RESUMEN
Microneedle array patches (MAPs) are extensively studied for transdermal drug delivery. Additive manufacturing enables precise control over MAP customization and rapid fabrication. However, the scope of 3D-printable, bioresorbable materials is limited. Dexamethasone (DXM) is widely used to manage inflammation and pain, but its application is limited by systemic side effects. Thus, it is crucial to achieve high local drug concentrations while maintaining low serum levels. Here, poly(propylene fumarate-co-propylene succinate) oligomers are fabricated into DXM-loaded, bioresorbable MAPs via continuous liquid interface production 3D printing. Thiol-ene click chemistry yields MAPs with tailorable mechanical and degradation properties. DXM-loaded MAPs exhibit controlled elution of drug in vitro. Transdermal application of DXM-loaded MAPs in a murine tibial fracture model leads to substantial relief of postoperative pain. Pharmacokinetic analysis shows that MAP administration is able to control pain at a significantly lower dose than intravenous administration. This work expands the material properties of 3D-printed poly(propylene fumarate-co-propylene succinate) copolyesters and their use in drug delivery applications.
RESUMEN
G protein-coupled receptor 37-like 1 (GPR37L1) is an orphan GPCR with largely unknown functions. Here, we report that Gpr37l1/GRP37L1 ranks among the most highly expressed GPCR transcripts in mouse and human dorsal root ganglia (DRGs) and is selectively expressed in satellite glial cells (SGCs). Peripheral neuropathy induced by streptozotoxin (STZ) and paclitaxel (PTX) led to reduced GPR37L1 expression on the plasma membrane in mouse and human DRGs. Transgenic mice with Gpr37l1 deficiency exhibited impaired resolution of neuropathic pain symptoms following PTX- and STZ-induced pain, whereas overexpression of Gpr37l1 in mouse DRGs reversed pain. GPR37L1 is coexpressed with potassium channels, including KCNJ10 (Kir4.1) in mouse SGCs and both KCNJ3 (Kir3.1) and KCNJ10 in human SGCs. GPR37L1 regulates the surface expression and function of the potassium channels. Notably, the proresolving lipid mediator maresin 1 (MaR1) serves as a ligand of GPR37L1 and enhances KCNJ10- or KCNJ3-mediated potassium influx in SGCs through GPR37L1. Chemotherapy suppressed KCNJ10 expression and function in SGCs, which MaR1 rescued through GPR37L1. Finally, genetic analysis revealed that the GPR37L1-E296K variant increased chronic pain risk by destabilizing the protein and impairing the protein's function. Thus, GPR37L1 in SGCs offers a therapeutic target for the protection of neuropathy and chronic pain.
Asunto(s)
Ácidos Docosahexaenoicos , Ganglios Espinales , Neuroglía , Receptores Acoplados a Proteínas G , Transducción de Señal , Animales , Humanos , Masculino , Ratones , Ganglios Espinales/metabolismo , Homeostasis , Ratones Noqueados , Ratones Transgénicos , Neuralgia/metabolismo , Neuralgia/genética , Neuralgia/patología , Neuroglía/metabolismo , Canales de Potasio de Rectificación Interna/metabolismo , Canales de Potasio de Rectificación Interna/genética , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismoRESUMEN
Urinary tract infections (UTIs) account for almost 25% of infections in women. Many are recurrent (rUTI), with patients frequently experiencing chronic pelvic pain and urinary frequency despite clearance of bacteriuria after antibiotics. To elucidate the basis for these bacteria-independent bladder symptoms, we examined the bladders of patients with rUTI. We noticed a notable increase in neuropeptide content in the lamina propria and indications of enhanced nociceptive activity. In mice subjected to rUTI, we observed sensory nerve sprouting that was associated with nerve growth factor (NGF) produced by recruited monocytes and tissue-resident mast cells. Treatment of rUTI mice with an NGF-neutralizing antibody prevented sprouting and alleviated pelvic sensitivity, whereas instillation of native NGF into naïve mice bladders mimicked nerve sprouting and pain behavior. Nerve activation, pain, and urinary frequency were each linked to the presence of proximal mast cells, because mast cell deficiency or treatment with antagonists against receptors of several direct or indirect mast cell products was each effective therapeutically. Thus, our findings suggest that NGF-driven sensory sprouting in the bladder coupled with chronic mast cell activation represents an underlying mechanism driving bacteria-independent pain and voiding defects experienced by patients with rUTI.
