Neuroscience and Neurobiology Commons^™

The Endocannabinoid System's Influence And Modulation Of Nociception, Doreen M. Flannery

Honors Thesis

The anatomy and physiology of pain is a well-defined pathway where noxious stimuli is processed by different systems in the brain. The central research question of this review is how can we better understand the neurobiological effects pain has, and assess if there is therapeutic potential in using endocannabinoids to modulate these effects. Endocannabinoids are signaling molecules that play a key role at both the cellular and molecular level in modulating both acute and chronic pain by influencing different processes within each level that affect how the body responds to both internal and external stimuli. The endocannabinoid system is a …

Androgen Hormones Regulate The Production On The Pain-Inducing Inflammatory Molecule Il-1Β In A Mouse Model Of Inflammatory Pain, Hariharan Ramakrishnan, Geoffroy Laumet, Jaewon Sim

Medical Student Research Symposium

Chronic pain prevalence varies between sexes with a higher incidence and duration reported in women compared to men. This disparity suggests that biological factors, such as sexual hormones, may influence pain perception and development. Among the key players in pain mechanisms, interleukin-1 beta (IL-1β), an inflammatory molecule, has been identified to activate neurons involved in pain sensation. This study explores the hypothesis that sexual hormones, particularly androgens, regulate IL-1β production in inflamed tissues, thereby influencing pain responses. To investigate this, we induced inflammatory pain in male and female mice using Complete Freund’s Adjuvant (CFA), injected into the hind paw. To …

High Fat Diet & Social Isolation: Interactive Effects On Pain, Cognition, & Neuroinflammation, Ian M. Campuzano

Research Psychology Theses

Prior research has established a role for both social isolation and exposure to high fat Western diets in altering a range of behaviors from reduced memory performance to increased depression-like behaviors. The present study scrutinizes the interplay among these variables during the peri-adolescent developmental phase, utilizing Long-Evans rats as the experimental model. Our overarching hypothesis is that rats exposed to either social isolation, a high-fat diet, or both will result in heightened pain sensitivity, diminished cognitive flexibility, and increased neuroinflammatory responses within brain regions implicated in sociability, cognition, memory, and pain processing. Behavioral flexibility will be assessed using a maze-based …

Improved Efficiency And Sensitivity Analysis Of 3-D Agent-Based Model For Pain-Related Neural Activity In The Amygdala, Kayla Kraeuter, Carley Reith, Benedict J. Kolber, Rachael Miller Neilan

Spora: A Journal of Biomathematics

Neuropathic pain is caused by nerve injury and involves brain areas such as the central nucleus of the amygdala (CeA). We developed the first 3-D agent-based model (ABM) of neuropathic pain-related neurons in the CeA using NetLogo3D. The execution time of a single ABM simulation using realistic parameters (e.g., 13,000 neurons and 22,000+ neural connections) is an important factor in the model’s usability. In this paper, we describe our efforts to improve the computational efficiency of our 3-D ABM, which resulted in a 28% reduction in execution time on average for a typical simulation. With this upgraded model, we performed …

Social Exclusion : How Inhibition And Excitation Of The Dorsal Lateral Prefrontal Cortex (Dlpfc) Influences Feelings Of Social Exclusion, Anthony Minervini

Theses, Dissertations and Culminating Projects

Social exclusion refers to the experience of rejection by one or more people during a social event. Cyberball, a computer program, is one of the most common tools for analyzing social exclusion. Cyberball simulates a game of catch in which any number of individuals or computer- generated players can pass a virtual ball to one another. Regions of the brain that underlies pain perception include networks lined to the Dorsal Lateral Prefrontal Cortex (DLPFC). Direct manipulation of this area may provide a better understanding of how the DLPFC can influence the perception of social exclusion. Transcranial magnetic stimulation (TMS) was …

Effects Of Cannabichromene On Pain And Neuroinflammation In Hiv-1 Tat Transgenic Mice, Sydney Wheeler

