Browsing by Subject "Pain"

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    Advancing Treatment for Pancreatitis: A Prospective Observational Study of TPIAT (POST Study). Protocol, Manual of Procedures, and Case Report Forms
    (2024-08-08) Bellin, Melena; post@umn.edu; POST, Staff Members; University of Minnesota Division of Pediatric Endocrinology and Division of Biostatistics and Health Data Science
    This "dataset" contains supplemental materials only: the final version of the POST Study's protocol, Manual of Procedures (MOP), and Case Report Forms (CRFs), for reference generally and specifically for the public-use datasets, which will be made available after the primary publications appear. Please contact POST study staff at post@umn.edu to request access to the actual data.
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    Association of opioid requirement and cancer pain with survival in advanced non-small cell lung cancer
    (2017-05) Zylla, Dylan
    Background: Pain is associated with shorter survival in non-small cell lung cancer (NSCLC). Lung cancer cells express opioid receptors. Opioids promote angiogenesis, tumor growth and metastases, and shorten survival in animal models. Methods: To examine if long-term opioid requirement, independently of chronic pain, is associated with survival, we studied 209 patients treated with chemotherapy for stage IIIB/IV NSCLC. Pain was stratified by proportion of time patients reported specific levels of pain. Opioids were converted to oral morphine equivalents (OME) for comparison. The effects of pain, opioid requirement, and known prognostic variables on survival were analyzed in univariable and multivariable models. Results: Both severity of pain and greater opioid requirement in first 90 days after starting chemotherapy were strongly predictive of shorter survival on univariable analysis. Patients with no/mild chronic pain and requiring <5 mg/day OME during first 90 days had nearly 12 months longer median survival compared to patients requiring ≥5 mg/day OME and/or experiencing more pain. Differences in survival remained remarkably similar when chronic pain and opioid requirement were assessed over the entire clinical course (until death or last follow-up). In multivariable models, both opioid requirement and chronic pain remained independent predictors of survival, after adjustment for age, stage and performance status. Conclusions: Severity of chronic cancer-related pain or greater opioid requirement are associated with shorter survival in advanced NSCLC, independently of known prognostic factors. While pain adversely influences prognosis, controlling it with opioids does not improve survival. Prospective studies should determine if achieving pain control using opioid-sparing approaches improves outcomes.
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    Bivalent Ligand MMG22 Reduces Bone Cancer Pain without Tolerance or Sedation
    (2022-07) Shueb, Sarah
    Pain is among the most common symptoms in cancer and approximately 90% of patients experience end-stage cancer pain. The management of cancer pain is challenging due to the significant side effects associated with opioids, and novel therapeutic approaches are needed. MMG22 is a bivalent ligand containing MOR agonist and mGluR5 antagonist pharmacophores joined by a 22-atom spacer. MMG22 exhibited extraordinary analgesia following intrathecal administration in a mouse model of bone cancer pain. Here, we assessed the effectiveness of systemic administration of MMG22 in reducing cancer pain and evaluated whether MMG22 displays side effects associated with opioids. Fibrosarcoma cells were injected into and around the calcaneus bone in C3H mice. Mechanical hyperalgesia was defined as an increase in the paw withdrawal frequencies (PWFs) evoked by the application of a von Frey monofilament (3.9 mN bending force) applied to the plantar surface of the hind paw.Subcutaneous (s.c.), intramuscular (i.m.), and oral (p.o.) administration of MMG22 produced robust dose-dependent antihyperalgesic, whose ED50 was orders of magnitude lower than morphine. Moreover, the ED50 for MMG22 decreased with disease progression. Importantly, s.c. administration of MMG22 did not produce acute (24 h) or long-term (9 days) tolerance, was not rewarding (conditioned place preference test), and did not produce naloxone-induced precipitated withdrawal or altered motor function. A possible mechanism of action of MMG22 is discussed in terms of inhibition of spinal NMDAR via antagonism of its co-receptor, mGluR5, and concomitant activation of neuronal MOR. We suggest that MMG22 may be a powerful alternative to traditional opioids for managing cancer pain.
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    Cannabinoid modulation of nociception and nociceptor activity during inflammation.
