Publications by authors named "Patrick M Dougherty"

87 Publications

Studying human nociceptors: from fundamentals to clinic.

Brain 2021 Jun 15. Epub 2021 Jun 15.

Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford OX3 9DU, UK.

Chronic pain affects one in five of the general population and is the third most important cause of disability-adjusted life-years globally. Unfortunately, treatment remains inadequate due to poor efficacy and tolerability. There has been a failure in translating promising preclinical drug targets into clinic use. This reflects challenges across the whole drug development pathway, from preclinical models to trial design. Nociceptors remain an attractive therapeutic target: their sensitization makes an important contribution to many chronic pain states, they are located outside the blood-brain barrier, and they are relatively specific. The past decade has seen significant advances in the techniques available to study human nociceptors, including: the use of corneal confocal microscopy and biopsy samples to observe nociceptor morphology, the culture of human nociceptors (either from surgical or post-mortem tissue or using human induced pluripotent stem cell derived nociceptors), the application of high throughput technologies such as transcriptomics, the in vitro and in vivo electrophysiological characterization through microneurography, and the correlation with pain percepts provided by quantitative sensory testing. Genome editing in human induced pluripotent stem cell-derived nociceptors enables the interrogation of the causal role of genes in the regulation of nociceptor function. Both human and rodent nociceptors are more heterogeneous at a molecular level than previously appreciated, and while we find that there are broad similarities between human and rodent nociceptors there are also important differences involving ion channel function, expression, and cellular excitability. These technological advances have emphasized the maladaptive plastic changes occurring in human nociceptors following injury that contribute to chronic pain. Studying human nociceptors has revealed new therapeutic targets for the suppression of chronic pain and enhanced repair. Cellular models of human nociceptors have enabled the screening of small molecule and gene therapy approaches on nociceptor function, and in some cases have enabled correlation with clinical outcomes. Undoubtedly, challenges remain. Many of these techniques are difficult to implement at scale, current induced pluripotent stem cell differentiation protocols do not generate the full diversity of nociceptor populations, and we still have a relatively poor understanding of inter-individual variation in nociceptors due to factors such as age, sex, or ethnicity. We hope our ability to directly investigate human nociceptors will not only aid our understanding of the fundamental neurobiology underlying acute and chronic pain but also help bridge the translational gap.
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http://dx.doi.org/10.1093/brain/awab048DOI Listing
June 2021

Role of innate immunity in chemotherapy-induced peripheral neuropathy.

Neurosci Lett 2021 06 4;755:135941. Epub 2021 May 4.

The Department of Pain Medicine Research, The Division of Anesthesiology, Critical Care and Pain Medicine, The University of Texas M.D. Anderson Cancer Center, United States. Electronic address:

It has become increasingly clear that the innate immune system plays an essential role in the generation of many types of neuropathic pain including that which accompanies cancer treatment. In this article we review current findings of the role of the innate immune system in contributing to cancer treatment pain at the distal endings of peripheral nerve, in the nerve trunk, in the dorsal root ganglion and in the spinal dorsal horn.
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http://dx.doi.org/10.1016/j.neulet.2021.135941DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8190706PMC
June 2021

Human cells and networks of pain: Transforming pain target identification and therapeutic development.

Neuron 2021 05;109(9):1426-1429

Department of Neuroscience and Center for Advanced Pain Studies, University of Texas at Dallas, Richardson, TX 75080, USA. Electronic address:

Chronic pain is a disabling disease with limited treatment options. While animal models have revealed important aspects of pain neurobiology, therapeutic translation of this knowledge requires our understanding of these cells and networks of pain in humans. We propose a multi-institutional collaboration to rigorously and ethically address this challenge.
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http://dx.doi.org/10.1016/j.neuron.2021.04.005DOI Listing
May 2021

Cancer-Associated Neurogenesis and Nerve-Cancer Cross-talk.

Cancer Res 2021 03 17;81(6):1431-1440. Epub 2020 Dec 17.

Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.

In this review, we highlight recent discoveries regarding mechanisms contributing to nerve-cancer cross-talk and the effects of nerve-cancer cross-talk on tumor progression and dissemination. High intratumoral nerve density correlates with poor prognosis and high recurrence across multiple solid tumor types. Recent research has shown that cancer cells express neurotrophic markers such as nerve growth factor, brain-derived neurotrophic factor, and glial cell-derived neurotrophic factor and release axon-guidance molecules such as ephrin B1 to promote axonogenesis. Tumor cells recruit new neural progenitors to the tumor milieu and facilitate their maturation into adrenergic infiltrating nerves. Tumors also rewire established nerves to adrenergic phenotypes via exosome-induced neural reprogramming by p53-deficient tumors. In turn, infiltrating sympathetic nerves facilitate cancer progression. Intratumoral adrenergic nerves release noradrenaline to stimulate angiogenesis via VEGF signaling and enhance the rate of tumor growth. Intratumoral parasympathetic nerves may have a dichotomous role in cancer progression and may induce Wnt-β-catenin signals that expand cancer stem cells. Importantly, infiltrating nerves not only influence the tumor cells themselves but also impact other cells of the tumor stroma. This leads to enhanced sympathetic signaling and glucocorticoid production, which influences neutrophil and macrophage differentiation, lymphocyte phenotype, and potentially lymphocyte function. Although much remains unexplored within this field, fundamental discoveries underscore the importance of nerve-cancer cross-talk to tumor progression and may provide the foundation for developing effective targets for the inhibition of tumor-induced neurogenesis and tumor progression.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-2793DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7969424PMC
March 2021

Sex-based differences and aging in tactile function loss in persons with type 2 diabetes.

PLoS One 2020 12;15(11):e0242199. Epub 2020 Nov 12.

Department of Pain Medicine Research, University of Texas M.D. Anderson Cancer Center, Houston, TX, United States of America.

Background: Recent evidence of significant sex-based differences in the presentation of Type 2 Diabetes Mellitus (DM) and its complications has been found in humans, which may contribute to sex-based differences in reduced functionality and quality of life. Some functionality, such as tactile function of the hands, has significant direct impact on quality of life. The purpose of the current study was to explore the impact of DM and sex on tactile function, with consideration of variability in health state measures.

Research Design And Methods: A case-control single time point observational study from 2012-2020 in an ethnically diverse population-based community setting. The sample consists of 132 adult individuals: 70 independent community dwelling persons with DM (PwDM) and 62 age- and sex-matched controls (42 males and 90 females in total). The Semmes-Weinstein monofilament test was used to evaluate tactile sensation of the hands.

