RESUMEN

Research on the relationship between macrophages and neuropathic pain has flourished in the past two decades. It has long been believed that macrophages are strong immune effector cells that play well-established roles in tissue homeostasis and lesions, such as promoting the initiation and progression of tissue injury and improving wound healing and tissue remodeling in a variety of pathogenesis-related diseases. They are also heterogeneous and versatile cells that can switch phenotypically/functionally in response to the micro-environment signals. Apart from microglia (resident macrophages of both the spinal cord and brain), which are required for the neuropathic pain processing of the CNS, neuropathic pain signals in PNS are influenced by the interaction of tissue-resident macrophages and BM infiltrating macrophages with primary afferent neurons. And the current review looks at new evidence that suggests sexual dimorphism in neuropathic pain are caused by variations in the immune system, notably macrophages, rather than the neurological system.

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Neuropathic pain is defined by the International Association for the Study of Pain as pain triggered or caused by primary damage to or dysfunction of the nervous system. Following intensive research into the mechanisms of neuropathic pain, macrophages have been revealed to play an important role in pathologic pain following nerve injury. Macrophages dynamically monitor the microenvironment to maintain tissue homeostasis. Once a macrophage is exposed to a pathologic stimulus, it in turn alters its functional phenotype and interacts with nociceptors, leading to neuropathic pain. This review wants to delve into the biology of macrophages in the central and peripheral nervous system, how they are related to play a role in neuropathic pain and whether there is sexual dimorphism in macrophages.

Asunto(s)

Macrófagos , Neuralgia , Neuralgia/inmunología , Neuralgia/metabolismo , Neuralgia/etiología , Humanos , Macrófagos/inmunología , Macrófagos/metabolismo , Animales , Microglía/inmunología , Microglía/metabolismo , Caracteres Sexuales

RESUMEN

We have recently developed a mouse monoclonal antibody (12-10H) binding to the head domain region in rat P2X4 receptor (rP2X4R, which is crucial for the pathogenesis of neuropathic pain) expressed on the cell with the highest binding affinity (KD = 20 nM). However, the 12-10H antibody failed to detect endogenously expressed P2X4Rs in microglia isolated from the spinal cord of rats whose spinal nerves were injured. Then, we prepared R5 mutant, in which five arginine residues were introduced into variable regions except for the "hot spot" in the 12-10H antibody to increase electrostatic interactions with the head domain, an anionic region, in rP2X4R. The mutation resulted in an increase of 50-fold in the affinity of the R5 mutant for the head domain with respect to the intact 12-10H antibody. As a result, detection of P2X4Rs endogenously expressed on primary cultured microglial cells originated from the neonatal rat brain and spinal cord microglia isolated from a rat model of neuropathic pain was achieved. These findings suggest a strategy to improve the affinity of a monoclonal antibody for an anionic antigen by the introduction of several arginine residues into variable regions other than the "hot spot" in the paratope.

Asunto(s)

Anticuerpos Monoclonales/farmacología , Microglía/efectos de los fármacos , Neuralgia/tratamiento farmacológico , Antagonistas del Receptor Purinérgico P2X/farmacología , Receptores Purinérgicos P2X4/efectos de los fármacos , Animales , Anticuerpos Monoclonales/inmunología , Afinidad de Anticuerpos , Especificidad de Anticuerpos , Células CHO , Línea Celular Tumoral , Cricetulus , Modelos Animales de Enfermedad , Humanos , Masculino , Microglía/inmunología , Microglía/metabolismo , Mutación , Neuralgia/inmunología , Neuralgia/metabolismo , Unión Proteica , Conformación Proteica , Antagonistas del Receptor Purinérgico P2X/inmunología , Ratas Wistar , Receptores Purinérgicos P2X4/genética , Receptores Purinérgicos P2X4/inmunología , Receptores Purinérgicos P2X4/metabolismo , Electricidad Estática , Relación Estructura-Actividad

