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Translating Mechanisms Orofacial Neurological D...

Swallowing is complex at anatomical, functional, and neurological levels. The connections among these levels are poorly understood, yet they underpin mechanisms of swallowing pathology. The complexity of swallowing physiology means that multiple failure points may exist that lead to the same clinical diagnosis (e.g., aspiration). The superior laryngeal nerve (SLN) and the recurrent laryngeal nerve (RLN) are branches of the vagus that innervate different structures involved in swallowing. Although they have distinct sensory fields, lesion of either nerve is associated clinically with increased aspiration. We tested the hypothesis that despite increased aspiration in both case, oropharyngeal kinematic changes and their relationship to aspiration would be different in RLN and SLN lesioned infant pigs. We compared movements of the tongue and epiglottis in swallows before and after either RLN or SLN lesion. We rated swallows for airway protection. Posterior tongue ratio of safe swallows changed in RLN (p = 0.01) but not SLN lesioned animals. Unsafe swallows post lesion had different posterior tongue ratios in RLN and SLN lesioned animals. Duration of epiglottal inversion shortened after lesion in SLN animals (p = 0.02) but remained unchanged in RLN animals. Thus, although SLN and RLN lesion lead to the same clinical outcome (increased aspiration), the mechanisms of failure of airway protection are different, which suggests that effective therapies may be different with each injury. Understanding the specific pathophysiology of swallowing associated with specific neural insults will help develop targeted, disease appropriate treatments.

Translating Mechanisms Orofacial Neurological D...


Eric Chudler Cortical and basal ganglia mechanisms of nociception and pain, the neuroactive properties of medicinal plants and herbs, and translating basic neuroscientific research into language and activities for the general public.

Chronic itch is the most common clinical symptom in numerous dermatological and systemic conditions in humans and animals, and it significantly reduces the quality of life of the patients and their families. Unfortunately, treatments selective for chronic itch are still limited due in large part to a lack of understanding of the mechanisms related to the neurological underpinning of itch. For more than decades, numerous studies have been performed to understand how itch is transduced and transmitted from the periphery via trigeminal (afferents projecting into head and face, TG) and dorsal root ganglia (afferents projecting into rest of the body, DRGs; a collection of cell bodies of cutaneous sensory neurons) into the central nervous system. The vast majority of these studies were performed in rodent models, but the limited success of translating findings from these rodents to the human disease situation has raised criticism about the benefit of such translational studies. Interestingly, recent comparative analyses of mice and humans demonstrated different expression patterns of nociceptors on DRGs in these two species, thus, indicating that different itch treatment strategies might be required in each species. These findings also may be applied to other animals where it is anecdotally said, ""cats are not small dogs"" or ""horses are large cats"" based on the clinical response to many drugs, including anti-itch medications. The value of translating data from mouse experiments to companion animal species remains largely unknown.Next-generation sequencing technologies have provided many valuable insights into complex biological systems. Currently, however, the majority of transcriptome analysis experiments use whole tissue samples that consist of a great variety of cell types, and it is based on the assumption that cells from a given tissue are homogeneous; thus, it does not give us any information regarding cell types and gene expression profile from same cell. Here, we proposed using a single cell multiome approach (ATAC-seq + gene expression) to elucidate the transcriptional landscape by systematically comparing the data obtained from sensory ganglia involved in itch detection and neurotransmission from multiple species and cell types and states in ganglia based on their location. Although single cell could be a good target but due to variation in cell sizes of the DRG neurons from largest being (>100 um in diameter) and the size of a single cell channel diameter is approx. 100 um), therefore, we focus on nuclei as a target for the multiomics analysis. Our proposed study will help elucidate the similarities and key differences of cellular and molecular pathways involved in multiple species and provide insight into trigeminal ganglia (TG) and DRG biology, which will guide the development of potential species-specific therapeutic targets, thus helping to improve itch treatment successfully.

Millions of people suffer from chronic pain, which is a major health problem. Chronic orofacial pain is highly prevalent in the US. The most common persistent orofacial pain condition, temporomandibular joint disorders (TMJD), affects the musculoskeletal and joint tissues and is heterogeneous in origin. The current treatment for chronic pain conditions is unsatisfactory and there is an urgent need for searching and developing alternative and effective chronic pain therapy. Recently, bone marrow stromal cells (BMSC) have generated considerable interest as a candidate for cell-based therapy. Interestingly, BMSC appear to have potential to treat chronic pain conditions. In rat models of tissue or nerve injury with long-lasting pain hypersensitivity, intravenous infusion of rat BMSC produced long-term attenuation of orofacial hyperalgesia/allodynia (antihyperalgesia) and this effect was attenuated by the opioid receptor antagonist, suggesting the involvement of endogenous opioids. However, the mechanisms of the effect of BMSC on persistent pain remain elusive. Evidence indicates that the majority of the intravenously infused BMSC are trapped in the lungs and that the infused cells only stay in the system for a matter of days to a few weeks. Studies suggest that the infused BMSC produce their therapeutic effects through secretion of chemical mediators that interact with the body's immune system. We hypothesize that BMSC produce pain-relieving, or antinociceptive effect through their immune interactions and subsequent activation of the endogenous opioid system. We will test this hypothesis by a combination of approaches involving cell cultures, Reverse Transcription-quantitative real time Polymerase Chain Reaction, immunohistochemistry, Western blot, Enzyme-linked immunosorbent assay, fluorescence activated cell sorting, RNA interference (RNAi), transgenic mice and behavioral pharmacology in three Specific Aims. We will continue to use a rodent model of the masseter muscle tendon injury, which mimics prolonged orofacial nociception of myogenic origin. We will focus on using female animals since women exhibit a higher prevalence of TMJ disorders than men. Aim 1 will examine the effect of BMSC on pain and neuronal activity in female animals and test the hypothesis that BMSC engage brain endogenous opioids and regulate N-methyl-D-aspartate receptors. Aim 2 will test the hypothesis that the monocyte/macrophage population of immune cells are involved in mediating the BMSC-produced pain relief. Aim 3 will test the hypothesis that monocyte-derived chemokines are critical in the BMSC-produced upregulation of opioid receptors and attenuation of persistent pain. Findings will provide novel cellular mechanisms for BMSC-induced pain relief and help to develop an approach to effectively engage the endogenous pain modulation for the treatment of chronic pain and facilitate translating it into clinical settings.

It has been shown that intravenous infusion of bone marrow-derived mesenchymal stem cells, or bone marrow stromal cells (BMSC) from the rat produces long-term attenuation of pain hypersensitivity and that endogenous opioids are involved in this effect. This project will employ a rat model of persistent orofacial pain to further study mechanisms underlying the pain-relieving effect of BMSC. The findings will prompt translating this approach into clinical settings. 041b061a72


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