Asunto(s)
Mastocitos , Vejiga Urinaria , Humanos , Ratones , Femenino , Animales , Vejiga Urinaria/inervación , Vejiga Urinaria/metabolismo , Factor de Crecimiento Nervioso/metabolismo , Reinfección/complicaciones , Reinfección/metabolismo , Dolor/etiología , Dolor/metabolismo , Dolor/prevención & controlRESUMEN
ABSTRACT: Secreted microRNAs (miRNAs) have been detected in various body fluids including the cerebrospinal fluid, yet their direct role in regulating synaptic transmission remains uncertain. We found that intrathecal injection of low dose of let-7b (1 µg) induced short-term (<24 hours) mechanical allodynia and heat hyperalgesia, a response that is compromised in Tlr7-/- or Trpa1-/- mice. Ex vivo and in vivo calcium imaging in GCaMP6-report mice revealed increased calcium signal in spinal cord afferent terminals and doral root ganglion/dorsal root ganglia neurons following spinal perfusion and intraplantar injection of let-7b. Patch-clamp recordings also demonstrated enhanced excitatory synaptic transmission (miniature excitatory postsynaptic currents [EPSCs]) in spinal nociceptive neurons following let-7b perfusion or optogenetic activation of axonal terminals. The elevation in spinal calcium signaling and EPSCs was dependent on the presence of toll-like receptor-7 (TLR7) and transient receptor potential ion channel subtype A1 (TRPA1). In addition, endogenous let-7b is enriched in spinal cord synaptosome, and peripheral inflammation increased let-7b in doral root ganglion/dorsal root ganglia neurons, spinal cord tissue, and the cerebrospinal fluid. Notably, let-7b antagomir inhibited inflammatory pain and inflammation-induced synaptic plasticity (EPSC increase), suggesting an endogenous role of let-7b in regulating pain and synaptic transmission. Furthermore, intrathecal injection of let-7b, at a higher dose (10 µg), induced persistent mechanical allodynia for >2 weeks, which was abolished in Tlr7-/- mice. The high dose of let-7b also induced microgliosis in the spinal cord. Of interest, intrathecal minocycline only inhibited let-7b-induced mechanical allodynia in male but not female mice. Our findings indicate that the secreted microRNA let-7b has the capacity to provoke pain through both neuronal and glial signaling, thereby establishing miRNA as an emerging neuromodulator.
Asunto(s)
MicroARNs , Microglía , Médula Espinal , Transmisión Sináptica , Animales , Masculino , Ratones , Potenciales Postsinápticos Excitadores/fisiología , Ganglios Espinales/metabolismo , Hiperalgesia/fisiopatología , Hiperalgesia/metabolismo , Glicoproteínas de Membrana , Ratones Endogámicos C57BL , Ratones Noqueados , Microglía/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , Neuronas/metabolismo , Nociceptores/metabolismo , Nociceptores/fisiología , Transducción de Señal/fisiología , Médula Espinal/metabolismo , Médula Espinal/fisiopatología , Transmisión Sináptica/fisiología , Receptor Toll-Like 7/metabolismo , Receptor Toll-Like 7/genética , Canal Catiónico TRPA1/metabolismo , Canal Catiónico TRPA1/genéticaRESUMEN
Microglia, resident immune cells in the central nervous system, play a role in neuroinflammation and the development of neuropathic pain. We found that the stimulator of interferon genes (STING) is predominantly expressed in spinal microglia and upregulated after peripheral nerve injury. However, mechanical allodynia, as a marker of neuropathic pain following peripheral nerve injury, did not require microglial STING expression. In contrast, STING activation by specific agonists (ADU-S100, 35 nmol) significantly alleviated neuropathic pain in male mice, but not female mice. STING activation in female mice leads to increase in proinflammatory cytokines that may counteract the analgesic effect of ADU-S100. Microglial STING expression and type I interferon-ß (IFN-ß) signaling were required for the analgesic effects of STING agonists in male mice. Mechanistically, downstream activation of TANK-binding kinase 1 (TBK1) and the production of IFN-ß, may partly account for the analgesic effect observed. These findings suggest that STING activation in spinal microglia could be a potential therapeutic intervention for neuropathic pain, particularly in males.