RESUMEN

Neuropathic pain occurs in more than half of the patients suffering from peripheral neuropathies. We investigated the role of microRNA (miR)-21 in neuropathic pain using a murine-human translational approach. We applied the spared nerve injury (SNI) model at the sciatic nerve of mice and assessed the potential analgesic effect of perineurial miR-21-5p inhibitor application. Immune-related targets of miR-21-5p were determined by a qRT-PCR based cytokine and chemokine array. Bioinformatical analysis identified potential miR-21-5p targets interacting with CC-chemokine ligand (CCL)5. We validated CCL5 and tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein (YWHAE), an interaction partner of miR-21-5p and CCL5, by qRT-PCR in murine common peroneal and tibial nerves. Validated candidates were then investigated in white blood cell and sural nerve biopsy samples of patients with focal to generalized pain syndromes, i.e. small fiber neuropathy (SFN), polyneuropathy (PNP), and nerve lesion (NL). We showed that perineurial miR-21-5p inhibition reverses SNI-induced mechanical and heat hypersensitivity in mice and found a reduction of the SNI-induced increase of the pro-inflammatory mediators CCL5 (p < 0.01), CCL17 (p < 0.05), and IL-12ß (p < 0.05) in miR-21-5p inhibitor-treated mice. In silico analysis revealed several predicted and validated targets for miR-21-5p with CCL5 interaction. Among these, we found lower YWHAE gene expression in mice after SNI and perineurial injections of a scrambled oligonucleotide compared to naïve mice (p < 0.05), but this was not changed by miR-21-5p inhibition. Furthermore, miR-21-5p inhibition led to a further increase of the SNI-induced increase in TGFß (p < 0.01). Patient biomaterial revealed different systemic expression patterns of miR-21-5p, with higher expression in SFN and lower expression in NL. Further, we showed higher systemic expression of pro-inflammatory mediators in white blood cells of SFN patients compared to healthy controls. We have conducted a translational study comparing results from animal models to human patients with three different neuropathic pain syndromes. We identified CCL5 as a miR-21 dependent common player in the mouse SNI model and the human painful disease SFN.

Asunto(s)

Proteínas 14-3-3/biosíntesis , Quimiocina CCL5/biosíntesis , MicroARNs/biosíntesis , Neuralgia/metabolismo , Dimensión del Dolor/métodos , Investigación Biomédica Traslacional/métodos , Proteínas 14-3-3/genética , Proteínas 14-3-3/inmunología , Animales , Quimiocina CCL5/genética , Quimiocina CCL5/inmunología , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , MicroARNs/genética , MicroARNs/inmunología , Neuralgia/genética , Neuralgia/inmunología

RESUMEN

BACKGROUND AND OBJECTIVES: The mechanisms of pain in patients with diabetic polyneuropathy are unknown. Studies have suggested a role of inflammation and increased neuropeptides peripherally in pain generation. This study examined the possible skin markers of painful diabetic polyneuropathy (P-DPN): macrophages, substance P (SP), and calcitonin gene-related peptide (CGRP). METHODS: The participants were included from a large Danish cross-sectional clinical study of type 2 diabetes. We diagnosed definite diabetic polyneuropathy using the Toronto criteria and used the Neuropathic Pain Special Interest Group classification for defining P-DPN. We included 60 skin biopsies from patients with diabetic polyneuropathy-30 with P-DPN and 30 with nonpainful diabetic polyneuropathy (NP-DPN)-and 30 biopsies from healthy controls of similar age and sex. The biopsies were stained using PGP 9.5, IbA1, and SP and CGRP primary markers. RESULTS: There was increased macrophage density in patients with P-DPN (8.0%) compared with that in patients with NP-DPN (5.1%, p < 0.001), and there was increased macrophage density in patients with NP-DPN (5.1%) compared with that in healthy controls (3.1%, p < 0.001). When controlling for neuropathy severity, body mass index, age, and sex, there was still a difference in macrophage density between patients with P-DPN and patients with NP-DPN. Patients with P-DPN had higher median nerve fiber length density (274.5 and 155 mm-2 for SP and CGRP, respectively) compared with patients with NP-DPN (176 and 121 mm-2 for SP and CGRP, respectively, p = 0.009 and 0.04) and healthy controls (185.5 and 121.5 mm-2 for SP and CGRP, respectively), whereas there was no difference between patients with NP-DPN and controls without diabetes (p = 0.64 and 0.49, respectively). The difference between P-DPN and NP-DPN for SP and CGRP was significant only in female patients, although a trend was seen in male patients. DISCUSSION: The findings point to a possible involvement of the innate immune system in the pathogenesis of neuropathic pain in patients with DPN, although markers of activated macrophages were not measured in this study.