Results: Tactile sensation thresholds were adversely impacted by sex, age, degree of handedness, high A1c, diagnosis of DM, and neuropathy. Overall, strongly right-handed older adult males with poorly controlled DM and neuropathy possessed the poorest tactile discrimination thresholds. When self-identified minority status was included in a secondary analysis, DM diagnosis was no longer significant; negative impacts of age, neuropathy, degree of handedness, and high A1c remained significant.

Conclusions: The data indicate significant impacts of male sex, age, degree of handedness, self-identified minority status, and metabolic health on the development of poor tactile sensation. This combination of modifiable and non-modifiable factors are important considerations in the monitoring and treatment of DM complications.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0242199PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7660517PMC
January 2021

Blockers of Wnt3a, Wnt10a, or β-Catenin Prevent Chemotherapy-Induced Neuropathic Pain In Vivo.

Neurotherapeutics 2021 01 30;18(1):601-614. Epub 2020 Oct 30.

Department of Pain Medicine, Division of Anesthesiology, Critical Care & Pain Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.

Although chemotherapy is a key cancer treatment, many chemotherapeutic drugs produce chronic neuropathic pain, called chemotherapy-induced neuropathic pain (CINP), which is a dose-limiting adverse effect. To date, there is no medicine that prevents CINP in cancer patients and survivors. We determined whether blockers of the canonical Wnt signaling pathway prevent CINP. Neuropathic pain was induced by intraperitoneal injection of paclitaxel (PAC) on four alternate days in male Sprague-Dawley rats or male Axin2-LacZ knock-in mice. XAV-939, LGK-974, and iCRT14, Wnt/β-catenin blockers, were administered intraperitoneally as a single or multiple doses before or after injury. Mechanical allodynia, phosphoproteome profiling, Wnt ligands, and inflammatory mediators were measured by von Frey filament, phosphoproteomics, reverse transcription-polymerase chain reaction, and Western blot analysis. Localization of β-catenin was determined by immunohistochemical analysis in the dorsal root ganglia (DRGs) in rats and human. Our phosphoproteome profiling of CINP rats revealed significant phosphorylation changes in Wnt signaling components. Importantly, repeated systemic injections of XAV-939 or LGK-974 prevented the development of CINP in rats. In addition, XAV-939, LGK-974, and iCRT14 ameliorated CINP. PAC increased Wnt3a and Wnt10a, activated β-catenin in DRG, and increased monocyte chemoattractant protein-1 and interleukin-1β in DRG. PAC also upregulated rAxin2 in mice. Furthermore, β-catenin was expressed in neurons, including calcitonin gene-related protein-expressing neurons and satellite cells in rat and human DRG. In conclusion, chemotherapy increases Wnt3a, Wnt10a, and β-catenin in DRG and their pharmacological blockers prevent and ameliorate CINP, suggesting a target for the prevention and treatment of CINP.
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http://dx.doi.org/10.1007/s13311-020-00956-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8116404PMC
January 2021

ACE2 and SCARF expression in human dorsal root ganglion nociceptors: implications for SARS-CoV-2 virus neurological effects.

Pain 2020 11;161(11):2494-2501

Department of Neuroscience and Center for Advanced Pain Studies, University of Texas at Dallas, Richardson, TX, United States.

SARS-CoV-2 has created a global crisis. COVID-19, the disease caused by the virus, is characterized by pneumonia, respiratory distress, and hypercoagulation and can be fatal. An early sign of infection is loss of smell, taste, and chemesthesis-loss of chemical sensation. Other neurological effects of the disease have been described, but not explained. It is now apparent that many of these neurological effects (for instance joint pain and headache) can persist for at least months after infection, suggesting a sensory neuronal involvement in persistent disease. We show that human dorsal root ganglion (DRG) neurons express the SARS-CoV-2 receptor, angiotensin-converting enzyme 2 at the RNA and protein level. We also demonstrate that SARS-CoV-2 and coronavirus-associated factors and receptors are broadly expressed in human DRG at the lumbar and thoracic level as assessed by bulk RNA sequencing. ACE2 mRNA is expressed by a subset of nociceptors that express MRGPRD mRNA, suggesting that SARS-CoV-2 may gain access to the nervous system through entry into neurons that form free nerve endings at the outermost layers of skin and luminal organs. Therefore, DRG sensory neurons are a potential target for SARS-CoV-2 invasion of the peripheral nervous system, and viral infection of human nociceptors may cause some of the persistent neurological effects seen in COVID-19.
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http://dx.doi.org/10.1097/j.pain.0000000000002051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7572821PMC
November 2020

Chemotherapy-induced peripheral neuropathy in a dish: dorsal root ganglion cells treated in vitro with paclitaxel show biochemical and physiological responses parallel to that seen in vivo.

Pain 2021 01;162(1):84-96

Department of Anesthesia and Pain Medicine Research, the University of Texas MD Anderson Cancer Center, Houston, TX, United States.

The mechanisms underlying chemotherapy-induced peripheral neuropathy have yet to be fully elucidated, but primary afferent neurons have emerged as an especially vulnerable initiating pathophysiological target. An important recent study has also shown that the initial toxicity produced by paclitaxel in patients was highly predictive of long-term outcome. In this study, we therefore focused on defining the mechanisms of acute toxicity produced by paclitaxel treatment on primary sensory neurons under in vitro conditions. In primary rat dorsal root ganglion (DRG) culture with paclitaxel, an increase of pERK and pp38 was observed at 2 hours, and this was accompanied by an increase in expression and release of C-C chemokine ligand 2 (CCL2). There was no change in pJNK. The increase in pERK was sustained at 48 hours of exposure when the expression of TLR4, MyD88, and IL-6 was also increased. IL-6 and CCL2 were colocalized to TLR4-positive cells, and all these responses were prevented by coincubation with a TLR4 antagonist (LPS-RS). Whole-cell patch-clamp recordings revealed that DRG neurons developed spontaneous depolarizing fluctuations (DSFs) in membrane potential and hyperexcitability to current injection but no ectopic action potential activity at 24 and 48 hours of paclitaxel incubation. However, CCL2 applied to cultured neurons not only induced DSFs but also evoked action potentials. Evidence of oxidative stress and mitotoxicity was observed at 48 hours of exposure. These results closely parallel the responses measured in the DRG with paclitaxel exposure in vivo and so indicate that acute toxicity of paclitaxel on the DRG can be modelled using an in vitro approach.
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http://dx.doi.org/10.1097/j.pain.0000000000002005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7744394PMC
January 2021

Cranial irradiation induces axon initial segment dysfunction and neuronal injury in the prefrontal cortex and impairs hippocampal coupling.

