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Brain, Behavior, and Immunity Aug 2023Originally identified in fibroblasts, Protease Inhibitor (PI)16 was recently shown to be crucial for the development of neuropathic pain via effects on blood-nerve...
Originally identified in fibroblasts, Protease Inhibitor (PI)16 was recently shown to be crucial for the development of neuropathic pain via effects on blood-nerve barrier permeability and leukocyte infiltration, though its impact on inflammatory pain has not been established. Using the complete Freund's Adjuvant inflammatory pain model, we show that Pi16 mice are protected against sustained inflammatory pain. Accordingly, intrathecal delivery of a PI16 neutralizing antibody in wild-type mice prevented sustained CFA pain. In contrast to neuropathic pain models, we did not observe any changes in blood-nerve barrier permeability due to PI16 deletion. Instead, Pi16 mice display reduced macrophage density in the CFA-injected hindpaw. Furthermore, there was a significant bias toward CD206 (anti-inflammatory) macrophages in the hindpaw and associated dorsal root ganglia. Following CFA, intrathecal depletion of CD206 macrophages using mannosylated clodronate liposomes promoted sustained pain in Pi16 mice. Similarly, an IL-10 neutralizing antibody also promoted sustained CFA pain in the Pi16 when administered intrathecally. Collectively, our results point to fibroblast-derived PI16 mediating substantial differences in macrophage phenotype in the pain neuroaxis under conditions of inflammation. The co-expression of PI16 alongside fibroblast markers in human DRG raise the likelihood that a similar mechanism operates in human inflammatory pain states. Collectively, our findings may have implications for targeting fibroblast-immune cell crosstalk for the treatment of chronic pain.
Topics: Mice; Humans; Animals; Chronic Pain; Neuralgia; Inflammation; Macrophages; Fibroblasts; Antibodies, Neutralizing; Ganglia, Spinal; Hyperalgesia; Carrier Proteins; Glycoproteins
PubMed: 37315702
DOI: 10.1016/j.bbi.2023.06.011 -
Toxicologic Pathology Oct 2023Biotherapeutic modalities such as cell therapies, gene therapies, nucleic acids, and proteins are increasingly investigated as disease-modifying treatments for severe...
Biotherapeutic modalities such as cell therapies, gene therapies, nucleic acids, and proteins are increasingly investigated as disease-modifying treatments for severe and life-threatening neurodegenerative disorders. Such diverse bio-derived test articles are fraught with unique and often unpredictable biological consequences, while guidance regarding nonclinical experimental design, neuropathology evaluation, and interpretation is often limited. This paper summarizes key messages offered during a half-day continuing education course on toxicologic neuropathology of neuro-targeted biotherapeutics. Topics included fundamental neurobiology concepts, pharmacology, frequent toxicological findings, and their interpretation including adversity decisions. Covered biotherapeutic classes included cell therapies, gene editing and gene therapy vectors, nucleic acids, and proteins. If agents are administered directly into the central nervous system, initial screening using hematoxylin and eosin (H&E)-stained sections of currently recommended neural organs (brain [7 levels], spinal cord [3 levels], and sciatic nerve) may need to expand to include other components (e.g., more brain levels, ganglia, and/or additional nerves) and/or special neurohistological procedures to characterize possible neural effects (e.g., cell type-specific markers for reactive glial cells). Scientists who evaluate the safety of novel biologics will find this paper to be a practical reference for preclinical safety testing and risk assessment.
Topics: Neuropathology; Brain; Spinal Cord; Sciatic Nerve; Nucleic Acids
PubMed: 38380881
DOI: 10.1177/01926233241230542 -
The Journal of Experimental Medicine Feb 2024In dorsal root ganglia (DRG), macrophages reside close to sensory neurons and have largely been explored in the context of pain, nerve injury, and repair. However, we...
