A5103238262- Pain Mechanisms and Treatments
- Nerve injury and regeneration
- Neuropeptides and Animal Physiology
- Ion channel regulation and function
- Neuroscience and Neuropharmacology Research
- Botulinum Toxin and Related Neurological Disorders
- Hereditary Neurological Disorders
- Pain Management and Placebo Effect
- Ion Channels and Receptors
- Pediatric Pain Management Techniques
- Pharmacological Receptor Mechanisms and Effects
- Neuroinflammation and Neurodegeneration Mechanisms
- Neurobiology and Insect Physiology Research
- Dermatology and Skin Diseases
- Anesthesia and Pain Management
- Receptor Mechanisms and Signaling
- Neurotransmitter Receptor Influence on Behavior
- Pharmacological Effects of Natural Compounds
- Musculoskeletal pain and rehabilitation
- Exercise and Physiological Responses
- Cancer, Stress, Anesthesia, and Immune Response
- Inflammatory mediators and NSAID effects
- Text Readability and Simplification
- Synthesis of β-Lactam Compounds
- Regulation of Appetite and Obesity
University of California, San Francisco
2015-2025
Creative Commons
2018
Baum Consult
2016
W. M. Keck Foundation
2001-2012
Sorbonne Université
2004
Inserm
2001-2004
Abstract Paralleling the activation of dorsal horn microglia after peripheral nerve injury is a significant expansion and proliferation macrophages around injured sensory neurons in root ganglia (DRG). Here we demonstrate critical contribution DRG macrophages, but not those at site, to both initiation maintenance mechanical hypersensitivity that characterizes neuropathic pain phenotype. In contrast reported sexual dimorphism microglial pain, depletion reduces injury-induced male female mice....
Neuropathic pain is a chronic debilitating disease that results from nerve damage, persists long after the injury has subsided, and characterized by spontaneous mechanical hypersensitivity. Although loss of inhibitory tone in dorsal horn spinal cord major contributor to neuropathic pain, molecular cellular mechanisms underlying this disinhibition are unclear. Here, we combined pharmacogenetic activation selective ablation approaches mice define contribution parvalbumin (PV)-expressing...
Primary afferent "pain" fibers (nociceptors) are divided into subclasses based on distinct molecular and anatomical features, these classes mediate noxious modality-specific contributions to behaviors evoked by painful stimuli. Whether the heat capsaicin receptor transient potential vanilloid-1 (TRPV1) is expressed heterogeneously across several sensory populations, or selectively a unique nociceptor subclass, however, unclear. Here we used two lines of <i>Trpv1</i> reporter mice investigate...
Protein kinase C γ (PKCγ), which is concentrated in interneurons of the inner part lamina II dorsal horn, has been implicated injury-induced allodynia, a condition wherein pain produced by innocuous stimuli. Although it generally assumed that these receive input from nonpeptidergic, IB4-positive subset nociceptors, fact PKCγ cells do not express Fos response to noxious stimulation suggests otherwise. Here, we demonstrate terminal field nonpeptidergic population fact, lies interneurons. There...
Peripheral nerve injury-induced neuropathic pain is a chronic and debilitating condition characterized by mechanical hypersensitivity. We previously identified microglial activation via release of colony-stimulating factor 1 (CSF1) from injured sensory neurons as mechanism contributing to pain. Here, we show that intrathecal administration CSF1, even in the absence injury, sufficient induce behavior, but only male mice. Transcriptional profiling morphologic analyses after CSF1 showed robust...
Rheumatoid arthritis is characterized by erosive inflammation of the joints, new bone proliferation, and ankylosis, leading to severely reduced locomotion intense chronic pain. In a model this disease, adjuvant-induced polyarthritis in rat, neurons involved pain transmission control undergo plastic changes, especially at spinal level. These changes affect notably that contain opioids, such as enkephalins deriving from preproenkephalin A (PA) precursor protein. Using recombinant herpes...
There is continuing controversy relating to the primary afferent neurotransmitter that conveys itch signals spinal cord. Here, we investigated DRG and cord expression of putative afferent-derived “itch” neurotransmitter, gastrin-releasing peptide (GRP). Using ISH, qPCR, immunohistochemistry, conclude GRP expressed abundantly in cord, but not neurons. Titration most commonly used antiserum tissues from wild-type mutant mice indicates only selective for at high dilutions. Paralleling these...
Decreased spinal cord GABAergic inhibition is a major contributor to the persistent neuropathic pain that can follow peripheral nerve injury. Recently, we reported restoring signaling by intraspinal transplantation of cortical precursors interneurons from embryonic medial ganglionic eminence (MGE) reverse mechanical hypersensitivity (allodynia) characterizes model in mouse. We show MGE cell transplants are also effective against both allodynia and heat hyperalgesia produced...