Neurooncol Adv 2020 Jan-Dec;2(1):vdaa058. Epub 2020 May 11.

Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

Background: Radiation therapy for brain tumors commonly induces cognitive dysfunction. The prefrontal cortex (PFC) is crucial for a diverse array of cognitive processes, however, its role in radiation-induced cognitive dysfunction is unknown. We previously found that cranial irradiation impairs neuroplasticity along the hippocampal-PFC pathway. Herein, we hypothesized that brain irradiation directly affects the firing properties of PFC neurons, contributing to deficits in neuronal functions.

Methods: In vivo recordings were used to monitor the firing activities of PFC neurons and local field potentials in both PFC and hippocampal CA1/subicular regions after cranial irradiation of Sprague Dawley rats. We further assessed the impacts of irradiation on axon initial segments (AISs) with immunofluorescence assays of PFC slices.

Results: We found that PFC neurons exhibited increased excitation 3 days after radiation and the timing of increased excitation coincided with elongation of the AIS. At 2 weeks, excitation levels returned to nearly normal levels however the population of spontaneously firing neurons decreased. While the number of NeuN-positive neurons in the PFC was not different, persistent neuronal injury, manifested as ATF-3 staining, was present at 2 weeks. Radiation also disrupted communication along the hippocampal-PFC pathway, with elongation of the phase lag between regions. Analysis of paired-pulse ratios suggested that this was secondary to presynaptic dysfunction.

Conclusions: Cranial irradiation excited and injured surviving PFC neurons and was associated with a partial block of PFC's functional coupling to the hippocampus. These deficits in the PFC may contribute to radiation-induced cognitive dysfunction.
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http://dx.doi.org/10.1093/noajnl/vdaa058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7260696PMC
May 2020

Loss of p53 drives neuron reprogramming in head and neck cancer.

Nature 2020 02 12;578(7795):449-454. Epub 2020 Feb 12.

Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

The solid tumour microenvironment includes nerve fibres that arise from the peripheral nervous system. Recent work indicates that newly formed adrenergic nerve fibres promote tumour growth, but the origin of these nerves and the mechanism of their inception are unknown. Here, by comparing the transcriptomes of cancer-associated trigeminal sensory neurons with those of endogenous neurons in mouse models of oral cancer, we identified an adrenergic differentiation signature. We show that loss of TP53 leads to adrenergic transdifferentiation of tumour-associated sensory nerves through loss of the microRNA miR-34a. Tumour growth was inhibited by sensory denervation or pharmacological blockade of adrenergic receptors, but not by chemical sympathectomy of pre-existing adrenergic nerves. A retrospective analysis of samples from oral cancer revealed that p53 status was associated with nerve density, which was in turn associated with poor clinical outcomes. This crosstalk between cancer cells and neurons represents mechanism by which tumour-associated neurons are reprogrammed towards an adrenergic phenotype that can stimulate tumour progression, and is a potential target for anticancer therapy.
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http://dx.doi.org/10.1038/s41586-020-1996-3DOI Listing
February 2020

Percutaneous Cordotomy for Pain Palliation in Advanced Cancer: A Randomized Clinical Trial Study Protocol.

Neurosurgery 2020 08;87(2):394-402

Department of Palliative Care and Rehabilitation Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Background: Cancer pain, one of the most common symptoms for patients with advanced cancer, is often refractory to maximal medical therapy. A controlled clinical trial is needed to provide definitive evidence to support the use of ablative procedures such as cordotomy for patients with medically refractory cancer pain.

Objective: To assess the efficacy of cordotomy for patients with unilateral advanced cancer pain using a controlled clinical trial study design. The secondary objectives are to define the patient experience of cordotomy for medically refractory cancer pain as well as to determine the utility of magnetic resonance imaging as a non-invasive biomarker for successful cordotomy.

Methods: We will undertake a single-institution, double-blind, sham-controlled clinical trial of cordotomy in patients with refractory cancer pain. Patients in the cordotomy arm will undergo a percutaneous computed tomography-guided cordotomy at C1-C2, while patients in the control arm will undergo a similar procedure where the needle will not penetrate the thecal sac. The primary endpoint will be the reduction in pain intensity, as measured by the Edmonton Symptoms Assessment Scale.

Expected Outcomes: We expect that patients randomized to cordotomy will have a significantly greater reduction in pain intensity than those patients randomized to the control surgical intervention.

Discussion: This randomized clinical trial comparing cordotomy with a control intervention will provide the level of evidence necessary to determine whether cordotomy should be the standard of care intervention for patients with advanced cancer pain.
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http://dx.doi.org/10.1093/neuros/nyz527DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7360878PMC
August 2020

Persistent and Chronic Postoperative Opioid Use in a Cohort of Patients with Oral Tongue Squamous Cell Carcinoma.

Pain Med 2020 05;21(5):1061-1067

Department of Anesthesiology and Perioperative Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Background: Recently, the concept of persistent postsurgical opioid use has been described for patients undergoing cancer surgery. Our hypothesis was based on the premise that patients with oral tongue cancer require high dosages of opioids before, during, and after surgery, and thus a large percentage of patients might develop persistent postsurgical opioid use.

Methods: After institutional review board approval, we conducted a retrospective study that included a cohort of patients with oral tongue cancers who underwent curative-intent surgery in our institution. Multivariable logistic regression models were fit to study the association of the characteristics of several patients with persistent (six months after surgery) and chronic (12 months after surgery) postoperative opioid use.

Results: A total of 362 patients with oral tongue malignancies were included in the study. The rate of persistent use of opioids after surgery was 31%. Multivariate analysis showed that patients taking opioids before surgery and those receiving adjuvant therapy were 2.9 and 1.78 times more likely to use opioids six months after surgery. Fifteen percent of the patients were taking opioids 12 months after surgery. After adjusting for clinically relevant covariates, patients complaining of moderate tongue pain before surgery and those taking opioids preoperatively had at least three times higher risk of still using these analgesics one year after surgery.

Conclusions: Patients with oral tongue cancers have a high risk of developing persistent and chronic postsurgical opioid use.
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http://dx.doi.org/10.1093/pm/pnz242DOI Listing
May 2020

Should we be itching for a CCL2 itch and pain medicine?

Brain Behav Immun 2019 10 1;81:12-13. Epub 2019 Jul 1.

