcitability: a role of homeostatic plasticity(Wolters Kluwer, 2019-01) Chai, Zhi; Ma, Cungen; Jin, Xiaoming; Anatomy and Cell Biology, IU School of MedicineHyperexcitability of neural network is a key neurophysiological mechanism in several neurological disorders including epilepsy, neuropathic pain, and tinnitus. Although standard paradigm of pharmacological management of them is to suppress this hyperexcitability, such as having been exemplified by the use of certain antiepileptic drugs, their frequent refractoriness to drug treatment suggests likely different pathophysiological mechanism. Because the pathogenesis in these disorders exhibits a transition from an initial activity loss after injury or sensory deprivation to subsequent hyperexcitability and paroxysmal discharges, this process can be regarded as a process of functional compensation similar to homeostatic plasticity regulation, in which a set level of activity in neural network is maintained after injury-induced activity loss through enhanced network excitability. Enhancing brain activity, such as cortical stimulation that is found to be effective in relieving symptoms of these disorders, may reduce such hyperexcitability through homeostatic plasticity mechanism. Here we review current evidence of homeostatic plasticity in the mechanism of acquired epilepsy, neuropathic pain, and tinnitus and the effects and mechanism of cortical stimulation. Establishing a role of homeostatic plasticity in these disorders may provide a theoretical basis on their pathogenesis as well as guide the development and application of therapeutic approaches through electrically or pharmacologically stimulating brain activity for treating these disorders.Item Differential expression of CaMKII isoforms and overall kinase activity in rat dorsal root ganglia after injury.(Elsevier, 2015-08-06) Bangaru, Madhavi Latha Yadav; Meng, Jingwei; Kaiser, Derek J.; Yu, Hongwei; Fischer, Greg; Hogan, Quinn H.; Hudmon, Andy; Department of Biochemistry & Molecular Biology, IU School of MedicineCa(2+)/calmodulin-dependent protein kinase II (CaMKII) decodes neuronal activity by translating cytoplasmic Ca(2+) signals into kinase activity that regulates neuronal functions including excitability, gene expression, and synaptic transmission. Four genes lead to developmental and differential expression of CaMKII isoforms (α, β, γ, δ). We determined mRNA levels of these isoforms in the dorsal root ganglia (DRG) of adult rats with and without nerve injury in order to determine if differential expression of CaMKII isoforms may contribute to functional differences that follow injury. DRG neurons express mRNA for all four isoforms, and the relative abundance of CaMKII isoforms was γ>α>β=δ, based on the CT values. Following ligation of the 5th lumbar (L5) spinal nerve (SNL), the β isoform did not change, but mRNA levels of both the γ and α isoforms were reduced in the directly injured L5 neurons, and the α isoform was reduced in L4 neurons, compared to their contemporary controls. In contrast, expression of the δ isoform mRNA increased in L5 neurons. CaMKII protein decreased following nerve injury in both L4 and L5 populations. Total CaMKII activity measured under saturating Ca(2+)/CaM conditions was decreased in both L4 and L5 populations, while autonomous CaMKII activity determined in the absence of Ca(2+) was selectively reduced in axotomized L5 neurons 21days after injury. Thus, loss of CaMKII signaling in sensory neurons after peripheral nerve injury may contribute to neuronal dysfunction and pain.Item Disruption of nNOS-NOS1AP protein-protein interactions suppresses neuropathic pain in mice(Wolters Kluwer, 2018-05) Lee, Wan-Hung; Li, Li-Li; Chawla, Aarti; Hudmon, Andy; Lai, Yvonne Y.; Courtney, Michael J.; Hohmann, Andrea G.; Biochemistry and Molecular Biology, School of MedicineElevated N-methyl-D-aspartate receptor (NMDAR) activity is linked to central sensitization and chronic pain. However, NMDAR antagonists display limited therapeutic potential because of their adverse side effects. Novel approaches targeting the NR2B-PSD95-nNOS complex to disrupt signaling pathways downstream of NMDARs show efficacy in preclinical pain models. Here, we evaluated the involvement of interactions between neuronal nitric oxide synthase (nNOS) and the nitric oxide synthase 1 adaptor protein (NOS1AP) in pronociceptive signaling and neuropathic pain. TAT-GESV, a peptide inhibitor of the nNOS-NOS1AP complex, disrupted the in vitro binding between nNOS and its downstream protein partner NOS1AP but not its upstream protein partner postsynaptic density 95 kDa (PSD95). Putative inactive peptides (TAT-cp4GESV and TAT-GESVΔ1) failed to do so. Only the active peptide protected primary cortical neurons from glutamate/glycine-induced excitotoxicity. TAT-GESV, administered intrathecally (i.t.), suppressed mechanical and cold allodynia induced by either the chemotherapeutic agent paclitaxel or a traumatic nerve injury induced by partial sciatic nerve ligation. TAT-GESV also blocked the paclitaxel-induced phosphorylation at Ser15 of p53, a substrate of p38 MAPK. Finally, TAT-GESV (i.t.) did not induce NMDAR-mediated motor ataxia in the rotarod test and did not alter basal nociceptive thresholds in the radiant heat tail-flick test. These observations support the hypothesis that antiallodynic efficacy of an nNOS-NOS1AP disruptor may result, at least in part, from blockade of p38 MAPK-mediated downstream effects. Our studies demonstrate, for the first time, that disrupting nNOS-NOS1AP protein-protein interactions attenuates mechanistically distinct forms of neuropathic