ABSTRACT
A chemogenetic screen reveals links between nociceptors and gut immune function.
Subject(s)
Gastrointestinal Microbiome , Gastrointestinal Tract , Nociceptors , T-Lymphocytes, Regulatory , TRPV Cation Channels , Animals , Humans , Mice , Gastrointestinal Microbiome/immunology , Gastrointestinal Tract/immunology , Nociceptors/physiology , Nociceptors/immunology , Ganglia, Spinal/immunology , Ganglia, Spinal/physiopathology , T-Lymphocytes, Regulatory/immunology , TRPV Cation Channels/metabolismABSTRACT
BACKGROUND: Central nervous system (CNS) disorders, such as stroke, often lead to spasticity, which result in limb deformities and significant reduction in quality of life. Spasticity arises from disruptions in the normal functioning of cortical and descending inhibitory pathways in the brainstem, leading to abnormal muscle contractions. Contralateral seventh cervical nerve cross transfer (CC7) surgery has been proven to effectively reduce spasticity, but the specific mechanism for its effectiveness is unclear. METHODS: This study aimed to investigate the changes in the dorsal root ganglia (DRG) following CC7 surgery. A comprehensive anatomical analysis was conducted through cadaveric study and magnetic resonance imaging (MRI) study, to accurately measure the regional anatomy of the C7 DRG. DRG perfusion changes were quantitatively assessed by comparing pre- and postoperative dynamic contrast-enhanced (DCE) MRI. RESULTS: In CC7 surgery, the C7 nerve root on the affected side is cut close to the DRG (3.6 ± 1.0 mm), while the C7 nerve root on the healthy side is cut further away from the DRG (65.0 ± 10.0 mm). MRI studies revealed that after C7 proximal neurotomy on the affected side, there was an increase in DRG volume, vascular permeability, and perfusion; after C7 distal neurotomy on the healthy side, there was a decrease in DRG volume, with no significant changes in vascular permeability and perfusion. CONCLUSION: This study provides preliminary insights into the mechanisms of spasticity reduction following CC7 surgery, indicating that changes in the DRG, such as increased vascular permeability and perfusion, could disrupt abnormal spinal γ-circuits. The resulting high-perfusion state of DRG, possibly due to heightened neuronal activity and metabolic demands, necessitating further research to verify this hypothesis.
Subject(s)
Ganglia, Spinal , Magnetic Resonance Imaging , Muscle Spasticity , Muscle Spasticity/surgery , Muscle Spasticity/physiopathology , Ganglia, Spinal/diagnostic imaging , Ganglia, Spinal/surgery , Ganglia, Spinal/physiopathology , Humans , Male , Female , Nerve Transfer/methods , Cadaver , Middle Aged , Aged , Spinal Nerve Roots/surgery , Spinal Nerve Roots/diagnostic imaging , Spinal Nerve Roots/physiopathologyABSTRACT
Fibromyalgia (FM) remains a condition with a pathogenesis that is not completely understood, affecting a significant portion of the global population. This article summarises the main advances in FM during the last year. Even in 2023, research on FM was notably active. From a clinimetric perspective, studies have been conducted to evaluate the possibilities of interchanging the primary indices of disease severity, primarily for studies with substantial case numbers. Regarding FM pathogenesis, ongoing research focuses on small fiber neuropathy: some studies have documented its association with central sensitisation, while others have revealed distinct sensory profiles in patients with FM and small fiber neuropathy compared to those solely with small fiber neuropathy. Dorsal root ganglia seem to play a crucial role in the pathogenesis of FM as they host satellite glial cells, which are targeted by pain-driving immunoglobulin G. These antibodies have been identified in a subset of patients exhibiting high symptom severity. An important study conducted on animal models confirmed the role of neuroinflammation at the level of dorsal root ganglia, in this case mediated by polymorphonuclear neutrophils. Mounting evidence underscores the link between COVID-19 and the persistence of FM symptoms after recovery. In identifying potential biomarkers aiding FM diagnosis, research has also concentrated on studying the expression of specific circulating microRNAs. Recent discoveries have unveiled novel therapeutic strategies for FM, especially focused in non-pharmacological interventions. This includes a focus on non-invasive brain stimulation and exercise programs, all directed towards relieving symptoms and improving functionality in individuals affected by the condition.
Subject(s)
COVID-19 , Fibromyalgia , Fibromyalgia/diagnosis , Fibromyalgia/therapy , Fibromyalgia/physiopathology , Fibromyalgia/immunology , Humans , COVID-19/complications , COVID-19/immunology , COVID-19/diagnosis , Animals , SARS-CoV-2/immunology , Ganglia, Spinal/physiopathology , Ganglia, Spinal/immunology , Ganglia, Spinal/metabolism , Severity of Illness Index , Biomarkers/bloodABSTRACT
BACKGROUND: Stimulation of dorsal root ganglion (DRG) is an ideal neuromodulative intervention, providing pain relief in localized chronic pain conditions because γ-band oscillations reflect the intensity of ongoing chronic pain in patients affected. OBJECTIVE: We aimed to observe the role of cortical γ-band power associated with the relief of chronic neuropathic pain through DRG stimulation (DRGS). MATERIALS AND METHODS: We examined nine patients (two women, mean age 56.8 years; range, 36-77 years) diagnosed with chronic neuropathic pain who underwent DRGS therapy. We used the numeric rating scale (NRS) on the painful limb and simultaneously recorded the electroencephalography to assess the broadband γ power. Assessments were conducted on the first day and on the seventh day after implantation of the DRGS system and then compared and correlated with the results of the NRS. RESULTS: The NRS scores showed a significant decrease from the first day to the seventh day (p = 0.007). The resting-state γ power revealed a significant decrease (p = 0.021) between 30 and 45 Hz, recorded through the central electrode contralateral to the painful limb from the first day (mean [M] = 0.46, SD = 0.25) to the seventh day (M = 0.31, SD = 0.12) after DRGS. There was no significant change in the resting-state γ-band power recorded through the central electrode ipsilateral to the painful limb. However, we found a positive correlation in the γ-band power (rs = 0.628, p = 0.005) with the NRS rating. CONCLUSIONS: A lateralized decrease in broadband γ power may be considered further evidence supporting a reduction in the hyperexcitability of the nociceptive system in response to DRGS therapy. In the future, γ-band power could serve as a biomarker for assessing the efficacy of DRGS during the seven-day test phase preceding the implantation of the DRGS system.