The Division of Anesthesiology, Critical Care and Pain Medicine, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe, Unit 409, Houston, TX 77030, United States. Electronic address:

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http://dx.doi.org/10.1016/j.bbi.2019.06.044DOI Listing
October 2019

Ectopic Spontaneous Afferent Activity and Neuropathic Pain.

Neurosurgery 2018 09;65(CN_suppl_1):49-54

The Departments of Pain Medicine Research, The Division of Anesthesia, Critical Care and Pain Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.

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http://dx.doi.org/10.1093/neuros/nyy119DOI Listing
September 2018

Electrophysiological and transcriptomic correlates of neuropathic pain in human dorsal root ganglion neurons.

Brain 2019 05;142(5):1215-1226

The Departments of Anesthesia and Pain Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA, USA.

Neuropathic pain encompasses a diverse array of clinical entities affecting 7-10% of the population, which is challenging to adequately treat. Several promising therapeutics derived from molecular discoveries in animal models of neuropathic pain have failed to translate following unsuccessful clinical trials suggesting the possibility of important cellular-level and molecular differences between animals and humans. Establishing the extent of potential differences between laboratory animals and humans, through direct study of human tissues and/or cells, is likely important in facilitating translation of preclinical discoveries to meaningful treatments. Patch-clamp electrophysiology and RNA-sequencing was performed on dorsal root ganglia taken from patients with variable presence of radicular/neuropathic pain. Findings establish that spontaneous action potential generation in dorsal root ganglion neurons is associated with radicular/neuropathic pain and radiographic nerve root compression. Transcriptome analysis suggests presence of sex-specific differences and reveals gene modules and signalling pathways in immune response and neuronal plasticity related to radicular/neuropathic pain that may suggest therapeutic avenues and that has the potential to predict neuropathic pain in future cohorts.
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http://dx.doi.org/10.1093/brain/awz063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6487328PMC
May 2019

Minimally Invasive Cordotomy for Refractory Cancer Pain: A Randomized Controlled Trial.

Oncologist 2019 07 22;24(7):e590-e596. Epub 2019 Feb 22.

Department of Palliative Care and Rehabilitation Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

Background: Up to 30% of patients with cancer continue to suffer from pain despite aggressive supportive care. The present study aimed to determine whether cordotomy can improve cancer pain refractory to interdisciplinary palliative care.

Materials And Methods: In this randomized controlled trial, we recruited patients with refractory unilateral somatic pain, defined as a pain intensity (PI) ≥4, after more than three palliative care evaluations. Patients were randomized to percutaneous computed tomography-guided cordotomy or continued interdisciplinary palliative care. The primary outcome was 33% improvement in PI at 1 week after cordotomy or study enrollment as measured by the Edmonton Symptom Assessment Scale.

Results: Sixteen patients were enrolled (nine female, median age 58 years). Six of seven patients (85.7%) randomized to cordotomy experienced >33% reduction in PI (median preprocedure PI = 7, range 6-10; 1 week after cordotomy median PI = 1, range 0-6; = .022). Zero of nine patients randomized to palliative care achieved a 33% reduction in PI. Seven patients (77.8%) randomized to palliative care elected to undergo cordotomy after 1 week. All of these patients experienced >33% reduction in PI (median preprocedure PI = 8, range 4-10; 1 week after cordotomy median PI = 0, range 0-1; = .022). No patients were withdrawn from the study because of adverse effects of the intervention.

Conclusion: These data support the use of cordotomy for pain refractory to optimal palliative care. The findings of this study justify a large-scale randomized controlled trial of percutaneous cordotomy.

Implications For Practice: This prospective clinical trial was designed to determine the improvement in pain intensity in patients randomized to either undergo cordotomy or comprehensive palliative care for medically refractory cancer pain. This study shows that cordotomy is effective in reducing pain for medically refractory cancer pain, and these results can be used to design a large-scale comparative randomized controlled trial that could provide the evidence needed to include cordotomy as a treatment modality in the guidelines for cancer pain management.
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http://dx.doi.org/10.1634/theoncologist.2018-0570DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6656471PMC
July 2019

Nociceptor Translational Profiling Reveals the Ragulator-Rag GTPase Complex as a Critical Generator of Neuropathic Pain.

J Neurosci 2019 01 20;39(3):393-411. Epub 2018 Nov 20.

University of Texas at Dallas, School of Behavioral and Brain Sciences, 800 Campbell Rd, Richardson, Texas, 75080,

Nociceptors, sensory neurons in the DRG that detect damaging or potentially damaging stimuli, are key drivers of neuropathic pain. Injury to these neurons causes activation of translation regulation signaling, including the mechanistic target of rapamycin complex 1 (mTORC1) and mitogen-activated protein kinase interacting kinase (MNK) eukaryotic initiation factor (eIF) 4E pathways. This is a mechanism driving changes in excitability of nociceptors that is critical for the generation of chronic pain states; however, the mRNAs that are translated to lead to this plasticity have not been elucidated. To address this gap in knowledge, we used translating ribosome affinity purification in male and female mice to comprehensively characterize mRNA translation in -positive nociceptors in chemotherapy-induced neuropathic pain (CIPN) caused by paclitaxel treatment. This unbiased method creates a new resource for the field, confirms many findings in the CIPN literature and also find extensive evidence for new target mechanisms that may cause CIPN. We provide evidence that an underlying mechanism of CIPN is sustained mTORC1 activation driven by MNK1-eIF4E signaling. RagA, a GTPase controlling mTORC1 activity, is identified as a novel target of MNK1-eIF4E signaling. This demonstrates a novel translation regulation signaling circuit wherein MNK1-eIF4E activity drives mTORC1 via control of RagA translation. CIPN and RagA translation are strongly attenuated by genetic ablation of eIF4E phosphorylation, MNK1 elimination or treatment with the MNK inhibitor eFT508. We identify a novel translational circuit for the genesis of neuropathic pain caused by chemotherapy with important implications for therapeutics. Neuropathic pain affects up to 10% of the population, but its underlying mechanisms are incompletely understood, leading to poor treatment outcomes. We used translating ribosome affinity purification technology to create a comprehensive translational profile of DRG nociceptors in naive mice and at the peak of neuropathic pain induced by paclitaxel treatment. We reveal new insight into how mechanistic target of rapamycin complex 1 is activated in neuropathic pain pointing to a key role of MNK1-eIF4E-mediated translation of a complex of mRNAs that control mechanistic target of rapamycin complex 1 signaling at the surface of the lysosome. We validate this finding using genetic and pharmacological techniques. Our work strongly suggests that MNK1-eIF4E signaling drives CIPN and that a drug in human clinical trials, eFT508, may be a new therapeutic for neuropathic pain.
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http://dx.doi.org/10.1523/JNEUROSCI.2661-18.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6335757PMC
January 2019

An updated understanding of the mechanisms involved in chemotherapy-induced neuropathy.