Asunto(s)
Neuralgia , Traumatismos de los Nervios Periféricos , Animales , Femenino , Masculino , Ratones , Analgésicos , Anticuerpos , Microglía , Traumatismos de los Nervios Periféricos/complicacionesRESUMEN
G protein coupled receptor 37-like 1 (GPR37L1) is an orphan GPCR and its function remains largely unknown. Here we report that GPR37L1 transcript is highly expressed compared to all known GPCRs in mouse and human dorsal root ganglia (DRGs) and selectively expressed in satellite glial cells (SGCs). Peripheral neuropathy following diabetes and chemotherapy by streptozotocin and paclitaxel resulted in downregulations of surface GPR37L1 in mouse and human DRGs. Transgenic mice with Gpr37l1 deficiency exhibited impaired resolution of neuropathic pain symptom (mechanical allodynia), whereas overexpression of Gpr37l1 in mouse DRGs can reverse neuropathic pain. Notably, GPR37L1 is co-expressed and coupled with potassium channels in SGCs. We found striking species differences in potassium channel expression in SGCs, with predominant expression of KCNJ10 and KCNJ3 in mouse and human SGCs, respectively. GPR37L1 regulates the surface expression and function of KCNJ10 and KCNJ3. We identified the pro-resolving lipid mediator maresin 1 (MaR1) as a GPR37L1 ligand. MaR1 increases KCNJ10/KCNJ3-mediated potassium influx in SGCs via GPR37L1. MaR1 protected chemotherapy-induced suppression of KCNJ13/KCNJ10 expression and function in SGCs. Finally, genetic analysis revealed that the GPR37L1-E296K variant is associated with increased chronic pain risk by destabilizing the protein. Thus, GPR37L1 in SGCs offers a new target for neuropathy protection and pain control.
RESUMEN
In this study, Perez-Sanchez et al.1 developed a chemogenetic method aimed at alleviating pain in mouse models while dampening excitability in human sensory neurons. This analgesic effect was attained through the introduction of human α7 nicotinic acetylcholine receptor and glycine receptor pore domain via virus-mediated expression in sensory neurons, forming a chloride channel. The activation of this channel was made possible by specific agonists. This study highlights the potential for treating clinical pain by gene therapy.
Asunto(s)
Manejo del Dolor , Células Receptoras Sensoriales , Ratones , Animales , Humanos , Dolor/tratamiento farmacológico , Receptor Nicotínico de Acetilcolina alfa 7/agonistas , Receptor Nicotínico de Acetilcolina alfa 7/fisiologíaRESUMEN
PURPOSE: Severe acute pain after Cesarean delivery increases the risk of developing persistent pain (~20% incidence) and postpartum depression (PPD) (~15% incidence). Both conditions contribute to maternal morbidity and mortality, yet early risk stratification remains challenging. Neuroinflammation has emerged as a key mechanism of persistent pain and depression in nonobstetric populations. Nevertheless, most studies focus on plasma cytokines, and the relationship between plasma and cerebrospinal fluid (CSF) cytokine levels is unclear. Our primary aim was to compare inflammatory marker levels between patients who developed the composite outcome of persistent pain and/or PPD vs those who did not. METHODS: We recruited term patients with singleton pregnancies undergoing elective Cesarean delivery under neuraxial anesthesia into an exploratory prospective cohort study. We collected baseline demographic, obstetric, and Edinburgh Postnatal Depression Scale information, and performed quantitative sensory tests. Plasma was collected preoperatively and 48 hr postoperatively. In the operating room, 10 mL of CSF was collected, followed by a standardized anesthetic. Intra- and postoperative management were according to standard practice. We obtained Edinburgh Postnatal Depression Scale and pain scores at six weeks and three months after delivery. The primary outcome was persistent pain and/or PPD at three months. We analyzed the difference in inflammatory marker levels between the groups (primary aim) using two-sided Mann-Whitney tests. RESULTS: Eighty participants were enrolled, and 63 patients completed the study; 23 (37%) experienced the primary outcome at three months. Preoperative plasma transforming growth factor beta 1 (TGF-ß1) concentration was higher in patients who developed the primary outcome compared with those who did not (median [interquartile range (IQR)], 2,879 [2,241-5,494] vs 2,292 [1,676-2,960] pg·mL-1; P = 0.04), while CSF IL-1ß concentration was higher in patients who developed the primary outcome than in those who did not (median [IQR], 0.36 [0.29-0.39] vs 0.30 [0.25-0.35] pg·mL-1; P = 0.03). CONCLUSIONS: We observed differential levels of plasma and CSF inflammatory biomarkers in patients who developed persistent pain and PPD compared with those who did not. We showed the feasibility of collecting plasma and CSF samples at Cesarean delivery, which may prove useful for future risk-stratification. STUDY REGISTRATION: ClinicalTrials.gov (NCT04271072); registered 17 February 2020.