Subject(s)
Chronic Pain , Ganglia, Spinal , Neuralgia , Humans , Middle Aged , Female , Neuralgia/therapy , Neuralgia/physiopathology , Male , Adult , Aged , Ganglia, Spinal/physiology , Ganglia, Spinal/physiopathology , Chronic Pain/therapy , Chronic Pain/physiopathology , Pain Measurement/methods , Gamma Rhythm/physiology , Electroencephalography/methods , Cerebral Cortex/physiopathology , Cerebral Cortex/physiology , Treatment OutcomeABSTRACT
AIMS: Activation of the endocannabinoid system by monoacylglycerol lipase (MAGL) blockade may affect the lower urinary tract function. We investigated the effect of an MAGL inhibitor, MJN110, on neurogenic lower urinary tract dysfunction (LUTD) in the mouse model of spinal cord injury (SCI). METHODS: Female C57BL/6 mice that underwent spinal cord transection at T8-10 level were divided into three groups consisting of (1) vehicle-treated SCI mice, (2) 5 mg/kg, or (3) 10 mg/kg of MJN110-treated SCI mice. MJN110 and vehicle were administered intraperitoneally for 7 days from 4 weeks after spinal cord transection. We then conducted awake cystometrograms and compared urodynamic parameters between three groups. The expression of cannabinoid (CB) receptors, TRP receptors, and inflammatory cytokines in L6-S1 dorsal root ganglia (DRG) or the bladder mucosa were evaluated and compared among three groups. Changes in the level of serum 2-arachidonoylglycerol (2-AG) and bladder MAGL were also evaluated. RESULTS: In the cystometrogram, detrusor overactivity (DO) parameters, such as the number of nonvoiding contraction (NVC), a ratio of time to the 1st NVC to intercontraction interval (ICI), and NVC integrals were improved by MJN110 treatment, and some effects were dose dependent. Although MJN110 did not improve voiding efficiency, it decreased bladder capacity, ICI, and residual urine volume compared to vehicle injection. MJN110 treatment groups had lower CB2, TRPV1, TRPA1, and inflammatory cytokines mRNA levels in DRG and bladder mucosa. Serum 2-AG was increased, and bladder MAGL was decreased after MAGL inhibitor treatment. CONCLUSIONS: MAGL inhibition improved LUTD including attenuation of DO after SCI. Thus, MAGL can be a therapeutic target for neurogenic LUTD after SCI.
Subject(s)
Mice, Inbred C57BL , Monoacylglycerol Lipases , Spinal Cord Injuries , Urinary Bladder , Urodynamics , Animals , Monoacylglycerol Lipases/antagonists & inhibitors , Monoacylglycerol Lipases/metabolism , Spinal Cord Injuries/physiopathology , Spinal Cord Injuries/drug therapy , Spinal Cord Injuries/complications , Spinal Cord Injuries/metabolism , Female , Urinary Bladder/drug effects , Urinary Bladder/physiopathology , Urodynamics/drug effects , Mice , Disease Models, Animal , Ganglia, Spinal/drug effects , Ganglia, Spinal/metabolism , Ganglia, Spinal/physiopathology , Receptors, Cannabinoid/metabolism , Receptors, Cannabinoid/drug effects , Enzyme Inhibitors/pharmacology , Endocannabinoids/metabolism , Cytokines/metabolism , Urinary Bladder, Neurogenic/drug therapy , Urinary Bladder, Neurogenic/physiopathology , Urinary Bladder, Neurogenic/etiology , Lower Urinary Tract Symptoms/drug therapy , Lower Urinary Tract Symptoms/physiopathology , Lower Urinary Tract Symptoms/etiology , Carbamates , SuccinimidesABSTRACT
Multiple Sclerosis (MS) is an autoimmune disease with notable sex differences. Women are not only more likely to develop MS but are also more likely than men to experience neuropathic pain in the disease. It has been postulated that neuropathic pain in MS can originate in the peripheral nervous system at the level of the dorsal root ganglia (DRG), which houses primary pain sensing neurons (nociceptors). These nociceptors become hyperexcitable in response to inflammation, leading to peripheral sensitization and eventually central sensitization, which maintains pain long-term. The mouse model experimental autoimmune encephalomyelitis (EAE) is a good model for human MS as it replicates classic MS symptoms including pain. Using EAE mice as well as naïve primary mouse DRG neurons cultured in vitro, we sought to characterize sex differences, specifically in peripheral sensory neurons. We found sex differences in the inflammatory profile of the EAE DRG, and in the TNFα downstream signaling pathways activated intracellularly in cultured nociceptors. We also found increased cell death with TNFα treatment. Given that TNFα signaling has been shown to initiate intrinsic apoptosis through mitochondrial disruption, this led us to investigate sex differences in the mitochondria's response to TNFα. Our results demonstrate that male sensory neurons are more sensitive to mitochondrial stress, making them prone to neuronal injury. In contrast, female sensory neurons appear to be more resistant to mitochondrial stress and exhibit an inflammatory and regenerative phenotype that may underlie greater nociceptor hyperexcitability and pain. Understanding these sex differences at the level of the primary sensory neuron is an important first step in our eventual goal of developing sex-specific treatments to halt pain development in the periphery before central sensitization is established.