Asunto(s)

Neuropatías Diabéticas , Macrófagos , Fibras Nerviosas , Neuralgia , Piel , Anciano , Biomarcadores , Biopsia , Péptido Relacionado con Gen de Calcitonina/metabolismo , Estudios Transversales , Neuropatías Diabéticas/complicaciones , Neuropatías Diabéticas/inmunología , Neuropatías Diabéticas/metabolismo , Neuropatías Diabéticas/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Fibras Nerviosas/metabolismo , Fibras Nerviosas/patología , Neuralgia/etiología , Neuralgia/inmunología , Neuralgia/metabolismo , Neuralgia/patología , Piel/inmunología , Piel/metabolismo , Piel/patología , Sustancia P/metabolismo

RESUMEN

Chronic pain is a prevalent medical problem, and its molecular basis remains poorly understood. Here, we demonstrate the significance of the transmembrane protein (Tmem) 160 for nerve injury-induced neuropathic pain. An extensive behavioral assessment suggests a pain modality- and entity-specific phenotype in male Tmem160 global knockout (KO) mice: delayed establishment of tactile hypersensitivity and alterations in self-grooming after nerve injury. In contrast, Tmem160 seems to be dispensable for other nerve injury-induced pain modalities, such as non-evoked and movement-evoked pain, and for other pain entities. Mechanistically, we show that global KO males exhibit dampened neuroimmune signaling and diminished TRPA1-mediated activity in cultured dorsal root ganglia. Neither these changes nor altered pain-related behaviors are observed in global KO female and male peripheral sensory neuron-specific KO mice. Our findings reveal Tmem160 as a sexually dimorphic factor contributing to the establishment, but not maintenance, of discrete nerve injury-induced pain behaviors in male mice.

Asunto(s)

Citocinas/metabolismo , Proteínas de la Membrana/inmunología , Proteínas de la Membrana/metabolismo , Neuralgia/inmunología , Neuralgia/metabolismo , Traumatismos de los Nervios Periféricos/metabolismo , Células Receptoras Sensoriales/metabolismo , Animales , Conducta Animal , Dolor Crónico/inmunología , Dolor Crónico/metabolismo , Femenino , Ganglios Espinales/metabolismo , Células HEK293 , Humanos , Inflamación , Masculino , Proteínas de la Membrana/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Neuroinmunomodulación , Pruebas Neuropsicológicas , Transducción de Señal , Canal Catiónico TRPA1/metabolismo