    (2009-06) Potenzieri, Carl Robert
    Previous studies have demonstrated that peripherally-administered cannabinoids at the site of injury produce antinociception in animal models of acute and persistent pain. Peripheral cannabinoid one (CB1) receptor-mediated antinociception has been attributed to CB1 receptors located on nociceptive DRG neurons and their peripheral nerve terminals. Although these studies suggest that activation of peripheral CB1 receptors located on nociceptive nerve terminals produces antinociception, how cannabinoids modulate nociceptor activity is not known. The overall aim of this thesis was to relate the behavioral antinociceptive effects of locally-administered cannabinoids with changes in the response properties of nociceptors during non-inflamed and inflamed conditions. It was hypothesized that activation of peripheral CB1 receptors attenuated nociception and nociceptor activity only during inflammation. In behavioral studies, intraplantar administration of complete Freund's adjuvant (CFA), but not saline, produced mechanical allodynia, mechanical hyperalgesia, and heat hyperalgesia. Activation of peripheral CB1 receptors produced antiallodynia and antihyperalgesia following inflammation, but did not alter nociception during non-inflamed conditions. In electrophysiological studies, only cutaneous nociceptors (Adelta and C) from inflamed skin were sensitized, and not Abeta mechanoreceptors. Local administration of CB1 receptor agonists attenuated mechanically-evoked responses of Adelta nociceptors from inflamed skin, but did not alter the evoked responses of Adelta nociceptors from non-inflamed skin. The responses of C nociceptors and Abeta mechanoreceptors from either non-inflamed or inflamed skin were not altered following local administration of cannabinoids. Our results demonstrated that peripherally-mediated cannabinoid antinociception through CB1 receptors is mediated, at least in part, by attenuation of Adelta nociceptor activity. The results from the present studies suggest that peripherally-acting CB1 receptor agonists could be administered alone or co-administered with other analgesic drugs to treat acute and persistent pain in humans and animals.
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    Chronic Musculoskeletal Pain Experiences of First Generation, Middle Aged Somali Women: A Descriptive Qualitative Study
    (2019-01) Swartz, Kristin L.
    Chronic pain is one of the most prevalent and costly health conditions in the United States. In refugees and immigrants, chronic pain is more prevalent and the severity of pain is higher. Musculoskeletal chronic pain is one the most common forms of pain that refugees and immigrants experience. In collaborating with a local community clinic, practitioners shared that middle-aged Somali women experienced a high incidence of non-specific musculoskeletal chronic pain that practitioners struggled to address through typical treatment measures. In a review of the literature it was found that no studies described chronic musculoskeletal pain for middle-aged Somali women, nor factors that contribute to their interpretation and management of pain. To date, there are no studies that specifically address chronic musculoskeletal pain in a refugee group in the United States, and few studies utilized a social ecological approach to describe the influence of environmental, societal, and immigration experiences in the management of pain. In this community-informed, descriptive qualitative study, musculoskeletal chronic pain experiences of first-generation, middle aged (40-65) Somali women living in the Minneapolis-St. Paul area are described. Utilizing the social ecological model and the dynamic biopsychosocial model, twelve core themes emerged that show the biological, psychological, social, and environmental factors that influenced participant experiences with pain. For Somali women in this study, the physical sensation of pain originated in the biological level and extended through the psychological and social levels of the microsystem. This physical experience of pain created a catalyzing influence that extended across the levels of the social ecological model. The core themes were: physical experience of pain, daily function and career, self-care practices, emotional experience of pain, recommendations for others experiencing pain, recommendations for community and clinics in treating pain, relationships with others, experience accessing care, financial impact, insurance affect, religious practice, traditional medicine and country of origin pain management, and sociopolitical issues. For these seventeen, first-generation, middle aged Somali women, pain was complex and multidimensional, and the physical experience of pain was only one aspect of chronic pain experience. Sociopolitical experiences were profound and triggered worry and fear that influenced pain. Insurance & financial issues compounded complexity with chronic pain management. Traditional medicine, memory of Somalia, and experience in Somalia were valuable resources and points of reference for managing pain. Pain influenced a Somali woman’s ability to secure a steady job. Pain management strategies were diverse and included integrative modalities. Religious practice was a key resource to pain management and overall pain experience. Participants sought alternatives to medications and used medications when necessary; and recommended and used exercise to manage pain. Health care providers played a key role in Somali women’s pain management. Many of these findings aligned with previous literature; however, the extensive multidimensionality of pain across the levels of the social ecological model is a new finding that should be further studied. In addition, further research is needed to expand knowledge related these findings and their potential to be generalized to other Somali women and men, and immigrants and refugees from other countries. In particular, to explore and define “Pain all over”, to investigate practitioner experiences in working with Somali patients and pain and how they approach the clinical interaction, and to examine outcomes of religious practice in pain-management. The implications of this research are several. Findings suggest the importance of story in working with Somali women to understand the meaning and cause of pain, in addition to the positive influence of health care providers when participants felt heard. Insights into how discrimination and an intense sociopolitical climate may influence the health and well-being of Somali women also emerged. Concerns were raised on language interpretation services and a need for further oversight and regulation was identified, in addition to the barriers participant’s experienced in understanding the ever-changing insurance landscape. More effort is needed to educate the greater community on experiences of immigrants and refugees in order to make informed changes in our communities, health systems, and political environment. These findings show that this social ecological approach to chronic pain treatment and management may be helpful in understanding the lived experience of pain for Somali women.