Subject(s)
Encephalomyelitis, Autoimmune, Experimental , Ganglia, Spinal , Multiple Sclerosis , Neuralgia , Sex Characteristics , Animals , Female , Humans , Male , Mice , Encephalomyelitis, Autoimmune, Experimental/physiopathology , Ganglia, Spinal/physiopathology , Multiple Sclerosis/physiopathology , Neuralgia/etiology , Neuralgia/physiopathology , Nociceptors/metabolism , Tumor Necrosis Factor-alpha/metabolismABSTRACT
Increased sympathetic nerve excitability has been reported to aggravate a variety of chronic pain conditions, and an increase in the number of sympathetic nerve fibers in the dorsal root ganglion (DRG) has been found in neuropathic pain (NP) models. However, the mechanism of the neurotransmitter norepinephrine (NE) released by sympathetic nerve fiber endings on the excitability of DRG neurons is still controversial, and the adrenergic receptor subtypes involved in this biological process are also controversial. In our study, we have two objectives: (1) To determine the effect of the neurotransmitter NE on the excitability of different neurons in DRG; (2) To determine which adrenergic receptors are involved in the excitability of DRG neurons by NE released by sprouting sympathetic fibers. In this experiment, a unique field potential recording method of spinal cord dorsal horn was innovatively adopted, which can be used for electrophysiological study in vivo. The results showed thatï¼ Forty days after SNI, patch clamp and field potential recording methods confirmed that NE enhanced the excitability of ipsilateral DRG large neurons, and then our in vivo electrophysiological results showed that the α2 receptor blocker Yohimbine could block the excitatory effect of NE on A-fiber and the inhibitory effect on C-fiber, while the α2A-adrenergic receptor agonist guanfacine (100 µM) had the same biological effect as NE. Finally, we concluded that NE from sympathetic fiber endings is involved in the regulation of pain signaling by acting on α2A-adrenergic receptors in DRG.
Subject(s)
Adrenergic Fibers/metabolism , Ganglia, Spinal/metabolism , Neuralgia/physiopathology , Neurons/metabolism , Norepinephrine/metabolism , Receptors, Adrenergic, alpha-2/metabolism , Adrenergic Fibers/pathology , Adrenergic alpha-2 Receptor Agonists/pharmacology , Adrenergic alpha-2 Receptor Antagonists/pharmacology , Animals , Disease Models, Animal , Evoked Potentials, Somatosensory/physiology , Ganglia, Spinal/physiopathology , Guanfacine/pharmacology , Male , Neuralgia/genetics , Neuralgia/metabolism , Neurons/pathology , Rats , Rats, Sprague-Dawley , Sciatic Nerve/metabolism , Sciatic Nerve/physiopathology , Spinal Cord Dorsal Horn/metabolism , Spinal Cord Dorsal Horn/physiopathology , Spinal Nerves/metabolism , Spinal Nerves/physiopathology , Stereotaxic Techniques , Yohimbine/pharmacologyABSTRACT
The incidence of chronic pain is especially high in women, but the underlying mechanisms remain poorly understood. Interleukin-23 (IL-23) is a pro-inflammatory cytokine and contributes to inflammatory diseases (e.g., arthritis and psoriasis) through dendritic/T cell signaling. Here we examined the IL-23 involvement in sexual dimorphism of pain, using an optogenetic approach in transgenic mice expressing channelrhodopsin-2 (ChR2) in TRPV1-positive nociceptive neurons. In situ hybridization revealed that compared to males, females had a significantly larger portion of small-sized (100-200 µm2) Trpv1+ neurons in dorsal root ganglion (DRG). Blue light stimulation of a hindpaw of transgenic mice induced intensity-dependent spontaneous pain. At the highest intensity, females showed more intense spontaneous pain than males. Intraplantar injection of IL-23 (100 ng) induced mechanical allodynia in females only but had no effects on paw edema. Furthermore, intraplantar IL-23 only potentiated blue light-induced pain in females, and intrathecal injection of IL-23 also potentiated low-dose capsaicin (500 ng) induced spontaneous pain in females but not males. IL-23 expresses in DRG macrophages of both sexes. Intrathecal injection of IL-23 induced significantly greater p38 phosphorylation (p-p38), a marker of nociceptor activation, in DRGs of female mice than male mice. In THP-1 human macrophages estrogen and chemotherapy co-application increased IL-23 secretion, and furthermore, estrogen and IL-23 co-application, but not estrogen and IL-23 alone, significantly increased IL-17A release. These findings suggest a novel role of IL-23 in macrophage signaling and female-dominant pain, including C-fiber-mediated spontaneous pain. Our study has also provided new insight into cytokine-mediated macrophage-nociceptor interactions, in a sex-dependent manner.