RESUMEN

BACKGROUND: Intractable neuropathic pain is a common symptom of neuromyelitis optica spectrum disorder (NMOSD). However, the underlying mechanism of NMOSD pain remains to be elucidated. In this study, we focused on ATP, which is one of the damage-associated molecular patterns, and also a well-recognized molecule involved in peripheral neuropathic pain. METHODS: We assessed the development of pain symptoms by injecting anti-AQP4 recombinant autoantibodies (rAQP4 IgG) into rat spinal cords. We incubated HEK293 cells expressing AQP4 (HEK-AQP4) and rat astrocytes with rAQP4 IgG and assessed the level of ATP in the supernatant. We performed transcriptome analysis of the spinal cords injected with rAQP4 IgG. Pharmacological inhibition was also applied to investigate the involvement of ATP in the development of neuropathic pain in our rat model. The ATP concentration within the cerebrospinal fluid was examined in patients with NMOSD and other neurological diseases. RESULTS: Development of mechanical allodynia was confirmed in rAQP4 IgG-treated rats. AQP4-Ab-mediated extracellular ATP release from astrocytes was observed in vitro, and pharmacological inhibition of ATP receptor reversed mechanical allodynia in the rAQP4 IgG-treated rats. Furthermore, transcriptome analysis revealed elevation of gene expressions related to several ATP receptors including P2rx4 and IL1B in the spinal cord of rAQP4 IgG-treated rats. In patients, CSF ATP concentration was significantly higher in the acute and remission phase of NMOSD than in multiple sclerosis or other neurological disorders. CONCLUSION: Anti-AQP4 antibody was shown to induce the release of extracellular ATP from astrocytes. The ATP-mediated development of mechanical allodynia was also suggested in rats treated with anti-AQP4 antibody. Our study indicates the pivotal role of ATP in the pain mechanism of NMOSD.

Asunto(s)

Adenosina Trifosfato/metabolismo , Acuaporina 4/inmunología , Astrocitos/inmunología , Autoanticuerpos/farmacología , Neuralgia/inmunología , Neuromielitis Óptica/inmunología , Animales , Astrocitos/efectos de los fármacos , Astrocitos/metabolismo , Células HEK293 , Humanos , Neuralgia/metabolismo , Neuromielitis Óptica/metabolismo , Ratas

RESUMEN

Pain is a under-recognized association of leucine-rich glioma-inactivated 1 (LGI1) and contactin-associated protein-like 2 (CASPR2) antibodies. Of 147 patients with these autoantibodies, pain was experienced by 17 of 33 (52%) with CASPR2- versus 20 of 108 (19%) with LGI1 antibodies (p = 0.0005), and identified as neuropathic in 89% versus 58% of these, respectively. Typically, in both cohorts, normal nerve conduction studies and reduced intraepidermal nerve fiber densities were observed in the sampled patient subsets. In LGI1 antibody patients, pain responded to immunotherapy (p = 0.008), often rapidly, with greater residual patient-rated impairment observed in CASPR2 antibody patients (p = 0.019). Serum CASPR2 antibodies, but not LGI1 antibodies, bound in vitro to unmyelinated human sensory neurons and rodent dorsal root ganglia, suggesting pathophysiological differences that may underlie our clinical observations. ANN NEUROL 2021;90:683-690.

Asunto(s)

Autoanticuerpos/metabolismo , Proteínas de la Membrana/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Neuralgia/inmunología , Neuralgia/metabolismo , Autoanticuerpos/inmunología , Moléculas de Adhesión Celular Neuronal/inmunología , Moléculas de Adhesión Celular Neuronal/metabolismo , Humanos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Canales de Potasio con Entrada de Voltaje/inmunología

RESUMEN

OBJECT: Ninjurin2 (nerve injury induced protein 2, NINJ2) is a molecule which mediates cell-to-cell and cell-to-extracellular matrix interactions in the nervous system. Clinical study shows NINJ2 is associated with the development of postherpetic neuralgia. However, it is lack of direct evidence that NINJ2 participated in neuropathic pain. In this study, we aim to investigate the role of NINJ2 in the development of neuropathic pain in spared sciatic nerve injury rats and the underlying mechanism. METHOD: Spared sciatic nerve injury (SNI) models were established. The level of NINJ2 and p-p65 (a NF-κB family member) were measured in SNI rats by western blots and immunofluorescent staining. Lentivirus encoding small interfering RNA targeting NINJ2 (RNAi) was intrathecally injected into rats. Then the change of pain behavior of rats induced by NINJ2 RNAi was tested by Von-Frey hairs. The change of p-p65 in the spinal cord in rats after NINJ2 RNAi treatment was also measured by western blots. inhibitor of p-p65-induced change of TNF-α, IL-1ß, and IL-6 levels were measured by ELISA. RESULTS: NINJ2 and p-p65 were increased in the spinal cord of SNI rats on the 3, 7, 14th days after modeling. NINJ2 were mainly expressed in neurons, and co-located with p-p65 in the spinal dorsal horn. When down regulating the level of NINJ2 by RNAi, the development of pain in SNI rats was partially blocked. Phosphorylation of p65 was also inhibited by NINJ2 RNAi. Blocking the phosphorylation of NF-κB pathway could inhibit the increase of TNF-α, IL-1ß, and IL-6 in the spinal cord of SNI rats. CONCLUSION: NINJ2 protein was increased in the spinal cord of SNI rats. It participated in the development of nerve injury-induced neuropathic pain by activating neuroinflammation in the spinal cord via NF-κB pathway. This study provides a new target to investigate the mechanism of neuropathic pain.

