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1.
Nat Immunol ; 25(7): 1296-1305, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38806708

RESUMEN

Inflammatory pain results from the heightened sensitivity and reduced threshold of nociceptor sensory neurons due to exposure to inflammatory mediators. However, the cellular and transcriptional diversity of immune cell and sensory neuron types makes it challenging to decipher the immune mechanisms underlying pain. Here we used single-cell transcriptomics to determine the immune gene signatures associated with pain development in three skin inflammatory pain models in mice: zymosan injection, skin incision and ultraviolet burn. We found that macrophage and neutrophil recruitment closely mirrored the kinetics of pain development and identified cell-type-specific transcriptional programs associated with pain and its resolution. Using a comprehensive list of potential interactions mediated by receptors, ligands, ion channels and metabolites to generate injury-specific neuroimmune interactomes, we also uncovered that thrombospondin-1 upregulated by immune cells upon injury inhibited nociceptor sensitization. This study lays the groundwork for identifying the neuroimmune axes that modulate pain in diverse disease contexts.


Asunto(s)
Nociceptores , Dolor , Animales , Ratones , Dolor/inmunología , Dolor/metabolismo , Nociceptores/metabolismo , Transcriptoma , Ratones Endogámicos C57BL , Inflamación/inmunología , Masculino , Macrófagos/inmunología , Macrófagos/metabolismo , Modelos Animales de Enfermedad , Trombospondina 1/metabolismo , Trombospondina 1/genética , Piel/inmunología , Piel/metabolismo , Piel/patología , Zimosan , Análisis de la Célula Individual , Neuroinmunomodulación , Perfilación de la Expresión Génica , Neutrófilos/inmunología , Neutrófilos/metabolismo
2.
Cell ; 173(1): 140-152.e15, 2018 03 22.
Artículo en Inglés | MEDLINE | ID: mdl-29570993

RESUMEN

Hunger and pain are two competing signals that individuals must resolve to ensure survival. However, the neural processes that prioritize conflicting survival needs are poorly understood. We discovered that hunger attenuates behavioral responses and affective properties of inflammatory pain without altering acute nociceptive responses. This effect is centrally controlled, as activity in hunger-sensitive agouti-related protein (AgRP)-expressing neurons abrogates inflammatory pain. Systematic analysis of AgRP projection subpopulations revealed that the neural processing of hunger and inflammatory pain converge in the hindbrain parabrachial nucleus (PBN). Strikingly, activity in AgRP → PBN neurons blocked the behavioral response to inflammatory pain as effectively as hunger or analgesics. The anti-nociceptive effect of hunger is mediated by neuropeptide Y (NPY) signaling in the PBN. By investigating the intersection between hunger and pain, we have identified a neural circuit that mediates competing survival needs and uncovered NPY Y1 receptor signaling in the PBN as a target for pain suppression.


Asunto(s)
Neuronas/metabolismo , Dolor/patología , Proteína Relacionada con Agouti/genética , Proteína Relacionada con Agouti/metabolismo , Analgésicos Opioides/farmacología , Animales , Antiinflamatorios no Esteroideos/farmacología , Conducta Animal/efectos de los fármacos , Dieta , Conducta Alimentaria/efectos de los fármacos , Formaldehído/toxicidad , Glutamato Descarboxilasa/metabolismo , Locomoción/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Morfina/farmacología , Neuronas/efectos de los fármacos , Dolor/etiología , Dolor/metabolismo , Núcleos Parabraquiales/efectos de los fármacos , Núcleos Parabraquiales/metabolismo , Receptores de Neuropéptido Y/metabolismo , Transducción de Señal
3.
Cell ; 160(4): 759-770, 2015 Feb 12.
Artículo en Inglés | MEDLINE | ID: mdl-25679765

RESUMEN

Sensitization of the capsaicin receptor TRPV1 is central to the initiation of pathological forms of pain, and multiple signaling cascades are known to enhance TRPV1 activity under inflammatory conditions. How might detrimental escalation of TRPV1 activity be counteracted? Using a genetic-proteomic approach, we identify the GABAB1 receptor subunit as bona fide inhibitor of TRPV1 sensitization in the context of diverse inflammatory settings. We find that the endogenous GABAB agonist, GABA, is released from nociceptive nerve terminals, suggesting an autocrine feedback mechanism limiting TRPV1 sensitization. The effect of GABAB on TRPV1 is independent of canonical G protein signaling and rather relies on close juxtaposition of the GABAB1 receptor subunit and TRPV1. Activating the GABAB1 receptor subunit does not attenuate normal functioning of the capsaicin receptor but exclusively reverts its sensitized state. Thus, harnessing this mechanism for anti-pain therapy may prevent adverse effects associated with currently available TRPV1 blockers.