Pain Manag 2018 Sep 13;8(5):363-375. Epub 2018 Sep 13.

Division of Anesthesiology, Critical Care & Pain Medicine, MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 0409, Houston, TX 77030, USA.

The burdensome condition of chemotherapy-induced peripheral neuropathy occurs with various chemotherapeutics, including bortezomib, oxaliplatin, paclitaxel and vincristine. The symptoms, which include pain, numbness, tingling and loss of motor function, can result in therapy titrations that compromise therapy efficacy. Understanding the mechanisms of chemotherapy-induced peripheral neuropathy is therefore essential, yet incompletely understood. The literature presented here will address a multitude of molecular and cellular mechanisms, beginning with the most well-understood cellular and molecular-level changes. These modifications include alterations in voltage-gated ion channels, neurochemical transmission, organelle function and intracellular pathways. System-level alterations, including changes to glial cells and cytokine activation are also explored. Finally, we present research on the current understanding of genetic contributions to this condition. Suggestions for future research are provided.
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http://dx.doi.org/10.2217/pmt-2018-0020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6462837PMC
September 2018

Trial designs for chemotherapy-induced peripheral neuropathy prevention: ACTTION recommendations.

Neurology 2018 08 27;91(9):403-413. Epub 2018 Jul 27.

From the University of Rochester (J.S.G., M.P.M., R.H.D.), NY; MetroHealth Medical Center (J.B.), Case Western Reserve University, Cleveland, OH; University of Milano-Bicocca (G.C.), Monza, Italy; MD Anderson Cancer Center (P.M.D.), Houston, TX; Milkin Institute School of Public Health (S.E.), George Washington University, Washington, DC; Division of Oncology Products (L.H.), US Food and Drug Administration, Silver Spring; National Institutes of Health (A.O.), Bethesda, MD; Virginia Commonwealth University (A.G.S.), Richmond; Mundipharma R&D Limited (D.D.-P.), Cambridge, UK; Université Laval (L.R.G.), Québec, Canada; Washington University (S.H.), St. Louis, MO; Regenacy Pharmaceuticals (M.J.), Boston; Analgesic Solutions (N.P.K.), Natick; Tufts University (N.P.K.), Boston, MA; Mayo Clinic (C.L.), Rochester, MN; Dana-Farber/Brigham and Women's Cancer Center (P.R., P.Y.W.) and Beth Israel Deaconess Medical Center (R.F.), Harvard Medical School, Boston, MA; University of Michigan (E.M.L.S.), Ann Arbor; and University of Washington (D.C.T.), Seattle.

Chemotherapy-induced peripheral neuropathy (CIPN) is a common and potentially dose-limiting side effect of neurotoxic chemotherapies. No therapies are available to prevent CIPN. The small number of positive randomized clinical trials (RCTs) evaluating preventive therapies for CIPN provide little guidance to inform the design of future trials. Moreover, the lack of consensus regarding major design features in this area poses challenges to development of new therapies. An Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities and Networks (ACTTION)-Consortium on Clinical Endpoints and Procedures for Peripheral Neuropathy Trials (CONCEPPT) meeting attended by neurologists, oncologists, pharmacists, clinical trialists, statisticians, and regulatory experts was convened to discuss design considerations and provide recommendations for CIPN prevention trials. This article outlines considerations related to design of RCTs that evaluate preventive therapies for CIPN including (1) selection of eligibility criteria (e.g., cancer types, chemotherapy types, inclusion of preexisting neuropathy); (2) selection of outcome measures and endpoints, including those that incorporate alterations in chemotherapy dosing, which may affect the rate of CIPN development and its severity; (3) potential effects of the investigational therapy on the efficacy of chemotherapy; and (4) sample size estimation. Our hope is that attention to the design considerations and recommendations outlined in this article will improve the quality and assay sensitivity of CIPN prevention trials and thereby accelerate the identification of efficacious therapies.
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http://dx.doi.org/10.1212/WNL.0000000000006083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6133627PMC
August 2018

Subclinical Peripheral Neuropathy in Patients with Head and Neck Cancer: A Quantitative Sensory Testing (QST) Study.

Pain Physician 2018 07;21(4):E419-E427

Department of Pain Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX.

Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a common and chronic complication associated with cancer treatment. Prior investigations have demonstrated the presence of subclinical peripheral neuropathy in patients with colorectal cancer even before the patients had received chemotherapy.

Objective: To investigate subclinical peripheral neuropathy of the upper limbs in patients with squamous cell carcinoma (SCC) of the head and neck which developed before their exposure to neurotoxic anticancer agents.

Study Design: Retrospective analysis.

Methods: With the use of our quantitative sensory testing (QST) data bank, we retrospectively assessed the afferent fiber function of 25 patients with SCC of the head and neck before they had received chemotherapy (the patient group) and compared our findings with those from 23 healthy control patients. Skin temperature, sensorimotor function, sharpness detection, thermal detection, and touch detection (using both von Frey monofilaments and the Bumps detection test) were measured.

Results: Touch thresholds were statistically higher in the patient group than in the healthy volunteer group at the palm (mean [± SD], 0.54 g [± 0.07 g] and 0.27 g [± 0.05 g], respectively [P < 0.01]) and at the forearm (0.74 g [± 0.12 g] and 0.41 g [± 0.08 g] [P < 0.05]). There was also a clear deficit in touch sensation as indicated by a Bumps detection threshold in patients of 6.5 µm ± 0.8 µm and in controls of 3.7 µm ± 0.5 µm. This yields an elevation in threshold to 165% in the patients relative to that of the control volunteers. The grooved pegboard test showed delayed completion times for patients compared with controls, with differences of 18.65 seconds in the dominant hand and of 23.36 seconds in the nondominant hand. The sharpness detection thresholds did not differ between patients and volunteers.

Limitations: Inadequacies in the original data acquisition and documentation of the QST and the medical records could not be addressed due to the retrospective nature of the study. In addition, based on available information, we did not find an objective parameter able to correlate the QST findings with pre-pain levels.

Conclusion: Patients with SCC were found to have deficits in sensory function before undergoing treatment, suggesting that cancer itself alters peripheral nerve function and may contribute to the development of CIPN. These results confirm the sensitivity of the Bumps detection test and highlight its potential role in early detection of peripheral neuropathy, especially in cancer patients for whom chemotherapies associated with CIPN have been prescribed.