pain without unwanted motor ataxic effects of NMDAR antagonists.Item Electroacupuncture Alleviates Anxiety-Like Behaviors Induced by Chronic Neuropathic Pain via Regulating Different Dopamine Receptors of the Basolateral Amygdala(Springer, 2022) Wu, Mengwei; Chen, Yeqing; Shen, Zui; Zhu, Yichen; Xiao, Siqi; Zhu, Xixiao; Wu, Zemin; Liu, Jinggen; Xu, Chi; Yao, Pingan; Xu, Weiwei; Liang, Yi; Liu, Boyi; Du, Junying; He, Xiaofen; Liu, Boyu; Jin, Xiaoming; Fang, Jianqiao; Shao, Xiaomei; Anatomy, Cell Biology and Physiology, School of MedicineChronic pain, such as neuropathic pain, causes anxiety and other negative emotions, which aggravates the pain sensation and increases the risk of chronic pain over time. Dopamine receptor D1 (DRD1) and dopamine receptor D2 (DRD2) in the basolateral amygdala (BLA) have been implicated in mediating anxiety-related behaviors, but their potential roles in the BLA in neuropathic pain-induced anxiety have not been examined. Electroacupuncture (EA) is commonly used to treat chronic pain and emotional disorders, but it is still unclear whether EA plays a role in analgesia and anxiety relief through DRD1 and DRD2 in the BLA. Here, we used western blotting to examine the expression of DRD1 and DRD2 and pharmacological regulation combined with behavioral testing to detect anxiety-like behaviors. We observed that injection of the DRD1 antagonist SCH23390 or the DRD2 agonist quinpirole into the BLA contributed to anxiety-like behaviors in naive mice. EA also activated DRD1 or inhibited DRD2 in the BLA to alleviate anxiety-like behaviors. To further demonstrate the role of DRD1 and DRD2 in the BLA in spared nerve injury (SNI) model-induced anxiety-like behaviors, we injected the DRD1 agonist SKF38393 or the DRD2 antagonist sulpiride into the BLA. We found that both activation of DRD1 and inhibition of DRD2 could alleviate SNI-induced anxiety-like behaviors, and EA had a similar effect of alleviating anxiety. Additionally, neither DRD1 nor DRD2 in the BLA affected SNI-induced mechanical allodynia, but EA did. Overall, our work provides new insights into the mechanisms of neuropathic pain-induced anxiety and a possible explanation for the effect of EA treatment on anxiety caused by chronic pain.Item Electroacupuncture Induces Bilateral S1 and ACC Epigenetic Regulation of Genes in a Mouse Model of Neuropathic Pain(MDPI, 2023-03-27) Ping, Xingjie; Xie, Junkai; Yuan, Chongli; Jin, Xiaoming; Anatomy, Cell Biology and Physiology, School of MedicineClinical and animal studies have shown that acupuncture may benefit controlling neuropathic pain. However, the underlying molecular mechanisms are poorly understood. In a well-established mouse unilateral tibial nerve injury (TNI) model, we confirmed the efficacy of electroacupuncture (EA) in reducing mechanical allodynia and measured methylation and hydroxy-methylation levels in the primary somatosensory cortex (S1) and anterior cingulate cortex (ACC), two cortical regions critically involved in pain processing. TNI resulted in increased DNA methylation of both the contra- and ipsilateral S1, while EA only reduced contralateral S1 methylation. RNA sequencing of the S1 and ACC identified differentially expressed genes related to energy metabolism, inflammation, synapse function, and neural plasticity and repair. One week of daily EA decreased or increased the majority of up- or downregulated genes, respectively, in both cortical regions. Validations of two greatly regulated genes with immunofluorescent staining revealed an increased expression of gephyrin in the ipsilateral S1 after TNI was decreased by EA; while TNI-induced increases in Tomm20, a biomarker of mitochondria, in the contralateral ACC were further enhanced after EA. We concluded that neuropathic pain is associated with differential epigenetic regulations of gene expression in the ACC and S1 and that the analgesic effect of EA may involve regulating cortical gene expression.Item Homeostatic activity regulation as a mechanism underlying the effect of brain stimulation(BMC, 2019-09-25) Chai, Zhi; Ma, Cungen; Jin, Xiaoming; Anatomy and Cell Biology, School of MedicineHyperexcitability of the neural network often occurs after brain injuries or degeneration and is a key pathophysiological feature in certain neurological diseases such as epilepsy, neuropathic pain, and tinnitus. Although the standard approach of pharmacological treatments is to directly suppress the hyperexcitability through reducing excitation or enhancing inhibition, different techniques for stimulating brain activity are often used to treat refractory neurological conditions. However, it is unclear why stimulating brain activity would be effective for controlling hyperexcitability. Recent studies suggest that the pathogenesis in these disorders exhibits a transition from an initial activity loss after acute injury or progressive neurodegeneration to subsequent development of hyperexcitability. This process mimics homeostatic activity regulation and may contribute to developing network hyperexcitability that underlies neurological symptoms. This hypothesis also predicts that stimulating brain activity should be effective in reducing hyperexcitability due to homeostatic activity regulation and in relieving symptoms. Here we review current evidence of homeostatic plasticity in the development of hyperexcitability in some neurological diseases and the effects of brain stimulation. The homeostatic plasticity hypothesis may provide new insights into the pathophysiology of neurological diseases and may guide the use of brain stimulation techniques for treating them.