RéSUMé: OBJECTIF: La douleur aiguë sévère après un accouchement par césarienne augmente le risque de douleur persistante (~20 % d'incidence) et de dépression post-partum (DPP) (~15 % d'incidence). Ces deux conditions contribuent à la morbidité et à la mortalité maternelles, mais la stratification précoce des risques demeure difficile. La neuroinflammation est apparue comme un mécanisme clé de la douleur persistante et de la dépression dans les populations non obstétricales. Néanmoins, la plupart des études se concentrent sur les cytokines plasmatiques, et la relation entre les taux de cytokines plasmatiques et de liquide céphalorachidien (LCR) n'est pas claire. Notre objectif principal était de comparer les taux de marqueurs inflammatoires entre les patient·es qui ont eu un résultat composite de douleur persistante et/ou de DPP vs les personnes qui n'en ont pas eu. MéTHODE: Nous avons recruté des patient·es à terme avec des grossesses uniques bénéficiant d'une césarienne programmée sous anesthésie neuraxiale dans une étude de cohorte prospective exploratoire. Nous avons recueilli des informations démographiques de base, obstétricales et tirées de l'Échelle de dépression postnatale d'Édimbourg, et effectué des tests sensoriels quantitatifs. Le plasma a été prélevé avant l'opération et 48 heures après l'opération. En salle d'opération, 10 mL de LCR ont été recueillis, suivis d'un anesthésie standardisée. La prise en charge per- et postopératoire était conforme à la pratique courante. Nous avons obtenu les scores sur l'Échelle de dépression postnatale d'Édimbourg et les scores de douleur six semaines et trois mois après l'accouchement. Le critère d'évaluation principal était la douleur persistante et/ou la DPP à trois mois. Nous avons analysé la différence dans les niveaux de marqueurs inflammatoires entre les groupes (objectif principal) en utilisant des tests bilatéraux de Mann-Whitney. RéSULTATS: Quatre-vingts personnes ont été recrutées et 63 patient·es ont terminé l'étude; 23 (37 %) ont rapporté le critère d'évaluation principal à trois mois. Le facteur TGF-ß1 (transforming growth factor beta 1) plasmatique préopératoire était plus élevé chez les patient·es qui ont manifesté le critère d'évaluation principal par rapport aux personnes qui ne l'ont pas manifesté (médiane [écart interquartile (ÉIQ)], 2879 [2241-5494] vs 2292 [16762960] pg·mL−1; P = 0,04), tandis que le IL-1ß dans le LCR était plus élevé chez les patient·es qui ont manifesté le critère d'évaluation principal que chez les personnes qui ne l'ont pas manifesté (médiane [ÉIQ], 0,36 [0,29-0,39] vs 0,30 [0,250,35] pg·mL−1; P = 0,03). CONCLUSION: Nous avons observé des taux différentiels de biomarqueurs inflammatoires plasmatiques et de LCR chez les patient·es qui ont manifesté une douleur persistante et une DPP par rapport aux personnes qui n'en ont pas manifesté. Nous avons montré la faisabilité de la collecte d'échantillons de plasma et de LCR lors de l'accouchement par césarienne, ce qui pourrait s'avérer utile pour la stratification future des risques. ENREGISTREMENT DE L'éTUDE: clinicaltrials.gov (NCT04271072); enregistrée le 17 février 2020.
Asunto(s)
Depresión Posparto , Embarazo , Femenino , Humanos , Depresión Posparto/epidemiología , Depresión Posparto/etiología , Estudios Prospectivos , Cesárea , Dolor/etiologíaRESUMEN
INTRODUCTION: Current treatments for chronic pain are inadequate. Here, we provide an update on the new therapeutic strategies that target dorsal root ganglia (DRGs) in the peripheral nervous system for a better and safer treatment of chronic pain. AREAS COVERED: Despite the complex nature of chronic pain and its underlying mechanisms, we do know that changes in the plasticity and modality of neurons in DRGs play a pivotal role. DRG neurons are heterogenous and offer potential pain targets for different therapeutic interventions. We discuss the last advancements of these interventions, which include the use of systemic and local administrations, selective nerve drug delivery, and gene therapy. In particular, we provide updates and further details on the molecular characterization of primary sensory neurons, new analgesics entering the market, and future gene therapy approaches. EXPERT OPINION: DRGs and primary sensory neurons are promising targets for chronic pain treatment due to their key role in pain signaling, unique anatomical location, and the potential for different targeted therapeutic interventions.