Key Words: Peripheral neuropathy, head and neck cancer, quantitative sensory testing.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6471511PMC
July 2018

Somatotopy and Organization of Spinothalamic Tracts in the Human Cervical Spinal Cord.

Neurosurgery 2019 06;84(6):E311-E317

Department of Neurosurgery, Baylor College of Medicine, Houston, Texas.

Background: Understanding spinothalamic tract anatomy may improve lesioning and outcomes in patients undergoing percutaneous cordotomy.

Objective: To investigate somatotopy and anatomical organization of spinothalamic tracts in the human cervical spinal cord.

Methods: Patients with intractable cancer pain undergoing cordotomy underwent preoperative and postoperative quantitative sensory testing for sharp pain and heat pain on day 1 and 7 after cordotomy. Intraoperative sensory stimulation was performed with computed tomography (CT) imaging to confirm the location of the radiofrequency electrode during cordotomy. Postoperative magnetic resonance (MR) imaging was performed to define the location of the lesion.

Results: Twelve patients were studied, and intraoperative sensory stimulation combined with CT imaging revealed a somatotopy where fibers from the legs were posterolateral to fibers from the hand. Sharpness detection thresholds were significantly elevated in the area of maximum pain on postoperative day 1 (P = .01). Heat pain thresholds for all areas were not elevated significantly on postoperative day 1, or postoperative day 7. MR imaging confirmed that the cordotomy lesion was in the anterolateral quadrant, and in this location the lesion had a sustained effect on sharp pain but a transient impact on heat pain.

Conclusion: In the high cervical spinal cord, spinothalamic fibers mediating sharp pain for the arms are located ventromedial to fibers for the legs, and these fibers are spatially distinct from fibers that mediate heat pain.
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http://dx.doi.org/10.1093/neuros/nyy330DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6702412PMC
June 2019

Morphological and Physiological Plasticity of Spinal Lamina II GABA Neurons Is Induced by Sciatic Nerve Chronic Constriction Injury in Mice.

Front Cell Neurosci 2018 24;12:143. Epub 2018 May 24.

Division of Anesthesiology and Critical Care Medicine, Department of Pain Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, United States.

Mice with transgenic insertion of code for enhanced green fluorescent protein (EGFP) at the locus for glutamic acid decarboxylase 67 (GAD67), one of two key enzymes for the synthesis of γ-aminobutyric acid (GABA) were used to test whether the morphological properties of these neurons show plasticity with nerve injury. Physiological properties and the delivery of intracellular label to EGFP-expressing lamina II neurons was done using whole-cell patch-clamp in spinal cord slices from sham and chronic constriction injury (CCI) mice. As well, whole cell recordings were made of non-EGFP labeled cells to ascertain changes in overall inhibitory signaling following CCI. The EGFP labeled neurons in both sham and CCI mice exhibited islet, central and vertical cell morphological profiles but no radial cell profiles were observed. The length of cell dendrites was found to be significantly shorter in CCI mice for all cell profile types. The longest neurites averaged 155.96 ± 18.29 μm in CCI mice compared to 334.93 ± 29.48 μm in sham control mice. No change was observed in either passive or evoked membrane properties of EGFP-expressing neurons in CCI versus sham mice. Meanwhile, the frequency of miniature inhibitory post-synaptic currents of non-EGFP expressing spinal lamina II neurons was significantly reduced. These results suggest that reduced inhibitory output from GABA neurons occurs with nerve injury in part due to altered cell morphology.
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http://dx.doi.org/10.3389/fncel.2018.00143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5976754PMC
May 2018

Radiation induces age-dependent deficits in cortical synaptic plasticity.

Neuro Oncol 2018 08;20(9):1207-1214

Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Background: Radiation-induced cognitive dysfunction is a significant side effect of cranial irradiation for brain tumors. Clinically, pediatric patients are more vulnerable than adults. However, the underlying mechanisms of dysfunction, including reasons for age dependence, are still largely unknown. Previous studies have focused on the loss of hippocampal neuronal precursor cells and deficits in memory. However, survivors may also experience deficits in attention, executive function, or other non-hippocampal-dependent cognitive domains. We hypothesized that brain irradiation induces age-dependent deficits in cortical synaptic plasticity.

Methods: In vivo recordings were used to test neuronal plasticity along the direct pathway from the cornu ammonis 1 (CA1)/subicular region to the prefrontal cortex (PFC). Specifically, long-term potentiation (LTP) in the CA1/subicular-PFC pathway was assessed after cranial irradiation of juvenile and adult Sprague Dawley rats. We further assessed a potential role for glutamate toxicity by evaluating the potential neuroprotective effects of memantine.

Results: LTP was greatly inhibited in both adult and juvenile animals at 3 days after radiation but returned to near-normal levels by 8 weeks-only in adult rats. Memantine given before, but not after, irradiation partially prevented LTP inhibition in juvenile and adult rats.

Conclusion: Cranial radiation impairs neuroplasticity along the hippocampal-PFC pathway; however, its effects vary by age. Pretreatment with memantine offered protection to both juvenile and adult animals. Deficits in cortical plasticity may contribute to radiation-induced cognitive dysfunction, including deficits in attention and age-dependent sensitivity of such pathways, which may underlie differences in clinical outcomes between juveniles and adults after cranial irradiation.
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http://dx.doi.org/10.1093/neuonc/noy052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6107999PMC
August 2018

Chemokine CCL2 and its receptor CCR2 in the dorsal root ganglion contribute to oxaliplatin-induced mechanical hypersensitivity.

Pain 2018 Jul;159(7):1308-1316

Department of Anesthesiology and Pain Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Activation of innate immune mechanisms within the dorsal root ganglion and spinal dorsal horn has been shown to play a key role in the development of neuropathic pain including paclitaxel-related chemotherapy-induced peripheral neuropathy (CIPN). Here, we tested whether similar mechanisms are generalizable to oxaliplatin-induced CIPN. After a single intraperitoneal injection of 3 mg/kg oxaliplatin, mechanical withdrawal threshold and the expression of C-C chemokine ligand 2 (CCL2) and its receptor, CCR2, in the dorsal root ganglion were measured by behavioral testing and immunohistochemical staining, respectively. Mechanical responsiveness increased from the first day after oxaliplatin injection and persisted until day 15, the last day of this experiment. Immunohistochemical showed that the expression of CCL2/CCR2 started to increase by 4 hours after oxaliplatin treatment, was significantly increased at day 4, and then both signals became normalized by day 15. Cotreatment with intrathecal anti-CCL2 antibodies prevented the development of oxaliplatin-induced mechanical hyperresponsiveness, and transiently reversed established hyperalgesia when given 1 week after chemotherapy. This is the first study to demonstrate CCL2/CCR2 signaling in a model of oxaliplatin-related CIPN; and it further shows that blocking of this signal can attenuate the development of oxaliplatin-induced mechanical hyperalgesia. Activation of innate immune mechanisms may therefore be a generalized basis for CIPN irrespective of the specific class of agent.
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http://dx.doi.org/10.1097/j.pain.0000000000001212DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6008166PMC
July 2018

Beyond symptomatic relief for chemotherapy-induced peripheral neuropathy: Targeting the source.