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    Comparing cutaneous sensory reactivity between children with and without global developmental delay
    (2014-05) Barney, Chantel C.
    Our scientific understanding of pain among individuals with developmental delays and disabilities with associated intellectual, motor, and/or communicative impairments is limited because of the difficulty in reliably and validly assessing a complex experience when verbal self-report is compromised. One approach is to rely on non-verbal pain behaviors. There has been no work comparing non-verbal pain behavior of very young children with global developmental delays with age and gender matched typically developing children. This study used a calibrated tactile sensory test to provide a mechanisms-based approach to indirectly compare the functionality of the somatosensory pathways in children with and without global developmental delay (GDD). A case control design was used to test the reactivity of 20 children with GDD (60% male; M age = 4.91 years, SD=1.13) and 20 typically developing children (60% male; M age = 3.49 years, SD=1.08). Sensory reactivity was indexed by vocal, facial, and body activity during the sensory test. This sample of children with GDD exhibited significantly greater duration of overall reactivity during the sensory test (p<.01) and specifically exhibited greater vocal (p<.01) and body (p<.05) reactivity compared to controls. For children with GDD, severity of self-injurious behavior significantly correlated with vocal (r=.58, p=.01) and body (r=.56, p<.05) reactivity during the pin prick trial. Children with GDD who were more reactive to the sensory test had significantly reduced epidermal nerve fiber densities (p<.05). This study was the first to measure the behavioral response of children with GDD to a calibrated sensory test and in comparison to a typically developing control group. The results of the study provide information about the physiology and nociceptive pathways of children with GDD. Despite limitations in verbal self-report, children with GDD exhibited non-verbal pain behaviors to signal their reactivity to a calibrated sensory test.
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    A comparison of Pharmaceutical regiments following first stage root canal treatment
    (2015-08) Lewis, Riley
    AIM: The purpose of this clinical trial was to investigate the analgesic efficacy of four oral medication groups on postoperative endodontic pain after first stage root canal treatment. The four groups will be Methodology: Patients presenting to the University of Minnesota emergency graduate endodontic clinic experiencing pain greater than or equal to 3/10 were considered potential condidiates. 22 patients were included based on an established inclusion criteria. Following administration of local anaestheisa, a pulpectomy was performed. The patients were administered the following at 4 hour time intervals: (1) 2 doses of Placebo; (2) 2 800mg doses of Ibuprofen; (3) 2 800mg Ibuprofen with Vicodin 325/7.5mg; (4) 1 dose of 550mg Anaprox DS (Naproxen) and 1 dose of Placebo. Patients recorded pain intensity following treatment on a visual analogue scale, Heft parker scale and a baseline four-point category pain scale before and immediately after treatment, then one hour after the initial dose of medication, and one hour after the second dose of medication. The following day, pain was recorded at breakfast, lunch, dinner and bedtime. Results: At about 24 hours, 27% had moderate to severe pain. All patients showed significant pain reduction after initial root canal therapy. The ibuprofen group showed a rebound in pain the following day. Males had more rebound pain compared to females. Anaprox DS and the combination of Ibuprofen and Vicodin showed the most pain reduction at all time periods. In our study, the results suggested that pulp vitality had little effect on post operative pain. Conclusion: Primary endodontic treatment will greatly decrease the pain felt by the patient. High doses of Ibuprofen followed by an abrupt stop might lead to a rebound in pain. Tooth vitality did not seem to affect post operative discomfort, nor did patient gender. More research using this model and analgesic combination is necessary to ensure statistically significant results.