Asunto(s)

Moléculas de Adhesión Celular Neuronal/inmunología , Neuralgia/inmunología , Enfermedades Neuroinflamatorias/inmunología , Nervio Ciático/lesiones , Factor de Transcripción ReIA/inmunología , Animales , Moléculas de Adhesión Celular Neuronal/genética , Masculino , Ratas Sprague-Dawley , Nervio Ciático/inmunología , Médula Espinal/inmunología

Asunto(s)

Extremidad Inferior/fisiopatología , Proteínas de la Membrana/inmunología , Proteínas del Tejido Nervioso/inmunología , Neuralgia/diagnóstico , Anciano , Autoanticuerpos , Electrodiagnóstico , Humanos , Potenciales Evocados por Láser/fisiología , Masculino , Neuralgia/inmunología , Neuralgia/fisiopatología

RESUMEN

OBJECTIVES: To assess the prevalence of antiplexin D1 antibodies (plexin D1-immunoglobulin G [IgG]) in small fiber neuropathy (SFN) and the effects of these antibodies in vivo. METHODS: We developed an ELISA for plexin D1-IgG using a recombinant extracellular domain of human plexin D1 containing the major epitope and sera from 58 subjects previously studied with a standard tissue-based indirect immunofluorescence assay (TBA). We screened 63 patients with probable SFN and 55 healthy controls (HCs) for serum plexin D1-IgG using ELISA. The results were confirmed by TBA. IgG from 3 plexin D1-IgG-positive patients, 2 plexin D1-IgG-negative inflammatory disease controls, and 2 HCs was intrathecally injected into mice, which were assessed for mechanical and thermal hypersensitivity 24 and 48 hours after injection. RESULTS: The ELISA had 75% sensitivity and 100% specificity using the TBA as a standard, and the coincidence rate of ELISA to TBA was 96.6% (56/58). The frequency of plexin D1-IgG was higher in patients with SFN than in HCs (12.7% [8/63] vs 0.0% [0/55], p = 0.007). Purified IgG from all 3 plexin D1-IgG-positive patients, but not 2 plexin D1-IgG-negative patients, induced significant mechanical and/or thermal hypersensitivity compared with IgG from HCs. In mice injected with plexin D1-IgG-positive but not D1-IgG-negative patient IgG, phosphorylated extracellular signal-regulated protein kinase immunoreactivity, an activation marker, was confined to small dorsal root ganglion neurons and was significantly more abundant than in mice injected with HC IgG. CONCLUSIONS: Plexin D1-IgG is pathogenic but with low prevalence and is a potential biomarker for immunotherapy in SFN.