Subject(s)
Ganglia, Spinal/drug effects , Interleukin-23/toxicity , Nerve Fibers, Unmyelinated/drug effects , Nociceptors/drug effects , Pain Threshold/drug effects , Pain/chemically induced , TRPV Cation Channels/metabolism , Animals , Capsaicin , Channelrhodopsins/genetics , Channelrhodopsins/metabolism , Disease Models, Animal , Female , Ganglia, Spinal/metabolism , Ganglia, Spinal/physiopathology , Humans , Interleukin-17/metabolism , Light , Macrophages/drug effects , Macrophages/metabolism , Male , Mice, Inbred C57BL , Mice, Transgenic , Nerve Fibers, Unmyelinated/metabolism , Nociceptors/metabolism , Optogenetics , Pain/genetics , Pain/metabolism , Pain/physiopathology , Sex Characteristics , THP-1 Cells , TRPV Cation Channels/genetics , p38 Mitogen-Activated Protein Kinases/metabolismABSTRACT
Oxaliplatin-induced neurotoxicity is expressed as a dose-limiting peripheral sensory neuropathy (PSN). Cannabinoid substances have been investigated for the analgesic effect. This study aimed to investigate the role of cannabinoid receptors in oxaliplatin-associated PSN. Swiss male mice received nine oxaliplatin injections (2 mg/kg, i.v.). Mechanical and thermal nociceptive tests were performed for 56 days. CB1, CB2, and c-Fos expression were assessed in dorsal root ganglia (DRG), spinal cord (SC), trigeminal ganglia (TG), spinal trigeminal nucleus caudalis (Sp5C), and periaqueductal gray (PAG). Iba-1 expression was assessed in DRG and ATF3 in TG. Cannabidiol (10 mg/kg, p.o.) or a CB1/CB2 non-selective agonist (WIN 55,212-2; 0.5 mg/kg, s.c.) or AM251 (CB1 antagonist) or AM630 (CB2 antagonist) (3 mg/kg, i.p.) were injected before oxaliplatin. Oxaliplatin increased CB1 in DRG, SC, TG, Sp5C, and ventrolateral PAG, with no interference in CB2 expression. Cannabidiol increased CB1 in DRG, reduced mechanical hyperalgesia and c-Fos expression in DRG and SC. Additionally, WIN 55,212-2 increased CB1 in DRG, reduced mechanical hyperalgesia, cold allodynia and c-Fos expression in DRG and SC. CB1 blockage hastened the cold allodynia response, but the CB2 antagonist failed to modulate the oxaliplatin-induced nociceptive behavior. Oxaliplatin also increased Iba-1 in DRG, suggesting immune response modulation which was reduced by cannabidiol and enhanced by AM630. The modulation of the endocannabinoid system, through the CB1 receptor, attenuates the oxaliplatin-associated PNS. The activation of the endocannabinoid system could be considered as a therapeutic target for controlling oxaliplatin-associated neuropathy.
Subject(s)
Endocannabinoids/metabolism , Nociception/drug effects , Oxaliplatin/adverse effects , Peripheral Nervous System Diseases/chemically induced , Receptor, Cannabinoid, CB1/agonists , Animals , Fluorescent Antibody Technique , Ganglia, Spinal/drug effects , Ganglia, Spinal/pathology , Ganglia, Spinal/physiopathology , Male , Mice , Oxaliplatin/antagonists & inhibitors , Pain Measurement , Peripheral Nervous System Diseases/metabolism , Receptor, Cannabinoid, CB1/metabolism , Rotarod Performance TestABSTRACT
Neurogenesis in the adult brain is well recognized and plays a critical role in the maintenance of brain function and homeostasis. However, whether neurogenesis also occurs in the adult peripheral nervous system remains unknown. Here, using sensory ganglia (dorsal root ganglia, DRGs) as a model, we show that neurogenesis also occurs in the peripheral nervous system, but in a manner different from that in the central nervous system. Satellite glial cells (SGCs) express the neuronal precursor markers Nestin, POU domain, class 4, transcription factor 1, and p75 pan-neurotrophin receptor. Following sciatic nerve injury, the suppression of endogenous proBDNF by proBDNF antibodies resulted in the transformation of proliferating SGCs into doublecortin-positive cells in the DRGs. Using purified SGCs migrating out from the DRGs, the inhibition of endogenous proBDNF promoted the conversion of SGCs into neuronal phenotypes in vitro. Our findings suggest that SGCs are neuronal precursors, and that proBDNF maintains the SGC phenotype. Furthermore, the suppression of proBDNF signaling is necessary for neuronal phenotype acquisition by SGCs. Thus, we propose that peripheral neurogenesis may occur via the direct conversion of SGCs into neurons, and that this process is negatively regulated by proBDNF.