Asunto(s)
Dolor Crónico , Humanos , Dolor Crónico/tratamiento farmacológico , Ganglios Espinales , Analgésicos , Células Receptoras SensorialesRESUMEN
Programmed death protein 1 (PD-1) and its ligand PD-L1 constitute an immune checkpoint pathway. We report that neuronal PD-1 signaling regulates learning/memory in health and disease. Mice lacking PD-1 (encoded by Pdcd1) exhibit enhanced long-term potentiation (LTP) and memory. Intraventricular administration of anti-mouse PD-1 monoclonal antibody (RMP1-14) potentiated learning and memory. Selective deletion of PD-1 in excitatory neurons (but not microglia) also enhances LTP and memory. Traumatic brain injury (TBI) impairs learning and memory, which is rescued by Pdcd1 deletion or intraventricular PD-1 blockade. Conversely, re-expression of Pdcd1 in PD-1-deficient hippocampal neurons suppresses memory and LTP. Exogenous PD-L1 suppresses learning/memory in mice and the excitability of mouse and NHP hippocampal neurons through PD-1. Notably, neuronal activation suppresses PD-L1 secretion, and PD-L1/PD-1 signaling is distinctly regulated by learning and TBI. Thus, conditions that reduce PD-L1 levels or PD-1 signaling could promote memory in both physiological and pathological conditions.
Asunto(s)
Antígeno B7-H1 , Lesiones Traumáticas del Encéfalo , Humanos , Antígeno B7-H1/metabolismo , Receptor de Muerte Celular Programada 1/genética , Receptor de Muerte Celular Programada 1/metabolismo , Aprendizaje , Hipocampo/metabolismo , Anticuerpos Monoclonales/metabolismo , Neuronas/metabolismoRESUMEN
It is generally believed that immune activation can elicit pain through production of inflammatory mediators that can activate nociceptive sensory neurons. Emerging evidence suggests that immune activation may also contribute to the resolution of pain by producing distinct pro-resolution/anti-inflammatory mediators. Recent research into the connection between the immune and nervous systems has opened new avenues for immunotherapy in pain management. This review provides an overview of the most utilized forms of immunotherapies (e.g., biologics) and highlight their potential for immune and neuronal modulation in chronic pain. Specifically, we discuss pain-related immunotherapy mechanisms that target inflammatory cytokine pathways, the PD-L1/PD-1 pathway, and the cGAS/STING pathway. This review also highlights cell-based immunotherapies targeting macrophages, T cells, neutrophils and mesenchymal stromal cells for chronic pain management.
Asunto(s)
Dolor Crónico , Humanos , Dolor Crónico/terapia , Neuroinmunomodulación , Inmunoterapia , Citocinas , NeuronasRESUMEN
Chemotherapy-induced peripheral neuropathy (CIPN) is the most prevalent neurological complication of chemotherapy for cancer, and has limited effective treatment options. Autologous conditioned serum (ACS) is an effective biologic therapy used by intra-articular injection for patients with osteoarthritis. However, ACS has not been systematically tested in the treatment of peripheral neuropathies such as CIPN. It has been generally assumed that the analgesic effect of this biologic therapy results from augmented concentrations of anti-inflammatory cytokines and growth factors. Here we report that a single intrathecal injection of human conditioned serum (hCS) produced long-lasting inhibition of paclitaxel chemotherapy-induced neuropathic pain (mechanical allodynia) in mice, without causing motor impairment. Strikingly, the analgesic effect of hCS in our experiments was maintained even 8 weeks after the treatment, compared with non-conditioned human serum (hNCS). Furthermore, the hCS transfer-induced pain relief in mice was fully recapitulated by rat or mouse CS transfer to mice of both sexes, indicating cross-species and cross-sex effectiveness. Mechanistically, CS treatment blocked the chemotherapy-induced glial reaction in the spinal cord and improved nerve conduction. Compared to NCS, CS contained significantly higher concentrations of anti-inflammatory and pro-resolving mediators, including IL-1Ra, TIMP-1, TGF-ß1, and resolvins D1/D2. Intrathecal injection of anti-TGF-ß1 and anti-Il-1Ra antibody transiently reversed the analgesic action of CS. Nanoparticle tracking analysis revealed that rat conditioned serum contained a significantly greater number of exosomes than NCS. Importantly, the removal of exosomes by high-speed centrifugation largely diminished the CS-produced pain relief, suggesting a critical involvement of small vesicles (exosomes) in the beneficial effects of CS. Together, our findings demonstrate that intrathecal CS produces a remarkable resolution of neuropathic pain mediated through a combination of small vesicles/exosomes and neuroimmune/neuroglial modulation.