Honors Theses

HIV-1 TransActivator of Transcription (Tat) is a vital regulatory protein involved in HIV replication and implicated in development of HIV-associated pain and neurocognitive deficits. Tat is thought to contribute to these pathologies through proinflammatory pathways. Developing mechanisms to curb Tat-mediated inflammation is a key step in improving the quality of life of those living with HIV. Both recreational and medicinal cannabis use is prevalent among many people living with HIV; given this prevalence and the perceived anti-inflammatory benefits of cannabis use, it is important to investigate how chemical constituents of cannabis may impact HIV. In the present study, the effects …

Editorial: Microglia In Neuroinflammation, Pinar Ayata, Ido Amit, Carla M. Cuda

Advanced Science Research Center

Microglia are a resident innate immune cell population of the central nervous system (CNS) derived from yolk sac erythro-myeloid progenitors that migrate to the developing brain prior to the formation of the blood-brain barrier. This critical cell population has gained considerable traction in the literature as it is considered a protective barrier from CNS damage and, yet, can also serve as a primary mediator of neuroinflammation. Under normal physiological conditions, microglia perform homeostatic functions, such as parenchymal surveillance, neurotrophic support, pathogen or debris removal, and maintenance of synaptic homeostasis and neuronal plasticity.

Efficacy Of Δ-9-Tetrahydrocannabinol For Hiv-Related Neuropathic Pain, Kaia Horne

Honors Theses

Despite the availability and success of antiretroviral therapeutics, ~30% of patients living with HIV experience neuropathic pain that is often intractable. The mechanisms are not known, but there is evidence to support a role for the HIV virotoxins, Tat and/or gp120, which can damage or degenerate neurons and peripheral nerves. One mechanism by which Tat and gp120 promote nerve damage involves the stimulation of proinflammatory cytokine production from immune cells which can damage or kill bystander cells. Notably, compounds found in Cannabis exert anti-inflammatory effects and many studies report HIV patients to consume more marijuana than seronegative individuals. When people …

Pain Sentience Criteria And Their Grading, Eva Jablonka, Simona Ginsburg

Animal Sentience

On the basis of the target article by Crump and colleagues, we suggest a more parsimonious scheme for evaluating the evidence for sentience. Since some of the criteria used by Crump et al. are not independent and some are uninformative we exclude some criteria and amalgamate others. We propose that evidence of flexible learning and prioritization, in conjunction with relevant data on brain organization, is sufficient for assigning pain-sentience to an animal and we suggest a scoring scheme based on four criteria.

Emotional Component Of Pain Perception In The Medicinal Leech?, Brian D. Burrell

Animal Sentience

Crump et al. have provided a series of criteria to assess animal sentience that is focused on the perception of pain, which is known to have both sensory and emotional components. They also provide a qualitative scoring system to assess data that address the eight criteria and apply this paradigm to decapod crustaceans. The criteria laid out have the potential to be applied to other invertebrates typically thought to have sensory response to tissue damage, but no emotional component to pain perception.

A Framework For Evaluating Evidence Of Pain In Animals, Matilda Gibbons, Lars Chittka

Animal Sentience

Crump et al. define eight criteria indicating sentience in animals, with a focus on pain. Here, we point out the risk of false negative or false positive diagnoses of pain. Criteria of different levels of inclusivity are useful for using the precautionary principle in animal welfare considerations, and for more formal scientific evidence of pain. We suggest tightening the criteria -- from more general evidence of sentience to pain alone -- because crucial evidence for animal welfare decisions might otherwise be missed for animals subjected to invasive and injurious procedures.