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    Differential regulation of opioid receptors during inflammation
    (2009-07) Satterfield, Catherine Suzanne
    Properties of the opium poppy have been exploited for centuries for the alleviation of pain and to induce euphoria. Classically thought to produce its effects solely in the central nervous system, peripheral opioid analgesic systems are now widely accepted. The activation of these systems leads to a reduction in primary afferent fiber excitability leading to the inhibition of sensory transduction. Opioid receptors function is modulated by a variety of mechanisms. An example of this is enhanced peripheral opioid receptor function following inflammation. The present study examined peripheral opioid receptor regulation in early and late stages of CFA inflammation. Additionally, a new model of UVB of inflammation was characterized. Peripheral MOR receptors are differentially regulated in late and early CFA inflammation. Peripheral MOR is not responsible for attenuated responses of nociceptors to mechanical stimuli 18 hours after CFA inflammation. DAMGO reduced mechanical responsiveness of nociceptors at 72 hours after CFA inflammation in a concentration and antagonist reversible manner indicating that MOR efficacy is enhanced during later stages of CFA inflammation. UVB produced severe but localized inflammation that differed from inflammation produced by CFA. This inflammation sensitizes nociceptor units innervating irradiated skin and results in enhanced peripheral opioid receptor efficacy.
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    Endogenous modulation of addiction: chronic pain and the NMDA/NOS cascade.
    (2010-07) Wade, Carrie Lynn
    Opioid treatment for chronic pain is controversial due to abuse potential and perceived addiction potential. Because of perceptions of addiction from chronic opioid treatment for pain it is important to clearly understand the biological bases for a number of factors related to opioid therapy in the context of chronic pain, including the effectiveness of opioid treatment under distinct conditions chronic pain and alterations in the effectiveness of opioid treatment under distinct conditions of chronic opioid pharmacotherapy. One way to approach this question is to study the changes that occur with chronic pain and see how those changes parallel those that occur with opioid addiction. Our approach to address the questions raised above is to apply a combination of rodent models of pain and opioid self-administration. In the first phase of this study we examine changes in oral fentanyl self-administration under distinct conditions of chronic pain including inflammatory pain, neuropathic pain and an idiopathic pain model of sickle cell anemia. The second set of studies examines the potential for an endogenous modulator of the NMDA/NOS cascade to interact with adverse opioid events such as tolerance and addiction. We observed that mice with inflammatory pain, neuropathic pain and sickle cell anemia had differential fentanyl self-administration profiles following induction of mechanical hyperalgesia. In the second set of studies we observed that agmatine reduced opioid-induced tolerance and abolished self-administration behaviors. We also found that endogenous agmatine may have a neuroprotective effect on these opioid effects.
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    Immunizations: What can I do to help ease my child’s stress?
    (2008-02-06) Arcilla, Lisa M.
    There are several things that parents, physicians, and nursing staff can do to decrease the amount of pain and distress children experience during routine immunizations. Those discussed in this pamphlet include parental behavior, positioning, distraction techniques, injection site, and sucrose administration.
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    A magnetoencephalographic (MEG) study of brain mechanisms in temporomandibular disorder.
    (2009-12) Alonso DDS, Aurelio Abdalla MS.
    The main goal of this study was to investigate, using MEG, the dynamic neural mechanisms underlying facial tactile stimulation in two groups of subjects, namely a control group (without pain) and a TMD pain group (arthromyalgia), by stimulating the facial skin with a non-painful air-driven plastic membrane. Our first specific aim was to investigate and compare the spatial and temporal features of the ECDs following innocuous tactile stimuli in both groups. And t he second specific aim was to investigate the differences in dynamic brain function between these two groups using a time-frequency analysis of the MEG data. In summary, innocuous tactile stimulation proved to be a successful way to measure brain spatio-temporal dynamics in two group population. We were able to demonstrate very clear the differences in brain organization and dynamics between these two groups using an innocuous stimulus and without causing an unpleasant feeling. The results obtained allow for a paradigm shift in future research of brain mechanisms in pain by the use of non-painful tactile stimuli to evaluate brain function in various orofacial (or other) pain conditions, including neurovascular and neuropathic pains and other complex orofacial pain disorders.
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    MMG22: A Novel Bivalent Ligand for the Treatment of Neuropathic Pain
    (2020-10) Speltz Paiz, Rebecca
    Functional interactions between the mu opioid receptor (MOR) and the metabotropic glutamate receptor 5 (mGluR5) in pain and analgesia have been well established. MMG22 is a bivalent ligand containing MOR agonist (oxymorphamine) and mGluR5 antagonist (MPEP) pharmacophores tethered by a 22-atom linker. MMG22 has been shown to produce potent analgesia in several models of chronic inflammatory and neuropathic pain. This study assessed the efficacy of systemic administration of MMG22 at reducing pain behavior in the spared nerve injury (SNI) model of neuropathic pain in mice, as well as its side effect profile and abuse potential. MMG22 reduced mechanical hyperalgesia and spontaneous ongoing pain after SNI, with greater potency early (10 days) as compared to late (30 days) after injury. Systemic administration of MMG22 did not induce place preference in naïve animals, suggesting absence of abuse liability when compared to traditional opioids. MMG22 also lacked the central locomotor, respiratory, and anxiolytic side effects of its monomeric pharmacophores. Evaluation of mRNA expression showed the transcripts for both receptors were co-localized in cells in the dorsal horn of the lumbar spinal cord and dorsal root ganglia. Teased nerve fiber recordings from the sural nerve of SNI mice show that MMG22 reduces the firing rate of C and Aδ fiber nociceptors evoked by suprathreshold stimuli. Thus, MMG22 reduces hyperalgesia after injury in the SNI model of neuropathic pain by decreasing nociceptor activity without the typical centrally mediated side effects associated with traditional opioids.