Asunto(s)
Comunicación Autocrina , Neuronas/metabolismo , Dolor/metabolismo , Receptores de GABA-B/metabolismo , Canales Catiónicos TRPV/metabolismo , Ácido gamma-Aminobutírico/metabolismo , Animales , Células Cultivadas , Retroalimentación , Femenino , Masculino , Ratones Endogámicos C57BL , Ratones Transgénicos
4.
Nature ; 625(7995): 557-565, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-38172636

RESUMEN

Osteoarthritis (OA) is the most common joint disease. Currently there are no effective methods that simultaneously prevent joint degeneration and reduce pain1. Although limited evidence suggests the existence of voltage-gated sodium channels (VGSCs) in chondrocytes2, their expression and function in chondrocytes and in OA remain essentially unknown. Here we identify Nav1.7 as an OA-associated VGSC and demonstrate that human OA chondrocytes express functional Nav1.7 channels, with a density of 0.1 to 0.15 channels per µm2 and 350 to 525 channels per cell. Serial genetic ablation of Nav1.7 in multiple mouse models demonstrates that Nav1.7 expressed in dorsal root ganglia neurons is involved in pain, whereas Nav1.7 in chondrocytes regulates OA progression. Pharmacological blockade of Nav1.7 with selective or clinically used pan-Nav channel blockers significantly ameliorates the progression of structural joint damage, and reduces OA pain behaviour. Mechanistically, Nav1.7 blockers regulate intracellular Ca2+ signalling and the chondrocyte secretome, which in turn affects chondrocyte biology and OA progression. Identification of Nav1.7 as a novel chondrocyte-expressed, OA-associated channel uncovers a dual target for the development of disease-modifying and non-opioid pain relief treatment for OA.


Asunto(s)
Condrocitos , Canal de Sodio Activado por Voltaje NAV1.7 , Osteoartritis , Bloqueadores del Canal de Sodio Activado por Voltaje , Animales , Humanos , Ratones , Calcio/metabolismo , Señalización del Calcio/efectos de los fármacos , Condrocitos/efectos de los fármacos , Condrocitos/metabolismo , Progresión de la Enfermedad , Ganglios Espinales/citología , Ganglios Espinales/metabolismo , Canal de Sodio Activado por Voltaje NAV1.7/deficiencia , Canal de Sodio Activado por Voltaje NAV1.7/genética , Canal de Sodio Activado por Voltaje NAV1.7/metabolismo , Neuronas/metabolismo , Osteoartritis/complicaciones , Osteoartritis/tratamiento farmacológico , Osteoartritis/genética , Osteoartritis/metabolismo , Dolor/complicaciones , Dolor/tratamiento farmacológico , Dolor/metabolismo , Bloqueadores del Canal de Sodio Activado por Voltaje/farmacología , Bloqueadores del Canal de Sodio Activado por Voltaje/uso terapéutico
5.
Cell ; 159(6): 1417-1432, 2014 Dec 04.
Artículo en Inglés | MEDLINE | ID: mdl-25467445

RESUMEN

Pain information processing in the spinal cord has been postulated to rely on nociceptive transmission (T) neurons receiving inputs from nociceptors and Aß mechanoreceptors, with Aß inputs gated through feed-forward activation of spinal inhibitory neurons (INs). Here, we used intersectional genetic manipulations to identify these critical components of pain transduction. Marking and ablating six populations of spinal excitatory and inhibitory neurons, coupled with behavioral and electrophysiological analysis, showed that excitatory neurons expressing somatostatin (SOM) include T-type cells, whose ablation causes loss of mechanical pain. Inhibitory neurons marked by the expression of dynorphin (Dyn) represent INs, which are necessary to gate Aß fibers from activating SOM(+) neurons to evoke pain. Therefore, peripheral mechanical nociceptors and Aß mechanoreceptors, together with spinal SOM(+) excitatory and Dyn(+) inhibitory neurons, form a microcircuit that transmits and gates mechanical pain. PAPERCLIP:


Asunto(s)
Neuronas/fisiología , Dolor/metabolismo , Médula Espinal/fisiología , Animales , Dinorfinas/metabolismo , Mecanorreceptores/metabolismo , Ratones , Percepción del Dolor , Somatostatina/metabolismo
6.
Physiol Rev ; 100(2): 725-803, 2020 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-31670612