Cgrp-Driven Lateralization Of Pain Modulation By The Central Amygdala, Heather Allen

Electronic Theses and Dissertations

The central amygdala (CeA) is a bilateral, mid limbic brain region involved in the processing of pain and emotion. Interestingly, the left and right CeA are functionally lateralized in the context of bladder pain, with the left and right CeA having opposing effects on bladder pain-like behavior. However, the specific mechanisms driving these divergent functions are unknown. Nociceptive signals from the bladder are relayed to the CeA via projection neurons in the parabrachial nucleus (PBN) that express high levels of calcitonin gene-related peptide (CGRP). In these studies, we investigated the influence of PBN CGRP signaling in the left and right …

Investigating Mechanisms In Nociceptors Driving Ongoing Activity And Ongoing Pain, Elia Lopez

Dissertations and Theses (Open Access)

Ongoing (apparently spontaneous) pain at rest is a major complaint of patients suffering from many forms of acute and chronic pain, including acute and persistent postsurgical pain. Accumulating evidence suggests ongoing activity in nociceptors is a major driver of ongoing pain. Ongoing activity can be generated in sensory neurons in the absence of sensory generator potentials if one or more of three neurophysiological alterations occur – prolonged depolarization of resting membrane potential (RMP), hyperpolarization of action potential (AP) threshold, and/or increased amplitude of depolarizing spontaneous fluctuations of membrane potential (DSFs) to bridge the gap between RMP and AP threshold. Cellular …

Opioid Use Disorder: The Timeline For Medication Assisted Therapy, Alexander Cristofori

Capstone Showcase

Opioid Use Disorder is patterns of opioid use leading to withdrawal, giving up important life events in order to use opioids, and excessive time spent using opioids, to name a few diagnostic criteria. The clinical progression of the disorder involves periods of acute exacerbation and remission that are cyclic in nature. Treatment is most effective when it includes both pharmacological and psychosocial modalities, referred to as medication assisted therapy (MAT). Three drugs used commonly in MAT-based treatment for OUD from oldest to newest include Methadone, Buprenorphine-naloxone, and Naltrexone. Treatment program models that prioritize total abstinence from the addictive substance attached …

Animal Sentience: History, Science, And Politics, Andrew N. Rowan, Joyce M. D'Silva, Ian J.H. Duncan, Nicholas Palmer

Animal Sentience

This target article has three parts. The first briefly reviews the thinking about nonhuman animals’ sentience in the Western canon: what we might know about their capacity for feeling, leading up to Bentham’s famous question “can they suffer?” The second part sketches the modern development of animal welfare science and the role that animal-sentience considerations have played therein. The third part describes the launching, by Compassion in World Farming, of efforts to incorporate animal sentience language into public policy and regulations concerning human treatment of animals.

Quench Assisted (Quest) Mri Used As A Novel Approach To Identify Reactive Oxygen Species As A Result Of Experimental Tbi, Ethan M. Cohen, Eric Chang, Michael C. Schneider, Abigail Teitelbaum, Alexander R. Woznicki, Rachel E. Godfrey, Robert H. Podolsky, Karen L. Childers, Robin Roberts, Bruce A. Berkowitz, Kelly E. Bosse, Alana C. Conti

Medical Student Research Symposium

Introduction:

Traumatic brain injury (TBI) generates reactive oxygen species (ROS), promoting inflammatory processes and impeding TBI recovery. Within the VA population, over 70% of military personnel that sustain a TBI receive opioid-based pain relief, however, opiates may actually exacerbate post-TBI complications through its documented recruitment of oxidative and inflammatory systems. Thus, we hypothesize that TBI and opioid treatment act synergistically to worsen post-TBI oxidative stress.

Methods:

Mice were exposed to either TBI or sham injury and administered morphine or saline in the acute post-injury period. Afterwards, neuroimaging was conducted using a novel technique, QUEnch assiSTed (QUEST) MRI, which compares standard …

Inhibition Of Pain Or Response To Injury In Invertebrates And Vertebrates, Matilda Gibbons, Sajedeh Sarlak

Animal Sentience

In certain situations, insects appear to lack a response to noxious stimuli that would cause pain in humans. For example, from the fact that male mantids continue to mate while being eaten by their partner it does not follow that insects do not feel pain; it could be the result of modulation of nociceptive inputs or behavioural outputs. When we try to infer the underlying mental state of an insect from its behaviour, it is important to consider the behavioural effects of the associated physiological and neurobiological mechanisms.