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    Mri Detection Of Vertical Root Fractures In Endodontically Treated Teeth
    (2020-08) Groenke, Beth
    INTRODUCTION: Vertical root fracture (VRF) is known to occur in root canal treated (RCT) teeth and results in tooth loss. VRFs are difficult to diagnose. Magnetic Resonance Imaging (MRI) has the potential to identify VRF due to beneficial partial volume averaging, without using ionizing radiation. This investigation aims to compare the sensitivity and specificity of MRI versus cone-beam computed tomography (CBCT) in detecting VRF, using micro-computed tomography (microCT) as the reference standard. It also will describe the limits of MRI for detecting VRF. METHODS: 115 extracted human tooth roots were RCT using common techniques. VRFs were induced in a proportion that resulted in 62 VRF samples and 53 non-fractured control samples. All samples were imaged in a phantom using MRI and CBCT. Axial images for MRI and CBCT were presented to three board-certified endodontists. Evaluators determined VRF status and a confidence assessment for that decision. 30% of images were resampled to calculate intra- and inter-rater reliability. For MRI, the most coronal slice with discernible VRF was measured on correlated microCT to determine the minimum VRF width (µm). RESULTS: Sensitivity for MRI and CBCT were 0.66 (95%CI:0.53-0.78) and 0.58 (95%CI:0.45-0.70). Specificity was 0.72 (95%CI:0.58-0.83) and 0.87 (95%CI:0.75-0.95). Intra-rater reliability ranged from k=0.29-0.48 for MRI and k=0.30-0.44 for CBCT. Inter-rater reliability for MRI was k=0.37 and CBCT k=0.49. Median VRF width detected using MRI was 39µm (first quartile:20µm, third quartile: 58µm). CONCLUSION: MRI demonstrated ability to repeatedly detect VRF as small as 20 µm. There was no significant difference between sensitivity nor specificity for MRI versus CBCT in detecting VRF, despite the early stage of MRI development.
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    Multimodal functional neuroimaging of epilepsy and Pain
    (2015-06) Zhang, Huishi
    The overall goal of this thesis work is to use advanced noninvasive neuroimaging modalities and techniques to study the underlying neurological mechanism of both diseased and healthy brains. The two main applications of this work are for the diagnosis of epilepsy and management of pain. Epilepsy is one of the most prevalent neurological disorders. It affects an estimated 2.7 million Americans. There are two broad types of epilepsies: partial and generalized epilepsy. For patients with drug resistant focal epilepsy, which account for one third of the patient population, surgical resection may provide the opportunity of seizure control. Existing presurgical planning methods are not only invasive in nature; they may also fail to provide additional information needed for surgery due to the relatively limited spatial coverage. On the other hand, idiopathic generalized epilepsy (IGE), unlike focal or partial epilepsy, often affects the whole or a larger portion of the brain without obvious, known cause. Treatment options are more restricted as resection is not a choice. Therefore, it is important to understand the underlying network which generates epileptic activity and through which epileptic activity propagates. The aim of the present study in the epilepsy portion was to use noninvasive imaging techniques including fMRI and EEG to localize epileptic areas for the purpose of assisting surgical planning in the focal epilepsy cases; and to improve our understanding the underlying mechanism of generalized epilepsy, thalamocortical relationship in the IGE cases. Chronic Pain is one of the biggest medical burdens in developed countries, affecting 20% of adult population with estimated economic cost in the United States alone over $150 billion. Functional imaging of brain networks associated with pain processing is of vital importance to aid developing new pain-relief therapies and to better understand the mechanisms of pain perception. The long-term goal of this project is to study the neurological mechanism of subjective perception of pain using non-invasive neuroimaging methods. In the present work of the pain portion, changes brain activities in healthy subjects experiencing sustained external painful stimuli were first studied. Neural activities in patient with sickle cell disease, who often surfer spontaneous acute or chronic pain as one of the comorbidities of the disease, were contrasted with healthy controls to study changes in neural network as a result of prolonged exposure to internal In summary, the present dissertation research developed and evaluated the spatiotemporal imaging approaches for the non-invasive mapping of network activities in the diseased and normal brain. Evaluations were conducted in patient and healthy control groups in order to test the clinical applicability of such a pre-surgical noninvasive imaging tool. An investigation has been conducted to study the widespread GSWDs of generalized epilepsy patients. The spatial resolution has been further improved by adding the component of fMRI through an EEG-fMRI integrated imaging framework. For the application in pain study, two investigations were conducted to study changes in network level activity due to external pain in healthy subjects and spontaneous pain in patients with SCD. All of the results that were obtained suggest the importance of noninvasive spatiotemporal neuroimaging approaches for solving clinical problems and for investigating neuroscience questions. Furthermore, an improved understanding of neurological diseases and their mechanisms would help us to develop and deliver curative treatments of neurological diseases.