RESUMEN

The transient receptor potential ankyrin (TRPA) channels are Ca2+-permeable nonselective cation channels remarkably conserved through the animal kingdom. Mammals have only one member, TRPA1, which is widely expressed in sensory neurons and in non-neuronal cells (such as epithelial cells and hair cells). TRPA1 owes its name to the presence of 14 ankyrin repeats located in the NH2 terminus of the channel, an unusual structural feature that may be relevant to its interactions with intracellular components. TRPA1 is primarily involved in the detection of an extremely wide variety of exogenous stimuli that may produce cellular damage. This includes a plethora of electrophilic compounds that interact with nucleophilic amino acid residues in the channel and many other chemically unrelated compounds whose only common feature seems to be their ability to partition in the plasma membrane. TRPA1 has been reported to be activated by cold, heat, and mechanical stimuli, and its function is modulated by multiple factors, including Ca2+, trace metals, pH, and reactive oxygen, nitrogen, and carbonyl species. TRPA1 is involved in acute and chronic pain as well as inflammation, plays key roles in the pathophysiology of nearly all organ systems, and is an attractive target for the treatment of related diseases. Here we review the current knowledge about the mammalian TRPA1 channel, linking its unique structure, widely tuned sensory properties, and complex regulation to its roles in multiple pathophysiological conditions.


Asunto(s)
Señalización del Calcio , Mecanotransducción Celular , Nocicepción , Células Receptoras Sensoriales/metabolismo , Canal Catiónico TRPA1/metabolismo , Sensación Térmica , Animales , Canalopatías/metabolismo , Canalopatías/fisiopatología , Células Quimiorreceptoras/metabolismo , Humanos , Inflamación/metabolismo , Inflamación/fisiopatología , Mecanorreceptores/metabolismo , Nociceptores/metabolismo , Dolor/metabolismo , Dolor/fisiopatología , Termorreceptores/metabolismo
7.
Nature ; 591(7849): 275-280, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-33442058

RESUMEN

The innate immune regulator STING is a critical sensor of self- and pathogen-derived DNA. DNA sensing by STING leads to the induction of type-I interferons (IFN-I) and other cytokines, which promote immune-cell-mediated eradication of pathogens and neoplastic cells1,2. STING is also a robust driver of antitumour immunity, which has led to the development of STING activators and small-molecule agonists as adjuvants for cancer immunotherapy3. Pain, transmitted by peripheral nociceptive sensory neurons (nociceptors), also aids in host defence by alerting organisms to the presence of potentially damaging stimuli, including pathogens and cancer cells4,5. Here we demonstrate that STING is a critical regulator of nociception through IFN-I signalling in peripheral nociceptors. We show that mice lacking STING or IFN-I signalling exhibit hypersensitivity to nociceptive stimuli and heightened nociceptor excitability. Conversely, intrathecal activation of STING produces robust antinociception in mice and non-human primates. STING-mediated antinociception is governed by IFN-Is, which rapidly suppress excitability of mouse, monkey and human nociceptors. Our findings establish the STING-IFN-I signalling axis as a critical regulator of physiological nociception and a promising new target for treating chronic pain.


Asunto(s)
Interferón Tipo I/metabolismo , Proteínas de la Membrana/metabolismo , Nocicepción/fisiología , Dolor/metabolismo , Células Receptoras Sensoriales/metabolismo , Analgesia , Animales , Femenino , Humanos , Interferón Tipo I/deficiencia , Interferón Tipo I/genética , Interferón Tipo I/inmunología , Macaca mulatta , Masculino , Proteínas de la Membrana/agonistas , Proteínas de la Membrana/deficiencia , Proteínas de la Membrana/genética , Ratones , Nocicepción/efectos de los fármacos , Transducción de Señal
8.
Annu Rev Neurosci ; 41: 453-473, 2018 07 08.
Artículo en Inglés | MEDLINE | ID: mdl-29852083

RESUMEN

Opioids are the most commonly used and effective analgesic treatments for severe pain, but they have recently come under scrutiny owing to epidemic levels of abuse and overdose. These compounds act on the endogenous opioid system, which comprises four G protein-coupled receptors (mu, delta, kappa, and nociceptin) and four major peptide families (ß-endorphin, enkephalins, dynorphins, and nociceptin/orphanin FQ). In this review, we first describe the functional organization and pharmacology of the endogenous opioid system. We then summarize current knowledge on the signaling mechanisms by which opioids regulate neuronal function and neurotransmission. Finally, we discuss the loci of opioid analgesic action along peripheral and central pain pathways, emphasizing the pain-relieving properties of opioids against the affective dimension of the pain experience.


