Biomechanically induced regulation of Damage-Regulated Autophagy Modulator 1 in periodontal cells and tissues.

Purpose: Autophagy is an important adaptive process for mechanotransduction, in which Damage-Regulated Autophagy Modulator 1 (DRAM1) has a key function in cell fate determination. This study aimed to analyze the influence of biomechanical loading on DRAM1 expression in periodontal cells and tissues.

Methods: Human periodontal ligament (PDL) fibroblasts were stimulated with different pressure protocols, physiological load and overload, in the presence and absence of autophagy inhibitor 3-methyladenine (3-MA) and compared with untreated cells.

The μ-opioid receptor differentiates two distinct human nociceptive populations relevant to clinical pain.

The shortfall in new analgesic agents is a major impediment to reducing reliance on opioid medications for control of severe pain. In both animals and man, attenuating nociceptive transmission from primary afferent neurons with a μ-opioid receptor agonist yields highly effective analgesia. Consequently, deeper molecular characterization of human nociceptive afferents expressing OPRM1, the μ-opioid receptor gene, is a key component for advancing analgesic drug discovery and understanding clinical pain control.

Analgesic candidate adenosine A 3 receptors are expressed by perineuronal peripheral macrophages in human dorsal root ganglion and spinal cord microglia.

Adenosine receptors are a family of purinergic G protein-coupled receptors that are widely distributed in bodily organs and in the peripheral and central nervous systems. Recently, antihyperalgesic actions have been suggested for the adenosine A 3 receptor, and its agonists have been proposed as new neuropathic pain treatments. We hypothesized that these receptors may be expressed in nociceptive primary afferent neurons.

Syntaxin1A overexpression and pain insensitivity in individuals with 7q11.23 duplication syndrome.

Genetic modifications leading to pain insensitivity phenotypes, while rare, provide invaluable insights into the molecular biology of pain and reveal targets for analgesic drugs. Pain insensitivity typically results from Mendelian loss-of-function mutations in genes expressed in nociceptive (pain-sensing) dorsal root ganglion (DRG) neurons that connect the body to the spinal cord. We document a pain insensitivity mechanism arising from gene overexpression in individuals with the rare 7q11.

Expression pattern analysis and characterization of the hereditary sensory and autonomic neuropathy 2 A (HSAN2A) gene with no lysine kinase (WNK1) in human dorsal root ganglion.

Inherited painless neuropathies arise due to genetic insults that either block the normal signaling of or destroy the sensory afferent neurons in the dorsal root ganglion (DRG) responsible for transducing noxious stimuli. Complete loss of these neurons leads to profound insensitivity to all sensory modalities including pain. Hereditary sensory and autonomic neuropathy type 2 (HSNAII) is a rare genetic neuropathy characterized by a progressive distal early onset sensory loss.

Biochemical and behavioral effects of decreasing dietary linoleic acid and increasing eicosapentaenoic acid and docosahexaenoic acid in a rat chronic monoarthrits model.

Clinical studies have demonstrated that decreasing linoleic acid (LA) while increasing eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in diets evokes an analgesic effect in headache sufferers. We utilized a rat chronic monoarthritis model to determine if these analgesic effects can be reproduced in rats and to and further probe potential analgesic mechanisms. We fed 8 rats a control diet (with fatty acid levels similar to standard US diets) and 8 rats a low LA diet with added EPA and DHA (H3L6 diet) and after 10 weeks, performed a unilateral intraarticular injection of Complete's Freund Adjuvant (CFA).

In-line miniature 3D-printed pressure-cycled ventilator maintains respiratory homeostasis in swine with induced acute pulmonary injury.

The COVID-19 pandemic demonstrated the need for inexpensive, easy-to-use, rapidly mass-produced resuscitation devices that could be quickly distributed in areas of critical need. In-line miniature ventilators based on principles of fluidics ventilate patients by automatically oscillating between forced inspiration and assisted expiration as airway pressure changes, requiring only a continuous supply of pressurized oxygen. Here, we designed three miniature ventilator models to operate in specific pressure ranges along a continuum of clinical lung injury (mild, moderate, and severe injury).