Abstract Excitatory interneurons account for the majority of neurons in superficial dorsal horn, but despite their presumed contribution to pain and itch, there is still limited information about organisation function. We recently identified 2 populations excitatory interneuron defined by expression gastrin-releasing peptide (GRP) or substance P (SP). Here, we demonstrate that these cells show major differences morphological, electrophysiological, pharmacological properties. Based on...
Dysfunction of inhibitory circuits in the rostral anterior cingulate cortex underlies affective (aversive), but not sensory-discriminative features (hypersensitivity) pain experience. To restore controls, we transplanted interneuron progenitor cells into a chemotherapy-induced neuropathic model. The transplants integrated, exerted GABA-A mediated inhibition host pyramidal and blocked gabapentin preference (i.e. relieved ongoing pain) conditioned place paradigm. Surprisingly, aversiveness...
Abstract The lipid prostaglandin E 2 (PGE ) mediates inflammatory pain by activating G protein-coupled receptors, including the E2 receptor 4 (EP4R). Nonsteroidal anti-inflammatory drugs (NSAIDs) reduce nociception inhibiting synthesis, however, disruption of upstream prostanoid biosynthesis can lead to pleiotropic effects gastrointestinal bleeding and cardiac complications. In contrast, acting downstream, EP4R antagonists may act specifically as agents and, date, no selective have been...
Abstract Large library docking of tangible molecules has revealed potent ligands across many targets. While make-on-demand libraries now exceed 75 billion enumerated molecules, their synthetic routes are dominated by a few reaction types, reducing diversity and inevitably leaving interesting bioactive-like chemotypes unexplored. Here, we investigate the large-scale enumeration targeted isoquinuclidines. These “natural-product-like” rare in current functionally congested, making them as...
Virtual library docking can reveal unexpected chemotypes that complement the structures of biological targets. Seeking agonists for cannabinoid-1 receptor (CB1R), we dock 74 million tangible molecules and prioritize 46 high ranking ones de novo synthesis testing. Nine are active by radioligand competition, a 20% hit-rate. Structure-based optimization one most potent these (Ki = 0.7 µM) leads to '1350, 0.95 nM ligand full CB1R agonist Gi/o signaling. A cryo-EM structure '1350 in complex with...
Abstract Descending projections arising from brainstem serotonergic (5HT) neurons contribute to both facilitatory and inhibitory controls of spinal cord “pain” transmission neurons. Unclear, however, are the networks that influence output these 5HT To address this question, here we used a novel neuroanatomical tracing method in transgenic line mice which Cre recombinase is selectively expressed (ePet‐Cre mice). Specifically, injected conditional pseudorabies virus recombinant (BA2001) can...
Abstract Despite the evidence for a significant contribution of brainstem serotonergic (5HT) systems to control spinal cord “pain” transmission neurons, attention has turned recently influence nonserotonergic including facilitatory and inhibitory controls that originate from so‐called “on” “off” cells rostroventral medulla (RVM). Unclear, however, is extent which these latter circuits interact with or are influenced by cell groups. To address this question we selectively targeted expression...
Delivery of resiniferatoxin under CT guidance around lumbar dorsal root ganglia in pigs resulted selective deletion nociceptive neurons and lasting analgesia.
Primary sensory neurons are generally considered the only source of dorsal horn calcitonin gene-related peptide (CGRP), a neuropeptide critical to transmission pain messages. Using tamoxifen-inducible Calca CreER transgenic mouse, here we identified distinct population CGRP-expressing excitatory interneurons in lamina III spinal cord and trigeminal nucleus caudalis. These have spine-laden, dorsally directed, dendrites, ventrally directed axons. As under resting conditions, CGRP tonic...
Spinal cord transplants of embryonic cortical GABAergic progenitor cells derived from the medial ganglionic eminence (MGE) can reverse mechanical hypersensitivity in mouse models peripheral nerve injury- and paclitaxel-induced neuropathic pain. Here, we used electrophysiology, immunohistochemistry, electron microscopy to examine extent which MGE integrate into host circuitry recapitulate endogenous inhibitory circuits. Whether were performed before or after injury, developed mature neurons...
Abstract BDNF is a critical contributor to neuronal growth, development, learning, and memory. Although extensively studied in the brain, also expressed by primary afferent sensory neurons peripheral nervous system. Unfortunately, anatomical functional studies of afferent-derived have been limited availability appropriate molecular tools. Here, we used targeted, inducible approaches characterize expression pattern extent which it contributes variety pain itch behaviors. Using BDNF-LacZ...