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    On the formation and functions of the neurons in the spinal cord that project axons to the thalamus, in rodent and primate.
    (2009-07) Davidson, Steve
    Mammals and other advanced vertebrates possess a population of neurons located in the spinal cord that put forth axons to the thalamus. These cells are responsive to somatosensory stimuli and in humans are required for the normal perception of mechanical, thermal, and chemical stimuli. The studies contained in this thesis examine both the development of this pathway, called the spinothalamic tract (STT), and its physiological responses to stimuli that evoke somatosensory experiences. Experiments in adult mice show that the whole STT is made up of about 7000 cells and these are located in a pattern homologous to the STT in rat, cat and monkey. Experiments in neonatal and embryonic mice show that the axons of the STT reach the thalamus before birth. A study of the physiological characteristics of STT neurons located in the marginal zone of the spinal cord dorsal horn in the adult rat suggests that STT axons are topographically organized within the ventrobasal complex of the thalamus according to their responses to thermal stimuli. Studies in primates show that axons from the STT that project to the nuclei of the posterior thalamus are responsive to multiple modalities of somatosensory stimuli but differ from neurons projecting to VPL in some functional properties. A special focus of this thesis explores the poorly understood sensation of itch. Evidence is provided for at least two pathways for itch; one that is activated by cutaneous administered histamine and another that is activated by the protease contained within the spicules of the tropical legume cowhage. Despite this specificity for types of itch, each of these pathways is also responsive to noxious and/or innocuous mechanical, thermal and/or chemical stimuli. The population of cells that is responsive to histamine is transiently inhibited by scratching the skin during the histamine response, suggesting a mechanism for the well known relief from itch that is produced by scratching. The main conclusions from the studies in this thesis are that the STT is extant before the time of birth; that, in adults, it is a complex pathway that can contribute to the encoding of specific somatosensory sensations from cells that are responsive to multimodal stimuli.
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    Pain and sensory function in neuronal ceroid lipofuscinosis
    (2013-01) Burkitt, Chantel C.
    Aims: In individuals with Neuronal Ceroid Lipofuscinosis (NCL; Batten disease), a rare neurodegenerative disorder, to explore 1) the pain experience, 2) the relationship between pain and self-injurious behavior (SIB), 3) the degree of sensory reactivity, and 4) the degree of sensory reactivity in comparison to individuals without NCL. Method: Following informed consent, eight participants with NCL (M age= 14.8 years, range=8-22) were characterized in terms of pain experience (frequency, type, intensity, interference, expression, and coping) and severity of SIB. A brief sensory test (light touch, repeated Von Frey monofilament) was conducted with each participant with NCL as well as with a sibling comparison group without NCL (n=8, M age= 23.5 years, range = 8-37). During sensory testing, pain expression was measured using the Battens Observational Pain Scale (BOPS) and infrared thermography (IRT) was used to quantify changes in skin/eye temperature. Results: Individuals with NCL experienced pain frequently and from multiple sources that most negatively impacted enjoyment of life, mood, sleep, and social interactions. Individuals with NCL were significantly more likely to express their pain using vocal/social pain behaviors rather than body and limbs (p<.05) or physiological behaviors (p<.01). When in pain, individuals tended to seek social support more often. Individuals with NCL who had moderately severe SIB showed significantly more pain behaviors than individuals with mild or no SIB (p<.05). Individuals with NCL were reactive to the sensory testing as IRT temperatures significantly increased (p<.001). Across combined conditions (light touch, repeated Von Frey), individuals with NCL were significantly more reactive (BOPS total score) to sensory testing compared to individuals in the sibling comparison group (p< .05). Similarly, IRT difference scores between sensory conditions revealed a significant increase in temperature at all face/eye sites for individuals with NCL compared to siblings (p<.001). Interpretation: In this sample of individuals with NCL pain was intense and frequent with multiple sources that interfered with a range of daily activities. Individuals with moderately severe SIB may be more sensitive to pain or may experience more pain in general. BOPS scores were elevated prior to sensory testing suggesting that individuals with NCL are living with ongoing pain. The increased pain expression during the repeated application of the Von Frey filament, a partial test of central sensitization, further suggests that the pathophysiology of the ongoing pain individuals with NCL are living with is likely centrally not peripherally mediated.