Asunto(s)
Analgésicos Opioides/metabolismo , Analgésicos Opioides/uso terapéutico , Dolor/tratamiento farmacológico , Dolor/metabolismo , Animales , Humanos , Percepción del Dolor , Receptores Acoplados a Proteínas G/metabolismo
9.
PLoS Biol ; 21(6): e3001975, 2023 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-37347749

RESUMEN

Mas-related G-protein-coupled receptors X1-X4 (MRGPRX1-X4) are 4 primate-specific receptors that are recently reported to be responsible for many biological processes, including itch sensation, pain transmission, and inflammatory reactions. MRGPRX1 is the first identified human MRGPR, and its expression is restricted to primary sensory neurons. Due to its dual roles in itch and pain signaling pathways, MRGPRX1 has been regarded as a promising target for itch remission and pain inhibition. Here, we reported a cryo-electron microscopy (cryo-EM) structure of Gq-coupled MRGPRX1 in complex with a synthetic agonist compound 16 in an active conformation at an overall resolution of 3.0 Å via a NanoBiT tethering strategy. Compound 16 is a new pain-relieving compound with high potency and selectivity to MRGPRX1 over other MRGPRXs and opioid receptor. MRGPRX1 was revealed to share common structural features of the Gq-mediated receptor activation mechanism of MRGPRX family members, but the variable residues in orthosteric pocket of MRGPRX1 exhibit the unique agonist recognition pattern, potentially facilitating to design MRGPRX1-specific modulators. Together with receptor activation and itch behavior evaluation assays, our study provides a structural snapshot to modify therapeutic molecules for itch relieving and analgesia targeting MRGPRX1.


Asunto(s)
Prurito , Receptores Acoplados a Proteínas G , Animales , Humanos , Microscopía por Crioelectrón , Dolor/metabolismo , Prurito/inducido químicamente , Prurito/metabolismo , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Células Receptoras Sensoriales/metabolismo , Transducción de Señal
10.
Proc Natl Acad Sci U S A ; 120(11): e2215417120, 2023 03 14.
Artículo en Inglés | MEDLINE | ID: mdl-36897973

RESUMEN

Inflammation causes pain by shifting the balance of ionic currents in nociceptors toward depolarization, leading to hyperexcitability. The ensemble of ion channels within the plasma membrane is regulated by processes including biogenesis, transport, and degradation. Thus, alterations in ion channel trafficking may influence excitability. Sodium channel NaV1.7 and potassium channel KV7.2 promote and oppose excitability in nociceptors, respectively. We used live-cell imaging to investigate mechanisms by which inflammatory mediators (IM) modulate the abundance of these channels at axonal surfaces through transcription, vesicular loading, axonal transport, exocytosis, and endocytosis. Inflammatory mediators induced a NaV1.7-dependent increase in activity in distal axons. Further, inflammation increased the abundance of NaV1.7, but not of KV7.2, at axonal surfaces by selectively increasing channel loading into anterograde transport vesicles and insertion at the membrane, without affecting retrograde transport. These results uncover a cell biological mechanism for inflammatory pain and suggest NaV1.7 trafficking as a potential therapeutic target.


Asunto(s)
Axones , Nociceptores , Ratas , Animales , Axones/metabolismo , Dolor/metabolismo , Inflamación/metabolismo , Mediadores de Inflamación/metabolismo
11.
Proc Natl Acad Sci U S A ; 120(14): e2219624120, 2023 04 04.
Artículo en Inglés | MEDLINE | ID: mdl-36996107

RESUMEN

Gain-of-function mutations in voltage-gated sodium channel NaV1.7 cause severe inherited pain syndromes, including inherited erythromelalgia (IEM). The structural basis of these disease mutations, however, remains elusive. Here, we focused on three mutations that all substitute threonine residues in the alpha-helical S4-S5 intracellular linker that connects the voltage sensor to the pore: NaV1.7/I234T, NaV1.7/I848T, and NaV1.7/S241T in order of their positions in the amino acid sequence within the S4-S5 linkers. Introduction of these IEM mutations into the ancestral bacterial sodium channel NaVAb recapitulated the pathogenic gain-of-function of these mutants by inducing a negative shift in the voltage dependence of activation and slowing the kinetics of inactivation. Remarkably, our structural analysis reveals a common mechanism of action among the three mutations, in which the mutant threonine residues create new hydrogen bonds between the S4-S5 linker and the pore-lining S5 or S6 segment in the pore module. Because the S4-S5 linkers couple voltage sensor movements to pore opening, these newly formed hydrogen bonds would stabilize the activated state substantially and thereby promote the 8 to 18 mV negative shift in the voltage dependence of activation that is characteristic of the NaV1.7 IEM mutants. Our results provide key structural insights into how IEM mutations in the S4-S5 linkers may cause hyperexcitability of NaV1.7 and lead to severe pain in this debilitating disease.