Asunto(s)
Antineoplásicos , Exosomas , Neuralgia , Masculino , Femenino , Ratones , Ratas , Humanos , Animales , Exosomas/metabolismo , Neuralgia/metabolismo , Paclitaxel/efectos adversos , Hiperalgesia/metabolismo , Médula Espinal/metabolismo , Analgésicos/farmacología , Antineoplásicos/efectos adversosRESUMEN
IgE-mediated anaphylaxis is an acute life-threatening systemic reaction to allergens, including certain foods and venoms. Anaphylaxis is triggered when blood-borne allergens activate IgE-bound perivascular mast cells (MCs) throughout the body, causing an extensive systemic release of MC mediators. Through precipitating vasodilatation and vascular leakage, these mediators are believed to trigger a sharp drop in blood pressure in humans and in core body temperature in animals. We report that the IgE/MC-mediated drop in body temperature in mice associated with anaphylaxis also requires the body's thermoregulatory neural circuit. This circuit is activated when granule-borne chymase from MCs is deposited on proximal TRPV1+ sensory neurons and stimulates them via protease-activated receptor-1. This triggers the activation of the body's thermoregulatory neural network, which rapidly attenuates brown adipose tissue thermogenesis to cause hypothermia. Mice deficient in either chymase or TRPV1 exhibited limited IgE-mediated anaphylaxis, and, in wild-type mice, anaphylaxis could be recapitulated simply by systemically activating TRPV1+ sensory neurons. Thus, in addition to their well-known effects on the vasculature, MC products, especially chymase, promote IgE-mediated anaphylaxis by activating the thermoregulatory neural circuit.
Asunto(s)
Anafilaxia , Hipotermia , Ratones , Humanos , Animales , Quimasas , Mastocitos , Inmunoglobulina E , Alérgenos , NeuronasRESUMEN
Preclinical studies have identified glial cells as pivotal players in the genesis and maintenance of neuropathic pain after nerve injury associated with diabetes, chemotherapy, major surgeries, and virus infections. Satellite glial cells (SGCs) in the dorsal root and trigeminal ganglia of the peripheral nervous system (PNS) and astrocytes in the central nervous system (CNS) express similar molecular markers and are protective under physiological conditions. They also serve similar functions in the genesis and maintenance of neuropathic pain, downregulating some of their homeostatic functions and driving pro-inflammatory neuro-glial interactions in the PNS and CNS, i.e., "gliopathy". However, the role of SGCs in neuropathic pain is not simply as "peripheral astrocytes". We delineate how these peripheral and central glia participate in neuropathic pain by producing different mediators, engaging different parts of neurons, and becoming active at different stages following nerve injury. Finally, we highlight the recent findings that SGCs are enriched with proteins related to fatty acid metabolism and signaling such as Apo-E, FABP7, and LPAR1. Targeting SGCs and astrocytes may lead to novel therapeutics for the treatment of neuropathic pain.