In dorsal root ganglia (DRG), macrophages reside close to sensory neurons and have largely been explored in the context of pain, nerve injury, and repair. However, we discovered that most DRG macrophages interact with and monitor the vasculature by sampling macromolecules from the blood. Characterization of the DRG vasculature revealed a specialized endothelial bed that transformed in molecular, structural, and permeability properties along the arteriovenous axis and was covered by macrophage-interacting pericytes and fibroblasts. Macrophage phagocytosis spatially aligned with peak endothelial permeability, a process regulated by enhanced caveolar transcytosis in endothelial cells. Profiling the DRG immune landscape revealed two subsets of perivascular macrophages with distinct transcriptome, turnover, and function. CD163+ macrophages self-maintained locally, specifically participated in vasculature monitoring, displayed distinct responses during peripheral inflammation, and were conserved in mouse and man. Our work provides a molecular explanation for the permeability of the blood-DRG barrier and identifies an unappreciated role of macrophages as integral components of the DRG-neurovascular unit.
Topics: Humans; Ganglia, Spinal; Endothelial Cells; Macrophages; Pericytes; Permeability
PubMed: 38117255
DOI: 10.1084/jem.20230675 -
The Journal of Experimental Medicine May 2024Physiological pain serves as a warning of exposure to danger and prompts us to withdraw from noxious stimuli to prevent tissue damage. Pain can also alert us of an...
Physiological pain serves as a warning of exposure to danger and prompts us to withdraw from noxious stimuli to prevent tissue damage. Pain can also alert us of an infection or organ dysfunction and aids in locating such malfunction. However, there are instances where pain is purely pathological, such as unresolved pain following an inflammation or injury to the nervous system, and this can be debilitating and persistent. We now appreciate that immune cells are integral to both physiological and pathological pain, and that pain, in consequence, is not strictly a neuronal phenomenon. Here, we discuss recent findings on how immune cells in the skin, nerve, dorsal root ganglia, and spinal cord interact with somatosensory neurons to mediate pain. We also discuss how both innate and adaptive immune cells, by releasing various ligands and mediators, contribute to the initiation, modulation, persistence, or resolution of various modalities of pain. Finally, we propose that the neuroimmune axis is an attractive target for pain treatment, but the challenges in objectively quantifying pain preclinically, variable sex differences in pain presentation, as well as adverse outcomes associated with immune system modulation, all need to be considered in the development of immunotherapies against pain.
Topics: Female; Male; Humans; Pain; Neurons; Cognition; Ganglia, Spinal; Immunotherapy
PubMed: 38607420
DOI: 10.1084/jem.20221687 -
Anesthesiology Apr 2024Pain that accompanies deafferentation is one of the most mysterious and misunderstood medical conditions. Prevalence rates for the assorted conditions vary considerably...
Pain that accompanies deafferentation is one of the most mysterious and misunderstood medical conditions. Prevalence rates for the assorted conditions vary considerably but the most reliable estimates are greater than 50% for strokes involving the somatosensory system, brachial plexus avulsions, spinal cord injury, and limb amputation, with controversy surrounding the mechanistic contributions of deafferentation to ensuing neuropathic pain syndromes. Deafferentation pain has also been described for loss of other body parts (e.g., eyes and breasts) and may contribute to between 10% and upwards of 30% of neuropathic symptoms in peripheral neuropathies. There is no pathognomonic test or sign to identify deafferentation pain, and part of the controversy surrounding it stems from the prodigious challenges in differentiating cause and effect. For example, it is unknown whether cortical reorganization causes pain or is a byproduct of pathoanatomical changes accompanying injury, including pain. Similarly, ascertaining whether deafferentation contributes to neuropathic pain, or whether concomitant injury to nerve fibers transmitting pain and touch sensation leads to a deafferentation-like phenotype can be clinically difficult, although a detailed neurologic examination, functional imaging, and psychophysical tests may provide clues. Due in part to the concurrent morbidities, the physical, psychologic, and by extension socioeconomic costs of disorders associated with deafferentation are higher than for other chronic pain conditions. Treatment is symptom-based, with evidence supporting first-line antineuropathic medications such as gabapentinoids and antidepressants. Studies examining noninvasive neuromodulation and virtual reality have yielded mixed results.