Cancer 2018 06 20;124(11):2289-2298. Epub 2018 Feb 20.

Neuroimmunology Laboratory, Department of Symptom Research, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Chemotherapy-induced peripheral neuropathy (CIPN) is a serious adverse side effect of many chemotherapeutic agents, affecting >60% of patients with cancer. Moreover, CIPN persists long into survivorship in approximately 20% to 30% of these patients. To the authors' knowledge, no drugs have been approved to date by the US Food and Drug Administration to effectively manage chemotherapy-induced neuropathic pain. The majority of the drugs tested for the management of CIPN aim at symptom relief, including pain and paresthesia, yet are not very efficacious. The authors propose that there is a need to acquire a more thorough understanding of the etiology of CIPN so that effective, mechanism-based, disease-modifying interventions can be developed. It is important to note that such interventions should not interfere with the antitumor effects of chemotherapy. Mitochondria are rod-shaped cellular organelles that represent the powerhouses of the cell, in that they convert oxygen and nutrients into the cellular energy "currency" adenosine triphosphate. In addition, mitochondria regulate cell death. Neuronal mitochondrial dysfunction and the associated nitro-oxidative stress represent crucial final common pathways of CIPN. Herein, the authors discuss the potential to prevent or reverse CIPN by protecting mitochondria and/or inhibiting nitro-oxidative stress with novel potential drugs, including the mitochondrial protectant pifithrin-μ, histone deacetylase 6 inhibitors, metformin, antioxidants, peroxynitrite decomposition catalysts, and anti-inflammatory mediators including interleukin 10. This review hopefully will contribute toward bridging the gap between preclinical research and the development of realistic novel therapeutic strategies to prevent or reverse the devastating neurotoxic effects of chemotherapy on the (peripheral) nervous system. Cancer 2018;124:2289-98. © 2018 American Cancer Society.
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http://dx.doi.org/10.1002/cncr.31248DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5991994PMC
June 2018

Orally active Epac inhibitor reverses mechanical allodynia and loss of intraepidermal nerve fibers in a mouse model of chemotherapy-induced peripheral neuropathy.

Pain 2018 May;159(5):884-893

Laboratory of Neuroimmunology, Department of Symptom Research, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Chemotherapy-induced peripheral neuropathy (CIPN) is a major side effect of cancer treatment that significantly compromises quality of life of cancer patients and survivors. Identification of targets for pharmacological intervention to prevent or reverse CIPN is needed. We investigated exchange protein regulated by cAMP (Epac) as a potential target. Epacs are cAMP-binding proteins known to play a pivotal role in mechanical allodynia induced by nerve injury and inflammation. We demonstrate that global Epac1-knockout (Epac1-/-) male and female mice are protected against paclitaxel-induced mechanical allodynia. In addition, spinal cord astrocyte activation and intraepidermal nerve fiber (IENF) loss are significantly reduced in Epac1-/- mice as compared to wild-type mice. Moreover, Epac1-/- mice do not develop the paclitaxel-induced deficits in mitochondrial bioenergetics in the sciatic nerve that are a hallmark of CIPN. Notably, mice with cell-specific deletion of Epac1 in Nav1.8-positive neurons (N-Epac1-/-) also show reduced paclitaxel-induced mechanical allodynia, astrocyte activation, and IENF loss, indicating that CIPN develops downstream of Epac1 activation in nociceptors. The Epac-inhibitor ESI-09 reversed established paclitaxel-induced mechanical allodynia in wild-type mice even when dosing started 10 days after completion of paclitaxel treatment. In addition, oral administration of ESI-09 suppressed spinal cord astrocyte activation in the spinal cord and protected against IENF loss. Ex vivo, ESI-09 blocked paclitaxel-induced abnormal spontaneous discharges in dorsal root ganglion neurons. Collectively, these findings implicate Epac1 in nociceptors as a novel target for treatment of CIPN. This is clinically relevant because ESI-09 has the potential to reverse a debilitating and long-lasting side effect of cancer treatment.
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http://dx.doi.org/10.1097/j.pain.0000000000001160DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5908748PMC
May 2018

DRG Voltage-Gated Sodium Channel 1.7 Is Upregulated in Paclitaxel-Induced Neuropathy in Rats and in Humans with Neuropathic Pain.

J Neurosci 2018 01 18;38(5):1124-1136. Epub 2017 Dec 18.

Departments of Anesthesia and Pain Medicine,

Chemotherapy-induced peripheral neuropathy (CIPN) is a common adverse effect experienced by cancer patients receiving treatment with paclitaxel. The voltage-gated sodium channel 1.7 (Na1.7) plays an important role in multiple preclinical models of neuropathic pain and in inherited human pain phenotypes, and its gene expression is increased in dorsal root ganglia (DRGs) of paclitaxel-treated rats. Hence, the potential of change in the expression and function of Na1.7 protein in DRGs from male rats with paclitaxel-related CIPN and from male and female humans with cancer-related neuropathic pain was tested here. Double immunofluorescence in CIPN rats showed that Na1.7 was upregulated in small DRG neuron somata, especially those also expressing calcitonin gene-related peptide (CGRP), and in central processes of these cells in the superficial spinal dorsal horn. Whole-cell patch-clamp recordings in rat DRG neurons revealed that paclitaxel induced an enhancement of ProTx II (a selective Na1.7 channel blocker)-sensitive sodium currents. Bath-applied ProTx II suppressed spontaneous action potentials in DRG neurons occurring in rats with CIPN, while intrathecal injection of ProTx II significantly attenuated behavioral signs of CIPN. Complementarily, DRG neurons isolated from segments where patients had a history of neuropathic pain also showed electrophysiological and immunofluorescence results indicating an increased expression of Na1.7 associated with spontaneous activity. Na1.7 was also colocalized in human cells expressing transient receptor potential vanilloid 1 and CGRP. Furthermore, ProTx II decreased firing frequency in human DRGs with spontaneous action potentials. This study suggests that Na1.7 may provide a potential new target for the treatment of neuropathic pain, including chemotherapy (paclitaxel)-induced neuropathic pain. This work demonstrates that the expression and function of the voltage-gated sodium channel Na1.7 are increased in a preclinical model of chemotherapy-induced peripheral neuropathy (CIPN), the most common treatment-limiting side effect of all the most common anticancer therapies. This is key as gain-of-function mutations in human Na1.7 recapitulate both the distribution and pain percept as shown by CIPN patients. This work also shows that Na1.7 is increased in human DRG neurons only in dermatomes where patients are experiencing acquired neuropathic pain symptoms. This work therefore has major translational impact, indicating an important novel therapeutic avenue for neuropathic pain as a class.
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http://dx.doi.org/10.1523/JNEUROSCI.0899-17.2017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5792474PMC
January 2018

Psychometric Study of the Pain Drawing.