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    Pain-relevant behavior associated with VGF expression in primary afferent neurons
    (2015-07) Dykstra, Jaclyn
    Previously published work by our lab evaluating injury-induced changes in sensory neuron protein expression identified substantially increased levels of the neurosecretory protein VGF (non-acronymic), a neuropeptide precursor. To further characterize the functional role of VGF-derived peptides in sensory neuron signaling and in the development of pain-relevant behavior, we utilized animal models, behavior analyses, and complementary morphologic and molecular techniques to pursue two approaches: using adeno-associated virus (AAV) vectors to modulate VGF expression in primary afferent neurons, and exploring whether VGF up-regulation is limited to somatic pain. From this work, we learned intrasciatic administration of AAV5 vectors yields inefficient and variable transduction of sensory and motor neurons, reminiscent of the AAV8 serotype. Intrathecal administration of AAV5-VGF resulted in successful transduction of the choroid plexus but poor expression in dorsal root ganglion (DRG) sensory neurons. Unexpected DRG sensory neuron degeneration was observed following highly-efficient transduction of AAV9, warranting caution in future experiments utilizing this vector serotype. Antibiotic-induced visceral hypersensitivity was associated with up-regulation of VGF and other nociceptive neuropeptides in sensory neurons of the sixth lumbar DRG. However, contrary to expectations, referred cutaneous allodynia associated with antibiotic-induced visceral hypersensitivity was not readily detected using a non-invasive mechanical stimulation assay. Collectively, these findings encourage a re-evaluation of the tools employed to modulate VGF expression in primary afferent neurons in vivo, support the investigation of this novel signaling system beyond models of nerve injury, and are presented such that they can be used as an aid in the design of future work.
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    Persistent pain following root canal therapy-a nested case series study
    (2013-08) Sobieh, Radwa
    Introduction: Persistent pain following root canal treatment (RCT), a common dental procedure, can be either of odontogenic or nonodontogenic origin. The prognosis for patients experiencing such pain is dependent on differentiating patients into these 2 categories and deriving specific diagnoses, since appropriate treatment various dramatically. This study aims to present the proportions of specific diagnoses these patients have and provide information about their signs and symptoms, including radiographic findings. Methods: This study was nested within a parent prospective observational study that followed up patients for 6 months following RCT. Patients meeting criteria for persistent pain at 6 months and living in Minnesota were considered eligible cases. Cone-beam Computed Tomography (CBCT) and dental radiographs were obtained and patients were individually evaluated by an endodontist and an orofacial pain practitioner to derive consensus diagnoses. Results: A total of 38 patients met the criteria, of which 19 were evaluated. Odontogenic reasons for persistent pain occurred less frequently than nonodontogenic reasons (42% vs. 53% respectively). There was an overlap of odontogenic and nonodontigenic reasons in 10% of the patients. About 16% reported some level of pain that seemed to be related to normal "healing". Of patients with odontogenic reasons, about one third was related to the previously treated tooth and the other two thirds were related to adjacent teeth. Temporomandibular pain disorder (TMD) was the most common nondontogenic reason for pain, comprising 42% of all patients and 80% of those with nonodontogenic pain. Persistent dento-alveolar pain disorder (PDAP) was less common, comprising 10% of all patients and 20% of those with nonodontogenic pain.Conclusion: Data from this study help in quantifying the frequency of odontogenic versus nonodontogenic reasons for persistent pain following RCT.