Asunto(s)
Eritromelalgia , Canales de Sodio Activados por Voltaje , Humanos , Canal de Sodio Activado por Voltaje NAV1.7/genética , Canal de Sodio Activado por Voltaje NAV1.7/metabolismo , Dolor/genética , Dolor/metabolismo , Mutación , Eritromelalgia/genética , Eritromelalgia/metabolismo , Eritromelalgia/patología , Canales de Sodio Activados por Voltaje/genética , Treonina/genética
12.
Proc Natl Acad Sci U S A ; 120(22): e2302509120, 2023 05 30.
Artículo en Inglés | MEDLINE | ID: mdl-37216549

RESUMEN

Upon its mucosal transmission, HIV type 1 (HIV-1) rapidly targets genital antigen-presenting Langerhans cells (LCs), which subsequently transfer infectious virus to CD4+ T cells. We previously described an inhibitory neuroimmune cross talk, whereby calcitonin gene-related peptide (CGRP), a neuropeptide secreted by peripheral pain-sensing nociceptor neurons innervating all mucosal epithelia and associating with LCs, strongly inhibits HIV-1 transfer. As nociceptors secret CGRP following the activation of their Ca2+ ion channel transient receptor potential vanilloid 1 (TRPV1), and as we reported that LCs secret low levels of CGRP, we investigated whether LCs express functional TRPV1. We found that human LCs expressed mRNA and protein of TRPV1, which was functional and induced Ca2+ influx following activation with TRPV1 agonists, including capsaicin (CP). The treatment of LCs with TRPV1 agonists also increased CGRP secretion, reaching its anti-HIV-1 inhibitory concentrations. Accordingly, CP pretreatment significantly inhibited LCs-mediated HIV-1 transfer to CD4+ T cells, which was abrogated by both TRPV1 and CGRP receptor antagonists. Like CGRP, CP-induced inhibition of HIV-1 transfer was mediated via increased CCL3 secretion and HIV-1 degradation. CP also inhibited direct CD4+ T cells HIV-1 infection, but in CGRP-independent manners. Finally, pretreatment of inner foreskin tissue explants with CP markedly increased CGRP and CCL3 secretion, and upon subsequent polarized exposure to HIV-1, inhibited an increase in LC-T cell conjugate formation and consequently T cell infection. Our results reveal that TRPV1 activation in human LCs and CD4+ T cells inhibits mucosal HIV-1 infection, via CGRP-dependent/independent mechanisms. Formulations containing TRPV1 agonists, already approved for pain relief, could hence be useful against HIV-1.


Asunto(s)
Péptido Relacionado con Gen de Calcitonina , Infecciones por VIH , Humanos , Péptido Relacionado con Gen de Calcitonina/farmacología , Linfocitos T/metabolismo , Células de Langerhans/metabolismo , Membrana Mucosa/metabolismo , Capsaicina/farmacología , Dolor/metabolismo , Infecciones por VIH/metabolismo , Canales Catiónicos TRPV/genética , Canales Catiónicos TRPV/metabolismo
13.
J Neurosci ; 44(4)2024 01 24.
Artículo en Inglés | MEDLINE | ID: mdl-38124016

RESUMEN

The dorsal raphe nucleus (DRN) is an important nucleus in pain regulation. However, the underlying neural pathway and the function of specific cell types remain unclear. Here, we report a previously unrecognized ascending facilitation pathway, the DRN to the mesoaccumbal dopamine (DA) circuit, for regulating pain. Chronic pain increased the activity of DRN glutamatergic, but not serotonergic, neurons projecting to the ventral tegmental area (VTA) (DRNGlu-VTA) in male mice. The optogenetic activation of DRNGlu-VTA circuit induced a pain-like response in naive male mice, and its inhibition produced an analgesic effect in male mice with neuropathic pain. Furthermore, we discovered that DRN ascending pathway regulated pain through strengthened excitatory transmission onto the VTA DA neurons projecting to the ventral part of nucleus accumbens medial shell (vNAcMed), thereby activated the mesoaccumbal DA neurons. Correspondingly, optogenetic manipulation of this three-node pathway bilaterally regulated pain behaviors. These findings identified a DRN ascending excitatory pathway that is crucial for pain sensory processing, which can potentially be exploited toward targeting pain disorders.


Asunto(s)
Núcleo Dorsal del Rafe , Área Tegmental Ventral , Ratones , Masculino , Animales , Núcleo Dorsal del Rafe/fisiología , Área Tegmental Ventral/fisiología , Neuronas Dopaminérgicas/fisiología , Núcleo Accumbens , Dolor/metabolismo
14.
J Neurosci ; 44(6)2024 02 07.
Artículo en Inglés | MEDLINE | ID: mdl-38124021