Asunto(s)
Astrocitos , Neuralgia , Humanos , Ganglios Espinales/metabolismo , Neuroglía/metabolismo , Neuralgia/metabolismo , Neuronas/metabolismoRESUMEN
Excessive inflammation has been implicated in autism spectrum disorder (ASD), but the underlying mechanisms have not been fully studied. SHANK3 is a synaptic scaffolding protein and mutations of SHANK3 are involved in ASD. Shank3 expression in dorsal root ganglion sensory neurons also regulates heat pain and touch. However, the role of Shank3 in the vagus system remains unknown. We induced systemic inflammation by lipopolysaccharide (LPS) and measured body temperature and serum IL-6 levels in mice. We found that homozygous and heterozygous Shank3 deficiency, but not Shank2 and Trpv1 deficiency, aggravates hypothermia, systemic inflammation (serum IL-6 levels), and sepsis mortality in mice, induced by lipopolysaccharide (LPS). Furthermore, these deficits can be recapitulated by specific deletion of Shank3 in Nav1.8-expressing sensory neurons in conditional knockout (CKO) mice or by selective knockdown of Shank3 or Trpm2 in vagal sensory neurons in nodose ganglion (NG). Mice with Shank3 deficiency have normal basal core temperature but fail to adjust body temperature after perturbations with lower or higher body temperatures or auricular vagus nerve stimulation. In situ hybridization with RNAscope revealed that Shank3 is broadly expressed by vagal sensory neurons and this expression was largely lost in Shank3 cKO mice. Mechanistically, Shank3 regulates the expression of Trpm2 in NG, as Trpm2 but not Trpv1 mRNA levels in NG were significantly reduced in Shank3 KO mice. Our findings demonstrated a novel molecular mechanism by which Shank3 in vagal sensory neurons regulates body temperature, inflammation, and sepsis. We also provided new insights into inflammation dysregulation in ASD.
Asunto(s)
Trastorno del Espectro Autista , Sepsis , Canales Catiónicos TRPM , Ratones , Animales , Temperatura Corporal , Lipopolisacáridos , Interleucina-6 , Células Receptoras Sensoriales , Inflamación , Proteínas de Microfilamentos , Proteínas del Tejido Nervioso/genéticaRESUMEN
Mechanical distension/stretch in the colon provokes visceral hypersensitivity and pain. In this issue of Neuron, Xie et al. report that mechanosensitive Piezo2 channels, expressed by TRPV1-lineage nociceptors, are involved in visceral mechanical nociception and hypersensitivity.
Asunto(s)
Colon , Canales Iónicos , Dolor , Canales Catiónicos TRPV , Colon/fisiología , Canales Iónicos/fisiología , Neuronas , Nociceptores/fisiología , Canales Catiónicos TRPV/genéticaRESUMEN
Our understanding of neuropathic itch is limited due to a lack of relevant animal models. Patients with cutaneous T cell lymphoma (CTCL) experience severe itching. Here, we characterize a mouse model of chronic itch with remarkable lymphoma growth, immune cell accumulation, and persistent pruritus. Intradermal CTCL inoculation produced time-dependent changes in nerve innervations in lymphoma-bearing skin. In the early phase (20 days), CTCL caused hyperinnervations in the epidermis. However, chronic itch was associated with loss of epidermal nerve fibers in the late phases (40 and 60 days). CTCL was also characterized by marked nerve innervations in mouse lymphoma. Blockade of C-fibers reduced pruritus at early and late phases, whereas blockade of A-fibers only suppressed late-phase itch. Intrathecal (i.t.) gabapentin injection reduced late-phase, but not early-phase, pruritus. IL-31 was upregulated in mouse lymphoma, whereas its receptor Il31ra was persistently upregulated in Trpv1-expressing sensory neurons in mice with CTCL. Intratumoral anti-IL-31 treatment effectively suppressed CTCL-induced scratching and alloknesis (mechanical itch). Finally, i.t. administration of a TLR4 antagonist attenuated pruritus in early and late phases and in both sexes. Collectively, we have established a mouse model of neuropathic and cancer itch with relevance to human disease. Our findings also suggest distinct mechanisms underlying acute, chronic, and neuropathic itch.
Asunto(s)
Linfoma , Prurito , Animales , Femenino , Masculino , Ratones , Linfoma/complicaciones , Prurito/tratamiento farmacológico , Prurito/etiología , Células Receptoras Sensoriales , Piel/patología , Modelos Animales de EnfermedadRESUMEN
Specialized pro-resolving mediators (SPMs), including resolvins, protectins, and maresins, are endogenous lipid mediators that are synthesized from omega-3 polyunsaturated fatty acids during the acute phase or resolution phase of inflammation. Synthetic SPMs possess broad safety profiles and exhibit potent actions in resolving inflammation in preclinical models. Accumulating evidence in the past decade has demonstrated powerful analgesia of exogenous SPMs in rodent models of inflammatory, neuropathic, and cancer pain. Furthermore, endogenous SPMs are produced by sham surgery and neuromodulation (e.g., vagus nerve stimulation). SPMs produce their beneficial actions through multiple G protein-coupled receptors, expressed by immune cells, glial cells, and neurons. Notably, loss of SPM receptors impairs the resolution of pain. I also highlight the emerging role of SPMs in the control of itch. Pharmacological targeting of SPMs or SPM receptors has the potential to lead to novel therapeutics for pain and itch as emerging approaches in resolution pharmacology.