Topics: Humans; Causalgia; Neuralgia; Brachial Plexus; Spinal Cord Injuries
PubMed: 38470115
DOI: 10.1097/ALN.0000000000004881 -
Ultraschall in Der Medizin (Stuttgart,... Oct 2023The sciatic nerve (SN) is the biggest nerve in the human body and innervates a large skin surface of the lower limb and several muscles of the thigh, leg, and foot. It...
The sciatic nerve (SN) is the biggest nerve in the human body and innervates a large skin surface of the lower limb and several muscles of the thigh, leg, and foot. It originates from the ventral rami of spinal nerves L4 through S3 and contains fibers from both the posterior and anterior divisions of the lumbosacral plexus. After leaving the neural foramina, the nerve roots merge with each other forming a single peripheral nerve that travels within the pelvis and thigh. Non-discogenic pathologies of the SN are largely underdiagnosed entities due to nonspecific clinical tests and poorly described imaging findings. Likewise, to the best of our knowledge, a step-by-step ultrasound protocol to assess the SN is lacking in the pertinent literature. In this sense, the aim of the present manuscript is to describe the normal sono-anatomy of the SN from the greater sciatic foramen to the proximal thigh proposing a standardized and simple sonographic protocol. Then, based on the clinical experience of the authors, a few tips and tricks have been reported to avoid misinterpretation of confounding sonographic findings. Last but not least, we report some common pathological conditions encountered in daily practice with the main purpose of making physicians more confident regarding the sonographic "navigation" of a complex anatomical site and optimizing the diagnosis and management of non-discogenic neuropathies of the SN.
Topics: Humans; Sciatic Nerve; Peripheral Nervous System Diseases; Ultrasonography
PubMed: 37832532
DOI: 10.1055/a-2095-2842 -
Nutrients Oct 2023This study examined the effects of turmeric bioactive compounds, curcumin C3 complex® (CUR) and bisdemethoxycurcumin (BDMC), on mechanical hypersensitivity and the gene...
Turmeric Bioactive Compounds Alleviate Spinal Nerve Ligation-Induced Neuropathic Pain by Suppressing Glial Activation and Improving Mitochondrial Function in Spinal Cord and Amygdala.
This study examined the effects of turmeric bioactive compounds, curcumin C3 complex® (CUR) and bisdemethoxycurcumin (BDMC), on mechanical hypersensitivity and the gene expression of markers for glial activation, mitochondrial function, and oxidative stress in the spinal cord and amygdala of rats with neuropathic pain (NP). Twenty-four animals were randomly assigned to four groups: sham, spinal nerve ligation (SNL, an NP model), SNL+100 mg CUR/kg BW p.o., and SNL+50 mg BDMC/kg BW p.o. for 4 weeks. Mechanical hypersensitivity was assessed by the von Frey test (VFT) weekly. The lumbosacral section of the spinal cord and the right amygdala (central nucleus) were collected to determine the mRNA expression of genes (IBA-1, CD11b, GFAP, MFN1, DRP1, FIS1, PGC1α, PINK, Complex I, TLR4, and SOD1) utilizing qRT-PCR. Increased mechanical hypersensitivity and increased gene expression of markers for microglial activation (IBA-1 in the amygdala and CD11b in the spinal cord), astrocyte activation (GFAP in the spinal cord), mitochondrial dysfunction (PGC1α in the amygdala), and oxidative stress (TLR4 in the spinal cord and amygdala) were found in untreated SNL rats. Oral administration of CUR and BDMC significantly decreased mechanical hypersensitivity. CUR decreased CD11b and GFAP gene expression in the spinal cord. BDMC decreased IBA-1 in the spinal cord and amygdala as well as CD11b and GFAP in the spinal cord. Both CUR and BDMC reduced PGC1α gene expression in the amygdala, PINK1 gene expression in the spinal cord, and TLR4 in the spinal cord and amygdala, while they increased Complex I and SOD1 gene expression in the spinal cord. CUR and BDMC administration decreased mechanical hypersensitivity in NP by mitigating glial activation, oxidative stress, and mitochondrial dysfunction.