RESUMEN

Prolonged exposure to opioids causes an enhanced sensitivity to painful stimuli (opioid-induced hyperalgesia, OIH) and a need for increased opioid doses to maintain analgesia (opioid-induced tolerance, OIT), but the mechanisms underlying both processes remain obscure. We found that pharmacological block or genetic deletion of HCN2 ion channels in primary nociceptive neurons of male mice completely abolished OIH but had no effect on OIT. Conversely, pharmacological inhibition of central HCN channels alleviated OIT but had no effect on OIH. Expression of C-FOS, a marker of neuronal activity, was increased in second-order neurons of the dorsal spinal cord by induction of OIH, and the increase was prevented by peripheral block or genetic deletion of HCN2, but block of OIT by spinal block of HCN channels had no impact on C-FOS expression in dorsal horn neurons. Collectively, these observations show that OIH is driven by HCN2 ion channels in peripheral nociceptors, while OIT is driven by a member of the HCN family located in the CNS. Induction of OIH increased cAMP in nociceptive neurons, and a consequent shift in the activation curve of HCN2 caused an increase in nociceptor firing. The shift in HCN2 was caused by expression of a constitutively active µ-opioid receptor (MOR) and was reversed by MOR antagonists. We identified the opioid-induced MOR as a six-transmembrane splice variant, and we show that it increases cAMP by coupling constitutively to Gs HCN2 ion channels therefore drive OIH, and likely OIT, and may be a novel therapeutic target for the treatment of addiction.


Asunto(s)
Analgésicos Opioides , Hiperalgesia , Ratones , Masculino , Animales , Analgésicos Opioides/efectos adversos , Hiperalgesia/metabolismo , Canales Iónicos , Nociceptores , Médula Espinal/metabolismo , Dolor/metabolismo
15.
J Neurosci ; 44(42)2024 Oct 16.
Artículo en Inglés | MEDLINE | ID: mdl-39256047

RESUMEN

We recently demonstrated that transient attenuation of Toll-like receptor 4 (TLR4) in dorsal root ganglion (DRG) neurons, can both prevent and reverse pain associated with chemotherapy-induced peripheral neuropathy (CIPN), a severe side effect of cancer chemotherapy, for which treatment options are limited. Given the reduced efficacy of opioid analgesics to treat neuropathic, compared with inflammatory pain, the cross talk between nociceptor TLR4 and mu-opioid receptors (MORs), and that MOR and TLR4 agonists induce hyperalgesic priming (priming), which also occurs in CIPN, we determined, using male rats, whether (1) antisense knockdown of nociceptor MOR attenuates CIPN, (2) and attenuates the priming associated with CIPN, and (3) CIPN also produces opioid-induced hyperalgesia (OIH). We found that intrathecal MOR antisense prevents and reverses hyperalgesia induced by oxaliplatin and paclitaxel, two common clinical chemotherapy agents. Oxaliplatin-induced priming was also markedly attenuated by MOR antisense. Additionally, intradermal morphine, at a dose that does not affect nociceptive threshold in controls, exacerbates mechanical hyperalgesia (OIH) in rats with CIPN, suggesting the presence of OIH. This OIH associated with CIPN is inhibited by interventions that reverse Type II priming [the combination of an inhibitor of Src and mitogen-activated protein kinase (MAPK)], an MOR antagonist, as well as a TLR4 antagonist. Our findings support a role of nociceptor MOR in oxaliplatin-induced pain and priming. We propose that priming and OIH are central to the symptom burden in CIPN, contributing to its chronicity and the limited efficacy of opioid analgesics to treat neuropathic pain.


Asunto(s)
Antineoplásicos , Hiperalgesia , Enfermedades del Sistema Nervioso Periférico , Receptores Opioides mu , Animales , Masculino , Ratas , Analgésicos Opioides/farmacología , Antineoplásicos/efectos adversos , Antineoplásicos/toxicidad , Ganglios Espinales/metabolismo , Ganglios Espinales/efectos de los fármacos , Hiperalgesia/inducido químicamente , Hiperalgesia/metabolismo , Compuestos Organoplatinos/efectos adversos , Compuestos Organoplatinos/toxicidad , Oxaliplatino/toxicidad , Oxaliplatino/efectos adversos , Paclitaxel/toxicidad , Paclitaxel/efectos adversos , Dolor/inducido químicamente , Dolor/tratamiento farmacológico , Dolor/metabolismo , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Enfermedades del Sistema Nervioso Periférico/metabolismo , Ratas Sprague-Dawley , Receptores Opioides mu/metabolismo , Receptor Toll-Like 4/metabolismo
16.
Hum Mol Genet ; 32(8): 1380-1400, 2023 04 06.
Artículo en Inglés | MEDLINE | ID: mdl-36537577