Subject(s)
Brain-Derived Neurotrophic Factor/metabolism , Ganglia, Spinal/metabolism , Neural Stem Cells/metabolism , Neurogenesis , Neuroglia/metabolism , Peripheral Nerve Injuries/metabolism , Protein Precursors/metabolism , Action Potentials , Animals , Animals, Newborn , Brain-Derived Neurotrophic Factor/genetics , Cell Transdifferentiation , Cells, Cultured , Disease Models, Animal , Doublecortin Protein/metabolism , Female , Ganglia, Spinal/pathology , Ganglia, Spinal/physiopathology , Male , Neural Stem Cells/pathology , Neuroglia/pathology , Peripheral Nerve Injuries/pathology , Peripheral Nerve Injuries/physiopathology , Phenotype , Protein Precursors/genetics , Rats, Sprague-Dawley , Receptors, Nerve Growth Factor/genetics , Receptors, Nerve Growth Factor/metabolism , Signal TransductionABSTRACT
BACKGROUND AND OBJECTIVES: As autoantibodies to contactin-1 from patients with chronic inflammatory demyelinating polyradiculoneuropathy not only bind to the paranodes where they are supposed to cause conduction failure but also bind to other neuronal cell types, we aimed to investigate the effect of anti-contactin-1 autoantibodies on contactin-1 surface expression in cerebellar granule neurons, dorsal root ganglion neurons, and contactin-1-transfected human embryonic kidney 293 cells. METHODS: Immunocytochemistry including structured illumination microscopy and immunoblotting was used to determine expression levels of contactin-1 and/or sodium channels after long-term exposure to autoantibodies from 3 seropositive patients. For functional analysis of sodium channels, whole-cell recordings of sodium currents were performed on dorsal root ganglion neurons incubated with anti-contactin-1 autoantibodies. RESULTS: We found a reduction in contactin-1 expression levels on dorsal root ganglion neurons, cerebellar granule neurons, and contactin-1-transfected human embryonic kidney 293 cells and decreased dorsal root ganglion sodium currents after long-term exposure to anti-contactin-1 autoantibodies. Sodium channel density did not decrease. DISCUSSION: Our results demonstrate a direct effect of anti-contactin-1 autoantibodies on the surface expression of contactin-1 and sodium currents in dorsal root ganglion neurons. This may be the pathophysiologic correlate of sensory ataxia reported in these patients.
Subject(s)
Autoantibodies/immunology , Contactin 1/immunology , Contactin 1/metabolism , Ganglia, Spinal/metabolism , Ganglia, Spinal/physiopathology , Sodium Channels/physiology , Ganglia, Spinal/immunology , HEK293 Cells , Humans , Polyneuropathies/immunology , Sodium/metabolism , Sodium Channels/metabolismABSTRACT
A neuroimmune crosstalk is involved in somatic and visceral pathological pain including inflammatory and neuropathic components. Apart from microglia essential for spinal and supraspinal pain processing, the interaction of bone marrow-derived infiltrating macrophages and/or tissue-resident macrophages with the primary afferent neurons regulates pain signals in the peripheral tissue. Recent studies have uncovered previously unknown characteristics of tissue-resident macrophages, such as their origins and association with regulation of pain signals. Peripheral nerve macrophages and intestinal resident macrophages, in addition to adult monocyte-derived infiltrating macrophages, secrete a variety of mediators, such as tumor necrosis factor-α, interleukin (IL)-1ß, IL-6, high mobility group box 1 and bone morphogenic protein 2 (BMP2), that regulate the excitability of the primary afferents. Neuron-derived mediators including neuropeptides, ATP and macrophage-colony stimulating factor regulate the activity or polarization of diverse macrophages. Thus, macrophages have multitasks in homeostatic conditions and participate in somatic and visceral pathological pain by interacting with neurons.
Subject(s)
Ganglia, Spinal/metabolism , Macrophages/metabolism , Neuroimmunomodulation , Neurons/metabolism , Pain Threshold , Pain/metabolism , Signal Transduction , Animals , Cell Communication , Cytokines/metabolism , Ganglia, Spinal/immunology , Ganglia, Spinal/physiopathology , Humans , Inflammation Mediators/metabolism , Macrophages/immunology , Neurons/immunology , Neuropeptides/metabolism , Pain/immunology , Pain/physiopathology , PhenotypeABSTRACT
Agonists of the Gi protein-coupled A3 adenosine receptor (A3AR) have shown important pain-relieving properties in preclinical settings of several pain models. Active as a monotherapy against chronic pain, A3AR agonists can also be used in combination with classic opioid analgesics. Their safe pharmacological profile, as shown by clinical trials for other pathologies, i.e., rheumatoid arthritis, psoriasis and fatty liver diseases, confers a realistic translational potential, thus encouraging research studies on the molecular mechanisms underpinning their antinociceptive actions. A number of pathways, involving central and peripheral mechanisms, have been proposed. Recent evidence showed that the prototypical A3AR agonist Cl-IB-MECA and the new, highly selective, A3AR agonist MRS5980 inhibit neuronal (N-type) voltage-dependent Ca2+ currents in dorsal root ganglia, a known pain-related mechanism. Other proposed pathways involve reduced cytokine production, immune cell-mediated responses, as well as reduced microglia and astrocyte activation in the spinal cord. The aim of this review is to summarize up-to-date information on A3AR in the context of pain, including cellular and molecular mechanisms underlying this effect. Based on their safety profile shown in clinical trials for other pathologies, A3AR agonists are proposed as novel, promising non-narcotic agents for pain control.