Topics: Rats; Animals; Curcuma; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Rats, Sprague-Dawley; Superoxide Dismutase-1; Toll-Like Receptor 4; Spinal Cord; Spinal Nerves; Amygdala; Neuralgia
PubMed: 37892476
DOI: 10.3390/nu15204403 -
Neuromodulation : Journal of the... Jan 2024Spinal cord stimulation (SCS) has been used as a minimally invasive and effective treatment modality for various chronic pain disorders, with the main target being... (Review)
Review
OBJECTIVE
Spinal cord stimulation (SCS) has been used as a minimally invasive and effective treatment modality for various chronic pain disorders, with the main target being stimulation of the dorsal columns; however, certain neuropathic pain areas involve dermatomes that are suboptimally covered by SCS. Stimulation of the spinal nerve roots has the advantage of targeting one or several dermatomes at the same time. The aim of this systematic review is to investigate the efficacy of spinal nerve root stimulation (SNRS) for chronic pain disorders.
MATERIALS AND METHODS
A detailed literature review was performed through the Ovid Embase and MEDLINE data bases in addition to reference searching. Gray literature was included by searching through common search engines using a simplified search strategy. Studies included were focused on adult patients (aged >18 years), diagnosis of chronic pain syndrome (including but not limited to complex regional pain syndrome, persistent spinal pain syndrome, neuropathic pain secondary to trauma or infection, postherpetic pain, and cancer pain). Patients must have undergone SNRS insertion, with ≥six months of documented pain intensity scores on follow-up.
RESULTS
A total of 40 studies underwent full text review, and 13 articles were included in final analysis. Mean preoperative pain intensity was 8.14 ± 0.74 on the visual analog scale, whereas mean postoperative pain intensity at one year was 3.18 ± 1.44. Of 119 patients, 83 (70%) achieved ≥50% reduction in pain intensity after SNRS, whereas 36 (30%) achieved <50% reduction in pain intensity. Only three studies assessed changes in analgesia medication dose and reported morphine equivalent doses varied by case series. Overall, there was a trend toward a reduction in analgesia medications in the postoperative period.
CONCLUSIONS
SNRS led to a mean 44% reduction in pain intensity, with a low level of certainty. In addition, there is some evidence to suggest that using SNRS is associated with reduced use of analgesics, including morphine and gabapentin.
Topics: Adult; Humans; Chronic Pain; Analgesics; Spinal Nerve Roots; Spinal Cord Stimulation; Morphine; Neuralgia
PubMed: 37642627
DOI: 10.1016/j.neurom.2023.07.008 -
Science Translational Medicine Aug 2023Oncomodulin (Ocm) is a myeloid cell-derived growth factor that enables axon regeneration in mice and rats after optic nerve injury or peripheral nerve injury, yet the...
Oncomodulin (Ocm) is a myeloid cell-derived growth factor that enables axon regeneration in mice and rats after optic nerve injury or peripheral nerve injury, yet the mechanisms underlying its activity are unknown. Using proximity biotinylation, coimmunoprecipitation, surface plasmon resonance, and ectopic expression, we have identified armadillo-repeat protein C10 (ArmC10) as a high-affinity receptor for Ocm. ArmC10 deletion suppressed inflammation-induced axon regeneration in the injured optic nerves of mice. ArmC10 deletion also suppressed the ability of lesioned sensory neurons to regenerate peripheral axons rapidly after a second injury and to regenerate their central axons after spinal cord injury in mice (the conditioning lesion effect). Conversely, Ocm acted through ArmC10 to accelerate optic nerve and peripheral nerve regeneration and to enable spinal cord axon regeneration in these mouse nerve injury models. We showed that ArmC10 is highly expressed in human-induced pluripotent stem cell-derived sensory neurons and that exposure to Ocm altered gene expression and enhanced neurite outgrowth. ArmC10 was also expressed in human monocytes, and Ocm increased the expression of immune modulatory genes in these cells. These findings suggest that Ocm acting through its receptor ArmC10 may be a useful therapeutic target for nerve repair and immune modulation.
Topics: Animals; Humans; Mice; Axons; Ganglia, Spinal; Induced Pluripotent Stem Cells; Nerve Regeneration; Neuronal Outgrowth; Sensory Receptor Cells
PubMed: 37556559
DOI: 10.1126/scitranslmed.adg6241