Impact Of Uk Sport Fishing On Fish Welfare And Conservation, Tim Q. Holmes

Animal Sentience

Sport fishing or angling is the capture of fish for recreation or competition, i.e., for entertainment. Contrary to the claims of Key (2016), there is good evidence that fish feel pain and have the capacity for self-awareness (Sneddon et al., 2018; Woodruff, 2017). Wild fish experience a variety of adverse conditions in nature that can harm their welfare, but this does not justify humans intentionally inflicting such conditions on fish solely for our pleasure. This commentary summarises the many ways fish suffer harm to their welfare as a result of sport fishing. There are also discussions on associated activities that …

Detecting The Cold: Do Innexins Function In Cold Nociception?, Rachel Barborek

Senior Honors Projects, 2010-2019

Nociception is the perception of and response to harmful stimuli. Nociception is essential for minimizing tissue damage, but aberrant nociceptive pathways can result in chronic pain. Chronic pain in the U.S. is commonly managed with wide-acting opioids, and precisely defining the components of nociceptive pathways could uncover novel targets for pain therapies. I hypothesize that the vitally quick process of nociception would utilize electrical synapses because they transmit signals between neurons more quickly than chemical synapses do. This study, therefore, aims to uncover the potential role of the eight Drosophila melanogaster gap junction proteins, the Innexins, in cold nociception. Wild …

Characterization Of G-Protein Coupled Receptors In Pain, Depression And Anxiety, Neil Lax

Electronic Theses and Dissertations

Chronic pain and major depressive disorder are widespread conditions in the world. Interestingly, these conditions often occur comorbidly, with each individual disease amplifying the symptoms of the other. A significant amount of preclinical research in pain and depression focuses on G-protein coupled receptors (GPCRs), implying that GPCRs may be useful in treating this comorbidity. Our efforts have sought to characterize several poorly understood GPCRs, including the serotonin receptor subtypes 2C and 7 (5-HT2CR and 5-HT7R) and metabotropic glutamate receptor 5 (mGluR5), along with more well-known GPCRs such as the mu opioid receptor (MOR), and the role that they play in …

On Crabs And Statistics, Jonathan Birch

Animal Sentience

I respond to commentaries by Elwood and Seth & Dienes and to a recent critique by Diggles, discussing the link between avoidance learning and sentience, the relevance of the clash between frequentist and Bayesian statistics, the risks to decapod welfare in aquaculture, and the broader concerns one may have about a “precautionary” approach to protecting invertebrates.

If It Looks Like A Duck: Fish Fit The Criteria For Pain Perception, Julia E. Meyers-Manor

Animal Sentience

Whereas we have denied the experience of pain to animals, including human babies, the evidence is becoming clearer that animals across a variety of species have the capacity to feel pain (Bellieni, 2012). As converging findings are collected from pain studies and the study of cognition, it is becoming harder to deny that fish are among the species that do feel pain.

Pain In Fish: Evidence From Peripheral Nociceptors To Pallial Processing, Michael L. Woodruff

Animal Sentience

The target article by Sneddon et al. (2018) presents convincing behavioral and pharmacological evidence that ray-finned fish consciously perceive noxious stimuli as painful. One objection to this interpretation of the evidence is that the fish nervous system is not complex enough to support the conscious experience of pain. Data that contradict this objection are presented in this commentary. The neuroanatomy and neurophysiology of the fish nervous system from the peripheral nerves to the pallium is able to support the sentient appreciation of pain.

Denialism And Muddying The Water Or Organized Skepticism And Clarity? That Is The Question, Ben Diggles, Howard I. Browman

Animal Sentience

The research being commented on here has been criticized and defended in journals. Sneddon et al. (2018) add nothing substantive. We have nothing further to add. Readers are referred to Diggles (2018) and to Browman et al. (2018) for a detailed assessment.