RESUMEN

A functional nerve growth factor NGF-Tropomyosin Receptor kinase A (TrkA) system is an essential requisite for the generation and maintenance of long-lasting thermal and mechanical hyperalgesia in adult mammals. Indeed, mutations in the gene encoding for TrkA are responsible for a rare condition, named Hereditary Sensory and Autonomic Neuropathy type IV (HSAN IV), characterized by the loss of response to noxious stimuli, anhidrosis and cognitive impairment. However, to date, there is no available mouse model to properly understand how the NGF-TrkA system can lead to pathological phenotypes that are distinctive of HSAN IV. Here, we report the generation of a knock-in mouse line carrying the HSAN IV TrkAR649W mutation. First, by in vitro biochemical and biophysical analyses, we show that the pathological R649W mutation leads to kinase-inactive TrkA also affecting its membrane dynamics and trafficking. In agreement with the HSAN IV human phenotype, TrkAR649W/m mice display a lower response to thermal and chemical noxious stimuli, correlating with reduced skin innervation, in addition to decreased sweating in comparison to TrkAh/m controls. Moreover, the R649W mutation decreases anxiety-like behavior and compromises cognitive abilities, by impairing spatial-working and social memory. Our results further uncover unexplored roles of TrkA in thermoregulation and sociability. In addition to accurately recapitulating the clinical manifestations of HSAN IV patients, our findings contribute to clarifying the involvement of the NGF-TrkA system in pain sensation.


Asunto(s)
Modelos Animales de Enfermedad , Neuropatías Hereditarias Sensoriales y Autónomas , Receptor trkA , Humanos , Animales , Ratones , Mutación , Receptor trkA/genética , Técnicas de Sustitución del Gen , Factor de Crecimiento Nervioso/metabolismo , Fosforilación , Genes Letales , Dolor/metabolismo , Ganglios Espinales/metabolismo , Ganglios Espinales/patología , Piel/metabolismo , Piel/patología , Sistema Nervioso Simpático/metabolismo , Hipohidrosis/metabolismo , Conducta Animal
17.
Annu Rev Neurosci ; 40: 307-325, 2017 07 25.
Artículo en Inglés | MEDLINE | ID: mdl-28441116

RESUMEN

Nerve growth factor (NGF) antagonism is on the verge of becoming a powerful analgesic treatment for numerous conditions, including osteoarthritis and lower back pain. This review summarizes the historical research, both fundamental and clinical, that led to our current understanding of NGF biology. We also discuss the surprising number of questions that remain about NGF expression patterns and NGF's various functions and interaction partners in relation to persistent pain and the potential side effects of anti-NGF therapy.


Asunto(s)
Factor de Crecimiento Nervioso/metabolismo , Dolor/metabolismo , Receptor de Factor de Crecimiento Nervioso/metabolismo , Receptor trkA/metabolismo , Animales , Dolor Crónico/metabolismo , Humanos
18.
Development ; 149(16)2022 08 15.
Artículo en Inglés | MEDLINE | ID: mdl-35904071

RESUMEN

The perception of noxious environmental stimuli by nociceptive sensory neurons is an essential mechanism for the prevention of tissue damage. Etv4 is a transcriptional factor expressed in most nociceptors in dorsal root ganglia (DRG) during the embryonic development. However, its physiological role remains unclear. Here, we show that Etv4 ablation results in defects in the development of the peripheral peptidergic projections in vivo, and in deficits in axonal elongation and growth cone morphology in cultured sensory neurons in response to NGF. From a mechanistic point of view, our findings reveal that NGF regulates Etv4-dependent gene expression of molecules involved in extracellular matrix (ECM) remodeling. Etv4-null mice were less sensitive to noxious heat stimuli and chemical pain, and this behavioral phenotype correlates with a significant reduction in the expression of the pain-transducing ion channel TRPV1 in mutant mice. Together, our data demonstrate that Etv4 is required for the correct innervation and function of peptidergic sensory neurons, regulating a transcriptional program that involves molecules associated with axonal growth and pain transduction.


Asunto(s)
Factor de Crecimiento Nervioso , Nocicepción , Proteínas Proto-Oncogénicas c-ets/metabolismo , Animales , Ganglios Espinales/metabolismo , Ratones , Factor de Crecimiento Nervioso/genética , Nocicepción/fisiología , Dolor/metabolismo , Células Receptoras Sensoriales/metabolismo
19.
FASEB J ; 38(1): e23364, 2024 01.
Artículo en Inglés | MEDLINE | ID: mdl-38091247