Anatomical Analysis of Transient Potential Vanilloid Receptor 1 (+) and Mu-Opioid Receptor (+) Co-expression in Rat Dorsal Root Ganglion Neurons.

Primary afferent neurons of the dorsal root ganglia (DRG) transduce peripheral nociceptive signals and transmit them to the spinal cord. These neurons also mediate analgesic control of the nociceptive inputs, particularly through the μ-opioid receptor (encoded by ). While opioid receptors are found throughout the neuraxis and in the spinal cord tissue itself, intrathecal administration of μ-opioid agonists also acts directly on nociceptive nerve terminals in the dorsal spinal cord resulting in marked analgesia.

First-in-Human Evaluation of F-PF-06445974, a PET Radioligand That Preferentially Labels Phosphodiesterase-4B.

Phosphodiesterase-4 (PDE4), which metabolizes the second messenger cyclic adenosine monophosphate (cAMP), has 4 isozymes: PDE4A, PDE4B, PDE4C, and PDE4D. PDE4B and PDE4D have the highest expression in the brain and may play a role in the pathophysiology and treatment of depression and dementia. This study evaluated the properties of the newly developed PDE4B-selective radioligand F-PF-06445974 in the brains of rodents, monkeys, and humans.

Transcriptional Activation, Deactivation and Rebound Patterns in Cortex, Hippocampus and Amygdala in Response to Ketamine Infusion in Rats.

Ketamine, an -methyl-D-aspartate (NMDA)-receptor antagonist, is a recently revitalized treatment for pain and depression, yet its actions at the molecular level remain incompletely defined. In this molecular-pharmacological investigation in the rat, we used short- and longer-term infusions of high dose ketamine to stimulate neuronal transcription processes. We hypothesized that a progressively stronger modulation of neuronal gene networks would occur over time in cortical and limbic pathways.

Be in it for the Long Haul: A Commentary on Human Tissue Recovery Initiatives.

The strong need for a new foundational molecular framework for human nervous system research at the nociceptive level is now matched by comprehensive and quantitative capabilities for analyzing nociceptive tissues such as pathologic peripheral tissue, damaged peripheral nerve, dorsal root ganglia, spinal cord, and brain, where possible. However, this idea must be matched by equally strong organization and infrastructures for multisite tissue recovery, molecular analyses, data sharing, and long-term archiving. Experience from other human tissue analysis projects shows that a decades-long activity may be expected, hence "Be in it for the long haul.

Transcriptomic analysis of human sensory neurons in painful diabetic neuropathy reveals inflammation and neuronal loss.

Pathological sensations caused by peripheral painful neuropathy occurring in Type 2 diabetes mellitus (T2DM) are often described as 'sharp' and 'burning' and are commonly spontaneous in origin. Proposed etiologies implicate dysfunction of nociceptive sensory neurons in dorsal root ganglia (DRG) induced by generation of reactive oxygen species, microvascular defects, and ongoing axonal degeneration and regeneration. To investigate the molecular mechanisms contributing to diabetic pain, DRGs were acquired postmortem from patients who had been experiencing painful diabetic peripheral neuropathy (DPN) and subjected to transcriptome analyses to identify genes contributing to pathological processes and neuropathic pain.

Dietary alteration of n-3 and n-6 fatty acids for headache reduction in adults with migraine: randomized controlled trial.

Objective: To determine whether dietary interventions that increase n-3 fatty acids with and without reduction in n-6 linoleic acid can alter circulating lipid mediators implicated in headache pathogenesis, and decrease headache in adults with migraine.

Design: Three arm, parallel group, randomized, modified double blind, controlled trial.

Setting: Ambulatory, academic medical center in the United States over 16 weeks.