J Appl Biobehav Res 2017 Dec 7;22(4). Epub 2017 Apr 7.

Department of Pain Medicine, The University of Texas MD Anderson Cancer Center, 1400 Holcombe Boulevard, Unit 409, Houston, TX, USA 77030.

Purpose: The objectives of the study were to (1) assess the extent to which interrater reliability of pain drawing location and dispersion scoring methods are similar across pain disciplines in a sample of patients with cancer treatment-induced neuropathic pain ( = 56) and (2) investigate indicators of validity of the pain drawing in this unique sample.

Methods: Patients undergoing cancer therapy completed the Brief Pain Inventory Body Map, the MD Anderson Symptom Inventory, and the McGill Pain Questionnaire.

Results: Intraclass correlation coefficients among medical and psychology professionals ranged from .93-.99. Correlations between pain drawing score and symptom burden severity ranged from .29-.39; correlations between pain drawing score and symptom burden interference ranged from .28-.34. Patients who endorsed pain in the hands and feet more often described their pain as electric, numb, and shooting than patients without pain in the hands and feet. They also endorsed significantly more descriptors of neuropathic pain.

Conclusions: Results suggest a similar understanding among members of a multidisciplinary pain team as to the location and dispersion of pain as represented by patients' pain drawings. In addition, pain drawing scores were related to symptom burden severity and interference and descriptors of neuropathic pain in expected ways.
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http://dx.doi.org/10.1111/jabr.12095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5722249PMC
December 2017

Limited Midline Myelotomy for Intractable Visceral Pain: Surgical Techniques and Outcomes.

Neurosurgery 2018 10;83(4):783-789

Department of Neurosurgery, Baylor College of Medicine, Houston, Texas.

Background: Limited midline myelotomy targets the midline nociceptive pathway for intractable visceral pain. Multiple techniques are available for limited midline myelotomy; however, outcome data for each technique are sparse.

Objective: To review our experience with open and percutaneous approaches for limited midline myelotomy for intractable visceral pain.

Methods: Patients who underwent limited midline myelotomy for intractable visceral pain were reviewed. Myelotomy was performed using 3 techniques: open limited myelotomy, percutaneous radiofrequency myelotomy, and percutaneous mechanical myelotomy. Demographic and perioperative clinical data were recorded. In addition to the visual analog scale and Karnofsy performance score, outcomes were categorized as excellent (no pain), good (considerable reduction in pain, not requiring opioids stronger than codeine), fair (minimal reduction in pain, but no change in opioid medication requirement), and poor (no reduction in pain).

Results: Eight patients (median age 56.5 yr, 6 females) underwent limited myelotomy. Four patients underwent open limited thoracic myelotomy with excellent pain outcomes. Three patients underwent percutaneous radiofrequency lesioning with fair (n = 1) and poor outcomes (n = 2). One patient underwent percutaneous mechanical lesioning with a good outcome (n = 1). The median duration of follow-up was 11 wk (2-54 wk). Two patients reported minor sensory complications after the procedure.

Conclusion: In our preliminary experience, outcomes for open limited thoracic myelotomy were superior to percutaneous approaches. Given the limited utilization of this technique, multicenter registries are needed to further evaluate the best surgical technique for limited midline myelotomy.
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http://dx.doi.org/10.1093/neuros/nyx549DOI Listing
October 2018

Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers Modulate the Function of Myelinated Fibers after Chemotherapy: A Quantitative Sensory Testing Study.

Pain Physician 2017 05;20(4):281-292

Department of Pain Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX.

Background: Angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB) have sufficient scientific support for their use as tissue protectors. Preliminary studies suggest that their angiotensin-II type 2 receptor (AT2R)-blocking properties have a beneficial profile in the treatment of neuropathic pain.

Objectives: The purpose of the current study was to quantify the extent of the somatosensory effects of ACEI and ARB in cancer patients with chemotherapy-induced peripheral neuropathy.

Study Design: We performed a retrospective review of cancer patients with peripheral neuropathy of the upper limbs induced by known neurotoxic anti-cancer agents.

Setting: Pain Medicine department at academic tertiary care cancer center.

Methods: Using our quantitative sensory testing (QST) data bank, we retrospectively compared the tactile function and the touch, sharp, and thermal thresholds of patients who were previously receiving ACEI or ARB for high blood pressure with these variables in controls who were not receiving ACEI or ARB.

Results: Of the 209 patients available for analysis, 145 met inclusion criteria. Baseline characteristics of patients included were generally similar. We identified 29 patients who were receiving AT2R inhibitors prior to starting chemotherapy. Touch thresholds were statistically lower in the thenar aspect of hand in the study group (patients who received AT2R inhibitors) than in the control group [mean (± SD), median 3.03 g (± 11.05), median 0.56 g and 6.75 g (± 18.28), 0.56 g, respectively (P = 0.0441)]. Similarly, the cold pain threshold was statistically higher at the thenar area for the study group [mean (± SD), median 13.23°C (± 8.02), 11.73°C] than for controls [9.89°C (± 6.62), 10.05°C (P = 0.0369)].

Limitations: Inadequacies in the original data acquisition and documentation of the QST and the medical records could not be addressed due to the retrospective nature of the study. Similarly, a discrepancy on the size of the comparison groups could not be reconciled. In addition, based on the available information and the lack of documented concomitant pain levels, we did not find an objective parameter able to correlate the QST findings with pain levels.

Conclusions: AT2R inhibitors might offer partial and selective neuroprotective qualities of the myelinated fibers A-beta; and A-delta in cancer patients who receive neurotoxic chemotherapy.
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May 2017