Subject(s)
Adenosine A3 Receptor Agonists/therapeutic use , Calcium Signaling/drug effects , Ganglia, Spinal , Pain , Receptor, Adenosine A3/metabolism , Animals , Astrocytes/metabolism , Ganglia, Spinal/metabolism , Ganglia, Spinal/physiopathology , Humans , Microglia/metabolism , Pain/drug therapy , Pain/metabolism , Pain/physiopathologyABSTRACT
Fibromyalgia syndrome (FMS) is characterized by widespread pain and tenderness, and patients typically experience fatigue and emotional distress. The etiology and pathophysiology of fibromyalgia are not fully explained and there are no effective drug treatments. Here we show that IgG from FMS patients produced sensory hypersensitivity by sensitizing nociceptive neurons. Mice treated with IgG from FMS patients displayed increased sensitivity to noxious mechanical and cold stimulation, and nociceptive fibers in skin-nerve preparations from mice treated with FMS IgG displayed an increased responsiveness to cold and mechanical stimulation. These mice also displayed reduced locomotor activity, reduced paw grip strength, and a loss of intraepidermal innervation. In contrast, transfer of IgG-depleted serum from FMS patients or IgG from healthy control subjects had no effect. Patient IgG did not activate naive sensory neurons directly. IgG from FMS patients labeled satellite glial cells and neurons in vivo and in vitro, as well as myelinated fiber tracts and a small number of macrophages and endothelial cells in mouse dorsal root ganglia (DRG), but no cells in the spinal cord. Furthermore, FMS IgG bound to human DRG. Our results demonstrate that IgG from FMS patients produces painful sensory hypersensitivities by sensitizing peripheral nociceptive afferents and suggest that therapies reducing patient IgG titers may be effective for fibromyalgia.
Subject(s)
Fibromyalgia/immunology , Fibromyalgia/physiopathology , Animals , Case-Control Studies , Disease Models, Animal , Female , Fibromyalgia/etiology , Ganglia, Spinal/physiopathology , Humans , Immunization, Passive , Immunoglobulin G/administration & dosage , Immunoglobulin G/blood , Male , Mice , Mice, Inbred C57BL , Nociceptors/immunology , Nociceptors/physiology , Pain/physiopathology , Pain Threshold/physiologyABSTRACT
An exaggerated exercise pressor reflex (EPR) causes excessive sympathoexcitation and exercise intolerance during physical activity in the chronic heart failure (CHF) state. Muscle afferent sensitization contributes to the genesis of the exaggerated EPR in CHF. However, the cellular mechanisms underlying muscle afferent sensitization in CHF remain unclear. Considering that voltage-gated potassium (Kv) channels critically regulate afferent neuronal excitability, we examined the potential role of Kv channels in mediating the sensitized EPR in male rats with CHF. Real-time reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting experiments demonstrate that both mRNA and protein expressions of multiple Kv channel isoforms (Kv1.4, Kv3.4, Kv4.2, and Kv4.3) were downregulated in lumbar dorsal root ganglions (DRGs) of CHF rats compared with sham rats. Immunofluorescence data demonstrate significant decreased Kv channel staining in both NF200-positive and IB4-positive lumbar DRG neurons in CHF rats compared with sham rats. Data from patch-clamp experiments demonstrate that the total Kv current, especially IA, was dramatically decreased in medium-sized IB4-negative muscle afferent neurons (a subpopulation containing mostly Aδ neurons) from CHF rats compared with sham rats, indicating a potential functional loss of Kv channels in muscle afferent Aδ neurons. In in vivo experiments, adenoviral overexpression of Kv4.3 in lumbar DRGs for 1 wk attenuated the exaggerated EPR induced by muscle static contraction and the mechanoreflex by passive stretch without affecting the blunted cardiovascular response to hindlimb arterial injection of capsaicin in CHF rats. These data suggest that Kv channel dysfunction in DRGs plays a critical role in mediating the exaggerated EPR and muscle afferent sensitization in CHF.NEW & NOTEWORTHY The primary finding of this manuscript is that voltage-gated potassium (Kv) channel dysfunction in DRGs plays a critical role in mediating the exaggerated EPR and muscle afferent sensitization in chronic heart failure (CHF). We propose that manipulation of Kv channels in DRG neurons could be considered as a potential new approach to reduce the exaggerated sympathoexcitation and to improve exercise intolerance in CHF, which can ultimately facilitate an improved quality of life and reduce mortality.
Subject(s)
Exercise Tolerance/physiology , Ganglia, Spinal/physiopathology , Heart Failure/physiopathology , Neurons, Afferent/metabolism , Potassium Channels, Voltage-Gated/metabolism , Reflex, Abnormal , Afferent Pathways , Animals , Disease Models, Animal , Ganglia, Spinal/metabolism , Heart Failure/metabolism , Kv1.4 Potassium Channel/metabolism , Male , Muscle, Skeletal/innervation , Patch-Clamp Techniques , Rats , Rats, Sprague-Dawley , Reflex , Shal Potassium Channels/genetics , Shal Potassium Channels/metabolism , Shaw Potassium Channels/metabolismABSTRACT
Chronic pain is regarded to be one of the common and refractory diseases to cure in the clinic. One hundred Hz electroacupuncture (EA) is commonly used for inflammatory pain and 2 Hz for neuropathic pain possibly by modulating the transient receptor potential vanilloid subtype 1 (TRPV1) or the purinergic P2X3 related pathways. To clarify the mechanism of EA under various conditions of pathological pain, rats received a subcutaneous administration of complete Freund's adjuvant (CFA) for inflammatory pain and spared nerve injury (SNI) for neuropathic pain. The EA was performed at the bilateral ST36 and BL60 1 d after CFA or SNI being successfully established for 3 consecutive days. The mechanical hyperalgesia test was measured at baseline, 1 d after model establishment, 1 d and 3 d after EA. The co-expression changes, co-immunoprecipitation of TRPV1 and P2X3, and spontaneous pain behaviors (SPB) test were performed 3 d after EA stimulation. One hundred Hz EA or 2Hz EA stimulation could effectively down-regulate the hyperalgesia of CFA or SNI rats. The increased co-expression ratio between TRPV1 and P2X3 at the dorsal root ganglion (DRG) in two types of pain could be reduced by 100Hz or 2Hz EA intervention. While 100Hz or 2Hz EA was not able to eliminate the direct physical interaction between TRPV1 and P2X3. Moreover, EA could significantly inhibit the SPB induced by the co-activation of peripheral TRPV1 and P2X3. All results indicated that EA could significantly reduce the hyperalgesia and the SPB, which was partly related to inhibiting the co-expression and indirect interaction between peripheral TRPV1 and P2X3.