Longitudinal peripheral tissue RNA-Seq transcriptomic profiling, hyperalgesia, and wound healing in the rat plantar surgical incision model.

Postoperative pain and delayed healing in surgical wounds, which require complex management strategies have understudied complicated mechanisms. Here we investigated temporal changes in behavior, tissue structure, and transcriptomic profiles in a rat model of a surgical incision, using hyperalgesic behavioral tests, histological analyses, and next-generation RNA sequencing, respectively. The most rapidly (1 hour) expressed genes were the chemokines, Cxcl1 and Cxcl2.

Pain Treatment in the Companion Canine Model to Validate Rodent Results and Incentivize the Transition to Human Clinical Trials.

One of the biggest challenges for analgesic drug development is how to decide if a potential analgesic candidate will work in humans. What preclinical data are the most convincing, incentivizing and most predictive of success? Such a predicament is not unique to analgesics, and the pain field has certain advantages over drug development efforts in areas like neuropsychiatry where the etiological origins are either unknown or difficult to ascertain. For pain, the origin of the problem frequently is known, and the causative peripheral tissue insult might be observable.

The Persistent Pain Transcriptome: Identification of Cells and Molecules Activated by Hyperalgesia.

During persistent pain, the dorsal spinal cord responds to painful inputs from the site of injury, but the molecular modulatory processes have not been comprehensively examined. Using transcriptomics and multiplex in situ hybridization, we identified the most highly regulated receptors and signaling molecules in rat dorsal spinal cord in peripheral inflammatory and post-surgical incisional pain models. We examined a time course of the response including acute (2 hours) and longer term (2 day) time points after peripheral injury representing the early onset and instantiation of hyperalgesic processes.

Comparative Analysis of Dorsal Root, Nodose and Sympathetic Ganglia for the Development of New Analgesics.

Interoceptive and exteroceptive signals, and the corresponding coordinated control of internal organs and sensory functions, including pain, are received and orchestrated by multiple neurons within the peripheral, central and autonomic nervous systems. A central aim of the present report is to obtain a molecularly informed basis for analgesic drug development aimed at peripheral rather than central targets. We compare three key peripheral ganglia: nodose, sympathetic (superior cervical), and dorsal root ganglia in the rat, and focus on their molecular composition using next-gen RNA-Seq, as well as their neuroanatomy using immunocytochemistry and hybridization.

Longitudinal Transcriptomic Profiling in Carrageenan-Induced Rat Hind Paw Peripheral Inflammation and Hyperalgesia Reveals Progressive Recruitment of Innate Immune System Components.

Pain is a common but potentially debilitating symptom, often requiring complex management strategies. To understand the molecular dynamics of peripheral inflammation and nociceptive pain, we investigated longitudinal changes in behavior, tissue structure, and transcriptomic profiles in the rat carrageenan-induced peripheral inflammation model. Sequential changes in the number of differentially expressed genes are consistent with temporal recruitment of key leukocyte populations, mainly neutrophils and macrophages with each wave being preceded by upregulation of the cell-specific chemoattractants, Cxcl1 and Cxcl2, and Ccl2 and Ccl7, respectively.

Molecular Pathways Linking Oxylipins to Nociception in Rats.

Oxylipins are lipid peroxidation products that participate in nociceptive, inflammatory, and vascular responses to injury. Effects of oxylipins depend on tissue-specific differences in accumulation of precursor polyunsaturated fatty acids and the expression of specific enzymes to transform the precursors. The study of oxylipins in nociception has presented technical challenges leading to critical knowledge gaps in the way these molecules operate in nociception.

Identifying oxidized lipid mediators as prognostic biomarkers of chronic posttraumatic headache.

Chronic posttraumatic headache (PTH) is among the most common and disabling sequelae of traumatic brain injury (TBI). Current PTH treatments are often only partially effective and have problematic side effects. We previously showed in a small randomized trial of patients with chronic nontraumatic headaches that manipulation of dietary fatty acids decreased headache frequency, severity, and pain medication use.