Asunto(s)
Inflamación , Dolor , Humanos , Inflamación/tratamiento farmacológico , Dolor/tratamiento farmacológicoRESUMEN
ABSTRACT: Specialized proresolving mediators (SPMs) have demonstrated potent analgesic actions in animal models of pathological pain. The actions of SPMs in acute and chronic itch are currently unknown. Recently, n-3 docosapentaenoic acid (DPA) was found to be a substrate for the biosynthesis of several novel families of SPMs and 3-oxa-PD1 n-3 DPA (3-oxa-PD1) is an oxidation-resistant metabolic stable analogue of the n-3 DPA-derived protectin D1 (PD1). In this article, we demonstrate that 3-oxa-PD1 effectively reduces both acute and chronic itch in mouse models. Intrathecal injection of 3-oxa-PD1 (100 ng) reduced acute itch induced by histamine, chloroquine, or morphine. Furthermore, intrathecal 3-oxa-PD1 effectively reduced chronic itch, induced by cutaneous T-cell lymphoma (CTCL), allergic contact dermatitis with dinitrofluorobenzene, and psoriasis by imiquimod. Intratumoral injection of 3-oxa-PD1 also suppressed CTCL-induced chronic itch. Strikingly, the antipruritic effect lasted for several weeks after 1-week intrathecal 3-oxa-PD1 treatment. Whole-cell recordings revealed significant increase in excitatory postsynaptic currents in spinal dorsal horn (SDH) neurons of CTCL mice, but this increase was blocked by 3-oxa-PD1. 3-oxa-PD1 further increased inhibitory postsynaptic currents in SDH neurons of CTCL mice. Cutaneous T-cell lymphoma increased the spinal levels of lipocalin-2 (LCN2), an itch mediator produced by astrocytes. 3-oxa-PD1 suppressed LCN2 production in CTCL mice and LCN2 secretion in astrocytes. Finally, CTCL-induced anxiety was alleviated by intrathecal 3-oxa-PD1. Our findings suggest that 3-oxa-PD1 potently inhibits acute and chronic itch through the regulation of excitatory or inhibitory synaptic transmission and astroglial LCN2 production. Therefore, stable SPM analogs such as 3-oxa-PD1 could be useful to treat pruritus associated with different skin injuries.
Asunto(s)
Astrocitos , Ácidos Grasos Insaturados , Lipocalina 2 , Prurito , Animales , Ratones , Astrocitos/efectos de los fármacos , Astrocitos/metabolismo , Ácidos Grasos Insaturados/farmacología , Ácidos Grasos Insaturados/uso terapéutico , Lipocalina 2/metabolismo , Linfoma Cutáneo de Células T/complicaciones , Ratones Endogámicos C57BL , Prurito/tratamiento farmacológico , Prurito/etiología , Prurito/metabolismo , Transmisión Sináptica/efectos de los fármacosRESUMEN
Pain is a main symptom in inflammation, and inflammation induces pain via inflammatory mediators acting on nociceptive neurons. Macrophages and microglia are distinct cell types, representing immune cells and glial cells, respectively, but they share similar roles in pain regulation. Macrophages are key regulators of inflammation and pain. Macrophage polarization plays different roles in inducing and resolving pain. Notably, macrophage polarization and phagocytosis can be induced by specialized pro-resolution mediators (SPMs). SPMs also potently inhibit inflammatory and neuropathic pain via immunomodulation and neuromodulation. In this review, we discuss macrophage signaling involved in pain induction and resolution, as well as in maintaining physiological pain. Microglia are macrophage-like cells in the central nervous system (CNS) and drive neuroinflammation and pathological pain in various inflammatory and neurological disorders. Microglia-produced inflammatory cytokines can potently regulate excitatory and inhibitory synaptic transmission as neuromodulators. We also highlight sex differences in macrophage and microglial signaling in inflammatory and neuropathic pain. Thus, targeting macrophage and microglial signaling in distinct locations via pharmacological approaches, including immunotherapies, and non-pharmacological approaches will help to control chronic inflammation and chronic pain.