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    Pharmacokinetics and Pharmacodynamics of Strategically Substituted Agmatines
    (2022-10) Clements, Benjamin
    Chronic pain remains a major issue affecting patients, with current pharmacotherapy limited to drugs with low efficacy, negative side effects, and/or social stigma. Thus, there is a critical need to develop novel pharmacotherapies that are effective in reducing chronic pain while being safe for long-term use. Agmatine has been extensively shown to reduce chronic pain behaviors in animal models with no cardiac, motor, or neurological adverse effects1. This reduction is due to antagonism of the N-methyl-D-aspartate (NMDA) receptor, specifically at the GluN2B subunit2-4. This specificity allows agmatine to modulate the biological changes underlying chronic pain without the negative side effects observed with complete inhibition of the NMDA receptor. However, agmatine is a polar small molecule and does not efficiently diffuse passively across biological membranes. It has been shown to cross the intestinal epithelium and blood-brain barrier (BBB)5,6, but these distributions are limited, requiring high doses to generating quantifiable disposition. Additionally, the barrier in drug appearance in the CNS necessitates high doses (30-300 mg/kg in animal models) to achieve pharmacological effects. Furthermore, although agmatine has a long half-life in the CNS, its short elimination half-life in plasma restricts efficacy as a systemic therapeutic7. Therefore, our team and collaborators have designed and synthesized a series of agmatine-based prodrugs, the Strategically Substituted Agmatines (SSAs), which are designed to have increased lipophilicity, prolonged plasma half-lives, and equivalent pharmacological activity to agmatine. The central hypothesis of this thesis research is that the SSAs reduce pain behaviors in preclinical models of chronic pain in a manner comparable to agmatine while exhibiting improved pharmacokinetic parameters in rat. From this hypothesis, my objective has been to answer several questions: How can these compounds be measured in plasma and the central nervous system (CNS)? Do strategic substitutions improve pharmacokinetic parameters over agmatine? Do the SSAs distribute more readily to the CNS? Are the SSAs metabolized to agmatine within the CNS? And do the SSAs show improved potency over agmatine following oral administration? To answer these questions, my goals have been to develop techniques to quantify agmatine and the SSAs in complex tissues, determine the pharmacokinetic parameters of agmatine and the SSAs after IV and oral administration, investigate the prodrug activity of the SSAs, and explore the efficacy on chronic pain of these compounds as oral therapeutics. I accomplished these goals by completing the following specific aims: Specific Aim 1: Develop and Validate Analytical Methods to Accurately Quantify Agmatine and the SSAs in Complex MatricesUsing HPLC-MS/MS, a series of tissue preparation methods and chromatographic techniques were developed and validated according to FDA guidance8 to determine the concentration of agmatine, SSA1, SSA2, SSA3, and SSA4 in rat plasma, and quantify agmatine and SSA3 in rat brain and spinal cord. Specific Aim 2: Determine the Plasma Pharmacokinetic Parameters of Agmatine and the SSAs in Rat Following Intravenous and Oral DeliveryI hypothesized that the lipophilic substitutions of the SSAs would increase plasma half-life and volume of distribution over agmatine, as well as improve the oral bioavailability over agmatine. Sprague-Dawley rats with surgically implanted catheters received IV or oral agmatine, SSA1, SSA2, SSA3, or SSA4. Serial blood samples were collected, and plasma was analyzed using HPLC-MS/MS. These plasma concentrations were used to generate individual pharmacokinetic profiles of each drug in individual rats. Specific Aim 3: Assess the Tissue Distribution Profiles of Agmatine and SSA3 in RatI hypothesized that SSA3 would show increased CNS distribution across all tissues compared to agmatine. Furthermore, I hypothesized that SSA3 would be metabolized to agmatine within the CNS. Following IV administration of agmatine or SSA3 via tail-vein in Sprague-Dawley rat, multiple tissues from within the CNS were collected and heat-treated, along with plasma. Agmatine and SSA3 content were assessed using HPLC-MS/MS in each tissue, from which I determined distribution and pharmacokinetic profiles of each compound within individual tissues, such as spinal cord, cortex, ventral tegmental area (VTA), and nucleus accumbens (NAcc). Agmatine content was also assessed in CNS tissues following IV SSA3 and SSA4 to estimate prodrug activity. Specific Aim 4: Evaluate the Efficacy of Agmatine and the SSAs on NMDA-Evoked Responses and Chronic Pain Following Systemic Administration Intrathecal NMDA evokes characteristic behaviors in mice, including biting/scratching and tail-flick hyperalgesia. I hypothesized that the SSAs, due to their increased lipophilicity, would have increased systemic activity at lower doses than agmatine in the NMDA-evoked behavioral model. Additionally, I hypothesized that increased activity at lower doses would be observed in reversal of tactile hypersensitivity in inflammatory pain. I assessed changes in NMDA-evoked behaviors following subcutaneous and oral administration of agmatine and the SSAs to determine the CNS effects of these compounds from non-central delivery. Furthermore, these compounds were tested after oral administration for reduction of tactile hypersensitivity following inflammatory injury via CFA administration.