Fish Sentience Denial: Muddying The Waters, Lynne U. Sneddon, Javier Lopez-Luna, David C.C. Wolfenden, Matthew C. Leach, Ana M. Valentim, Peter J. Steenbergen, Nabila Bardine, Amanda D. Currie, Donald M. Broom, Culum Brown

Animal Sentience

Recent empirical studies have reported evidence that many aquatic species, including fish, cephalopods and crustaceans, have the capacity for nociception and pain, and that their welfare should be taken into consideration. Some sceptics, rejecting the precautionary principle, have denied that any study demonstrates pain or other aspects of sentience in fish. This target article discusses some of the scientific shortcomings of these critiques through a detailed analysis of a study exploring nociception and analgesia in larval zebrafish.

Complexities Of Chronic Opioid Exposure, Maciej Gonek

Theses and Dissertations

Studies on repeated exposure to opioids have been carried out for decades yet the mechanisms for certain phenomena such as tolerance are still not fully understood. Furthermore, different medications, such as frequently prescribed benzodiazepines, or different disease states, such as HIV, have their own effects and interactions with chronic opioid exposure that are not fully understood. The overall objective of this dissertation was to investigate the complexities of chronic opioid exposure and how different disease states and medications may modulate the effects of chronic opioids. Our findings demonstrate that the administration of diazepam, at doses that are not antinociceptive or …

Methylglyoxal Requires Ac1 And Trpa1 To Produce Pain And Spinal Neuron Activation, Ryan B. Griggs, Don E. Laird, Renee R. Donahue, Weisi Fu, Bradley K. Taylor

Physiology Faculty Publications

Methylglyoxal (MG) is a metabolite of glucose that may contribute to peripheral neuropathy and pain in diabetic patients. MG increases intracellular calcium in sensory neurons and produces behavioral nociception via the cation channel transient receptor potential ankyrin 1 (TRPA1). However, rigorous characterization of an animal model of methylglyoxal-evoked pain is needed, including testing whether methylglyoxal promotes negative pain affect. Furthermore, it remains unknown whether methylglyoxal is sufficient to activate neurons in the spinal cord dorsal horn, whether this requires TRPA1, and if the calcium-sensitive adenylyl cyclase 1 isoform (AC1) contributes to MG-evoked pain. We administered intraplantar methylglyoxal and then evaluated …

Complement 3a Receptor In Dorsal Horn Microglia Mediates Pronociceptive Neuropeptide Signaling, Suzanne Doolen, Jennifer Cook, Maureen Riedl, Kelley Kitto, Shinichi Kohsaka, Christopher N. Honda, Carolyn A. Fairbanks, Bradley K. Taylor, Lucy Vulchanova

Physiology Faculty Publications

The complement 3a receptor (C3aR1) participates in microglial signaling under pathological conditions and was recently shown to be activated by the neuropeptide TLQP‐21. We previously demonstrated that TLQP‐21 elicits hyperalgesia and contributes to nerve injury‐induced hypersensitivity through an unknown mechanism in the spinal cord. Here we determined that this mechanism requires C3aR1 and that microglia are the cellular target for TLQP‐21. We propose a novel neuroimmune signaling pathway involving TLQP‐21‐induced activation of microglial C3aR1 that then contributes to spinal neuroplasticity and neuropathic pain. This unique dual‐ligand activation of C3aR1 by a neuropeptide (TLQP‐21) and an immune mediator (C3a) represents a …

The “Precautionary Principle” – A Work In Progress, Shelley Adamo

Animal Sentience

The target article by Birch illustrates the practical difficulties with the “Animal Sentience Precautionary Principle” (ASPP) while presenting potential solutions. However, the ASPP will be difficult to use without guidelines detailing how evidence of sentience should be assessed. Moreover, extrapolating conclusions found for a single species to all species within an Order is problematic. Finally, I recommend that Birch demonstrate his ASPP framework using a controversial test case to help show how it could be used in real-world situations.

Assessing Negative And Positive Evidence For Animal Pain, Robert W. Elwood

Animal Sentience

Jonathan Birch suggests that we should take one well-conducted study that produces results consistent with the idea of pain as being sufficient to invoke the animal sentience precautionary principle. Here, I consider how to balance negative and positive results from such studies using examples from my own work. I also consider which criteria of pain might provide strong inference about pain and which may prove to be weaker.