Subject(s)
Electroacupuncture , Ganglia, Spinal/metabolism , Hyperalgesia/therapy , Neuralgia/therapy , Receptors, Purinergic P2X3/metabolism , TRPV Cation Channels/metabolism , Animals , Disease Models, Animal , Ganglia, Spinal/physiopathology , Hyperalgesia/metabolism , Hyperalgesia/physiopathology , Male , Neuralgia/metabolism , Neuralgia/physiopathology , Pain Threshold , Rats, Sprague-Dawley , Signal TransductionABSTRACT
BACKGROUND: Remifentanil can induce postinfusion cold hyperalgesia. N-methyl-d-aspartate receptor (NMDAR) activation and upregulation of transient receptor potential melastatin 8 (TRPM8) membrane trafficking in dorsal root ganglion (DRG) are critical to cold hyperalgesia derived from neuropathic pain, and TRPM8 activation causes NMDAR-dependent cold response. Contribution of P2Y1 purinergic receptor (P2Y1R) activation in DRG to cold pain hypersensitivity and NMDAR activation induced by P2Y1R upregulation in neurons are also unraveled. This study explores whether P2Y1R contributes to remifentanil-induced cold hyperalgesia via TRPM8-dependent regulation of NMDAR phosphorylation in DRG. METHODS: Rats with remifentanil-induced cold hyperalgesia were injected with TRPM8 antagonist or P2Y1R antagonist at 10 minutes before remifentanil infusion. Cold hyperalgesia (paw lift number and withdrawal duration on cold plate) was measured at -24, 2, 6, 24, and 48 hours following remifentanil infusion. After the last behavioral test, P2Y1R expression, TRPM8 expression and membrane trafficking, and NMDAR subunit (NR1 and NR2B) expression and phosphorylation in DRG were detected by western blot, and colocalization of P2Y1R with TRPM8 was determined by double-labeling immunofluorescence. Two-way repeated measures analysis of variance (ANOVA) or 2 × 2 factorial design ANOVA with repeated measures was used to analyze behavioral data of cold hyperalgesia. One-way ANOVA followed by Bonferroni post hoc comparisons was used to analyze the data in western blot and immunofluorescence. RESULTS: Remifentanil infusion (1 µg·kg-1·min-1 for 60 minutes) induced cold hyperalgesia (hyperalgesia versus control, paw lift number and withdrawal duration on cold plate at 2-48 hours, P < .0001) with upregulated NR1 (hyperalgesia versus naive, 48 hours, mean ± standard deviation [SD], 114.00% ± 12.48% vs 41.75% ± 5.20%, P < .005) and NR2B subunits expression (104.13% ± 8.37% vs 24.63% ± 4.87%, P < .005), NR1 phosphorylation at Ser896 (91.88% ± 7.08% vs 52.00% ± 7.31%, P < .005) and NR2B phosphorylation at Tyr1472 (115.75% ± 8.68% vs 59.75% ± 7.78%, P < .005), TRPM8 expression (115.38% ± 9.27% vs 40.50% ± 4.07%, P < .005) and membrane trafficking (112.88% ± 5.62% vs 48.88% ± 6.49%, P < .005), and P2Y1R expression (128.25% ± 14.86% vs 45.13% ± 7.97%, P < .005) in DRG. Both TRPM8 and P2Y1R antagonists attenuated remifentanil-induced cold hyperalgesia and downregulated increased NR1 and NR2B expression and phosphorylation induced by remifentanil (remifentanil + RQ-00203078 versus remifentanil + saline, NR1 phosphorylation, 69.38% ± 3.66% vs 92.13% ± 4.85%; NR2B phosphorylation, 72.25% ± 6.43% vs 111.75% ± 11.00%, P < .0001). NMDAR activation abolished inhibition of TRPM8 and P2Y1R antagonists on remifentanil-induced cold hyperalgesia. P2Y1R antagonist inhibited remifentanil-evoked elevations in TRPM8 expression and membrane trafficking and P2Y1R-TRPM8 coexpression (remifentanil + 2'-deoxy-N6-methyl adenosine 3',5'-diphosphate [MRS2179] versus remifentanil + saline, coexpression, 8.33% ± 1.33% vs 22.19% ± 2.15%, P < .0001). CONCLUSIONS: Attenuation of remifentanil-induced cold hyperalgesia by P2Y1R inhibition is attributed to downregulations in NMDAR expression and phosphorylation via diminishing TRPM8 expression and membrane trafficking in DRG.