RESUMEN

Degeneration of the intervertebral disc (IVD) results in a range of symptomatic (i.e., painful) and asymptomatic experiences. Components of the degenerative environment, including structural disruption and inflammatory cytokine production, often correlate with pain severity. However, the role of inflammation in the activation of pain and degenerative changes has been complex to delineate. The most common IVD injury model is puncture; however, it initiates structural damage that is not representative of the natural degenerative cascade. In this study, we utilized in vivo injection of lipopolysaccharide (LPS), a pro-inflammatory stimulus, into rat caudal IVDs using 33G needles to induce inflammatory activation without the physical tissue disruption caused by puncture using larger needles. LPS injection increased gene expression of pro-inflammatory cytokines (Tnfa, Il1b) and macrophage markers (Inos, Arg1), supported by immunostaining of macrophages (CD68, CCR7, Arg1) and systemic changes in blood cytokine and chemokine levels. Disruption of the IVD structural integrity after LPS injection was also evident through changes in histological grading, disc height, and ECM biochemistry. Ultimately, intradiscal inflammatory stimulation led to local mechanical hyperalgesia, demonstrating that pain can be initiated by inflammatory stimulation of the IVD. Gene expression of nociceptive markers (Ngf, Bdnf, Cgrp) and immunostaining for neuron ingrowth (PGP9.5) and sensitization (CGRP) in the IVD were also shown, suggesting a mechanism for the pain exhibited. To our knowledge, this rat IVD injury model is the first to demonstrate local pain behavior resulting from inflammatory stimulation of caudal IVDs. Future studies will examine the mechanistic contributions of inflammation in mediating pain.


Asunto(s)
Degeneración del Disco Intervertebral , Disco Intervertebral , Ratas , Animales , Degeneración del Disco Intervertebral/metabolismo , Lipopolisacáridos/toxicidad , Lipopolisacáridos/metabolismo , Péptido Relacionado con Gen de Calcitonina/metabolismo , Punción Espinal , Disco Intervertebral/metabolismo , Dolor/etiología , Dolor/metabolismo , Citocinas/metabolismo , Inflamación/metabolismo
20.
FASEB J ; 38(8): e23590, 2024 Apr 30.
Artículo en Inglés | MEDLINE | ID: mdl-38656553

RESUMEN

Studies have suggested that microglial IL-6 modulates inflammatory pain; however, the exact mechanism of action remains unclear. We therefore hypothesized that PKCε and MEG2 competitively bind to STAT3 and contribute to IL-6-mediated microglial hyperalgesia during inflammatory pain. Freund's complete adjuvant (FCA) and lipopolysaccharide (LPS) were used to induce hyperalgesia model mice and microglial inflammation. Mechanical allodynia was evaluated using von Frey tests in vivo. The interaction among PKCε, MEG2, and STAT3 was determined using ELISA and immunoprecipitation assay in vitro. The PKCε, MEG2, t-STAT3, pSTAT3Tyr705, pSTAT3Ser727, IL-6, GLUT3, and TREM2 were assessed by Western blot. IL-6 promoter activity and IL-6 concentration were examined using dual luciferase assays and ELISA. Overexpression of PKCε and MEG2 promoted and attenuated inflammatory pain, accompanied by an increase and decrease in IL-6 expression, respectively. PKCε displayed a stronger binding ability to STAT3 when competing with MEG2. STAT3Ser727 phosphorylation increased STAT3 interaction with both PKCε and MEG2. Moreover, LPS increased PKCε, MEG2, pSTAT3Tyr705, pSTAT3Ser727, IL-6, and GLUT3 levels and decreased TREM2 during microglia inflammation. IL-6 promoter activity was enhanced or inhibited by PKCε or MEG2 in the presence of STAT3 and LPS stimulation, respectively. In microglia, overexpression of PKCε and/or MEG2 resulted in the elevation of tSTAT3, pSTAT3Tyr705, pSTAT3Ser727, IL-6, and TREM2, and the reduction of GLUT3. PKCε is more potent than MEG2 when competitively binding to STAT3, displaying dual modulatory effects of IL-6 production, thus regulating the GLUT3 and TREM2 in microglia during inflammatory pain sensation.


Asunto(s)
Hiperalgesia , Inflamación , Interleucina-6 , Microglía , Proteína Quinasa C-epsilon , Factor de Transcripción STAT3 , Animales , Masculino , Ratones , Adyuvante de Freund , Hiperalgesia/metabolismo , Inflamación/metabolismo , Interleucina-6/metabolismo , Interleucina-6/genética , Lipopolisacáridos/toxicidad , Lipopolisacáridos/farmacología , Glicoproteínas de Membrana/metabolismo , Glicoproteínas de Membrana/genética , Ratones Endogámicos C57BL , Microglía/metabolismo , Dolor/metabolismo , Fosforilación , Unión Proteica , Proteína Quinasa C-epsilon/metabolismo , Proteína Quinasa C-epsilon/genética , Receptores Inmunológicos/metabolismo , Receptores Inmunológicos/genética , Factor de Transcripción STAT3/metabolismo , Proteínas Tirosina Fosfatasas no Receptoras/metabolismo
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