Subject(s)
Ganglia, Spinal/metabolism , Hyperalgesia/metabolism , Pain Threshold , Receptors, N-Methyl-D-Aspartate/metabolism , Receptors, Purinergic P2Y1/metabolism , TRPM Cation Channels/metabolism , Analgesics/pharmacology , Animals , Behavior, Animal , Cold Temperature , Disease Models, Animal , Ganglia, Spinal/drug effects , Ganglia, Spinal/physiopathology , Hyperalgesia/chemically induced , Hyperalgesia/physiopathology , Hyperalgesia/prevention & control , Male , Pain Threshold/drug effects , Phosphorylation , Protein Transport , Purinergic P2Y Receptor Antagonists/pharmacology , Rats, Sprague-Dawley , Receptors, Purinergic P2Y1/drug effects , Remifentanil , Signal Transduction , TRPM Cation Channels/antagonists & inhibitorsABSTRACT
BACKGROUND: Postherpetic neuralgia (PHN) is common in elderly patients and can be alleviated by pulsed radiofrequency (PRF). However, PRF treatments display different efficacy on different nerves. The purpose of this study was to evaluate the efficacy and safety of ultrasound-guided PRF modulation on thoracic dorsal root ganglion (DRG) or intercostal nerve (ICN) for PHN in aged patients and to provide a theoretical basis for clinical treatment. METHODS: We classified aged patients into two groups, DRG group and ICN group, based on the needle tip position. Visual analogue scale (VAS) and concise health status questionnaire (Short-form 36 health/survey questionnaire, SF-36) were used to evaluate the pain intensity and the life quality of the patients before and 2, 4 and 12 weeks after the PRF treatments. We also recorded the adverse reactions during the treatments. RESULTS: After the PRF treatment, the scores of VAS and SF-36 (assessing general health perception, social function, emotional role, mental health, and pain) improved significantly in both groups (P < 0.05). The mean VAS score in the DRG group was significantly lower than that in the ICN group 2 weeks after treatment, and remained for 12 weeks. The SF-36 scores in the DRG group were significantly higher than those in the ICN group (P < 0.05). We found a similar incidence of adverse reactions between the two groups (P > 0.05). CONCLUSIONS: PRF therapy is safe and effective for elderly patients with postherpetic neuralgia. However, PRF treatment in dorsal root ganglion is superior to that in intercostal nerve with improving VAS and SF-36 scores to a greater extent in older patients. TRIAL REGISTRATION: ChiCTR2100044176 .
Subject(s)
Ganglia, Spinal/physiopathology , Intercostal Nerves/physiopathology , Neuralgia, Postherpetic/therapy , Pulsed Radiofrequency Treatment , Aged , Emotions , Female , Ganglia, Spinal/diagnostic imaging , Humans , Male , Mental Health , Neuralgia, Postherpetic/pathology , Pain Management , Retrospective Studies , Treatment OutcomeABSTRACT
Neuropathic pain is one of the important challenges in the clinic. Although a lot of research has been done on neuropathic pain (NP), the molecular mechanism is still elusive. We aimed to investigate whether the Wnt/ß-catenin pathway was involved in NP caused by sustaining dorsal root ganglion (DRG) compression with the chronic compression of dorsal root ganglion model (CCD). Our RNA sequencing results showed that several genes related to the Wnt pathway have changed in DRG and spinal cord dorsal horn (SCDH) after CCD surgery. Therefore, we detected the activation of the Wnt/ß-catenin pathway in DRG and SCDH and found active ß-catenin significantly upregulated in DRG and SCDH 1 day after CCD surgery and peaked on days 7-14. Immunofluorescence results also confirmed nuclear translocalization of active ß-catenin in DRG and SCDH. Additionally, rats had obvious mechanical induced pain after CCD surgery and the pain was significantly alleviated after the application of the Wnt/ß-catenin pathway inhibitor XAV939. Furthermore, we found that the levels of proinflammatory factors tumor necrosis factor-α (TNF-α) and interleukin-18 (IL-18) were significantly elevated in CCD rat serum, while the levels of them were correspondingly decreased after the Wnt/ß-catenin pathway being inhibited. The results of Spearman correlation coefficient analysis showed that the levels of TNF-α and IL-18 were negatively correlated with the mechanical withdrawal thresholds (MWT) after CCD surgery. Collectively, our findings suggest that the Wnt/ß-catenin pathway plays a critical role in the pathogenesis of NP and may be an effective target for the treatment of NP.
Subject(s)
Cytokines/metabolism , Ganglia, Spinal/metabolism , Neuralgia/metabolism , Spinal Cord Compression/metabolism , Wnt Signaling Pathway , beta Catenin , Animals , Chronic Disease , Ganglia, Spinal/physiopathology , Heterocyclic Compounds, 3-Ring/pharmacology , Heterocyclic Compounds, 3-Ring/therapeutic use , Interleukin-18/metabolism , Male , Neuralgia/drug therapy , Pain Measurement , Pain Threshold , Posterior Horn Cells , Rats , Rats, Sprague-Dawley , Spinal Cord Compression/physiopathology , Tumor Necrosis Factor-alpha/metabolism , Wnt Signaling Pathway/drug effects , beta Catenin/drug effectsABSTRACT
In humans, intradermal administration of ß-alanine (ALA) and bovine adrenal medulla peptide 8-22 (BAM8-22) evokes the sensation of itch. Currently, it is unknown which human dorsal root ganglion (DRG) neurons express the receptors of these pruritogens, MRGPRD and MRGPRX1, respectively, and which cutaneous afferents these pruritogens activate in primate. In situ hybridization studies revealed that MRGPRD and MRGPRX1 are co-expressed in a subpopulation of TRPV1+ human DRG neurons. In electrophysiological recordings in nonhuman primates (Macaca nemestrina), subtypes of polymodal C-fiber nociceptors are preferentially activated by ALA and BAM8-22, with significant overlap. When pruritogens ALA, BAM8-22, and histamine, which activate different subclasses of C-fiber afferents, are administered in combination, human volunteers report itch and nociceptive sensations similar to those induced by a single pruritogen. Our results provide evidence for differences in pruriceptive processing between primates and rodents, and do not support the spatial contrast theory of coding of itch and pain.