Asunto(s)

Anticuerpos/inmunología , Péptidos y Proteínas de Señalización Intracelular/inmunología , Glicoproteínas de Membrana/inmunología , Neuralgia/inmunología , Neuropatía de Fibras Pequeñas/inmunología , Animales , Femenino , Humanos , Inmunoglobulina G/sangre , Inmunoglobulina G/inmunología , Péptidos y Proteínas de Señalización Intracelular/sangre , Masculino , Glicoproteínas de Membrana/sangre , Ratones Endogámicos ICR , Neuropatía de Fibras Pequeñas/sangre

RESUMEN

BACKGROUND: Changes in inflammatory cytokine levels contribute to the induction and maintenance of neuropathic pain. We have shown that external low intensity focused ultrasound (liFUS) reduces allodynia in a common peroneal nerve injury (CPNI). Here, we investigate an underlying mechanism of action for this treatment and measure the effect of liFUS on inflammatory markers. METHODS: Male rats were divided into four groups: CPNI/liFUS, CPNI/shamliFUS, shamCPNI/liFUS, and shamCPNI/shamliFUS. Mechanical nociceptive thresholds were measured using Von Frey filaments (VFF) to confirm the absence/presence of allodynia at baseline, after CPNI, and after liFUS. Commercial microarray and ELISA assays were used to assess cytokine expression in the treated L5 dorsal root ganglion (DRG) and dorsal horn (DH) tissue 24 and 72 h after liFUS. RESULTS: VFF thresholds were significantly reduced following CPNI in both groups that received the injury (p < 0.001). After liFUS, only the CPNI/liFUS cohort showed a significant increase in mechanical thresholds (p < 0.001). CPNI significantly increased TNFa, IL6, CNTF, IL1b (p < 0.05 for all) levels in the DRG and DH, compared to baseline, consistent with previous work in sciatic nerve injury. LiFUS in CPNI rats resulted in a decrease in these cytokines in DRG 72 h post-therapy (TNFa, IL6, CNTF and IL1b, p < 0.001). In the DH, IL1b, CNTF, and TNFa (p < 0.05 for all) decreased 72 h after liFUS. CONCLUSION: We have demonstrated that liFUS modifies inflammatory cytokines in both DRG and DH in CPNI rats. These data provide evidence that liFUS, reverses the allodynic phenotype, in part, by altering inflammatory cytokine pathways.

Asunto(s)

Hiperalgesia/terapia , Neuralgia/terapia , Traumatismos de los Nervios Periféricos/complicaciones , Terapia por Ultrasonido/métodos , Animales , Citocinas/metabolismo , Modelos Animales de Enfermedad , Ganglios Espinales/inmunología , Ganglios Espinales/metabolismo , Humanos , Hiperalgesia/diagnóstico , Hiperalgesia/inmunología , Masculino , Neuralgia/diagnóstico , Neuralgia/inmunología , Traumatismos de los Nervios Periféricos/inmunología , Traumatismos de los Nervios Periféricos/terapia , Nervio Peroneo/lesiones , Ratas , Ratas Sprague-Dawley , Transducción de Señal/inmunología , Transducción de Señal/efectos de la radiación , Asta Dorsal de la Médula Espinal/inmunología , Asta Dorsal de la Médula Espinal/metabolismo , Ondas Ultrasónicas

RESUMEN

It has become increasingly clear that the innate immune system plays an essential role in the generation of many types of neuropathic pain including that which accompanies cancer treatment. In this article we review current findings of the role of the innate immune system in contributing to cancer treatment pain at the distal endings of peripheral nerve, in the nerve trunk, in the dorsal root ganglion and in the spinal dorsal horn.

Asunto(s)

Antineoplásicos/efectos adversos , Inmunidad Innata/inmunología , Neuralgia/inducido químicamente , Neuralgia/inmunología , Animales , Ganglios Espinales/efectos de los fármacos , Ganglios Espinales/inmunología , Humanos , Inmunidad Innata/efectos de los fármacos , Neuralgia/patología , Asta Dorsal de la Médula Espinal/efectos de los fármacos , Asta Dorsal de la Médula Espinal/inmunología

RESUMEN

Bidirectional interplay between the peripheral immune and nervous systems plays a crucial role in maintaining homeostasis and responding to noxious stimuli. This crosstalk is facilitated by a variety of cytokines, inflammatory mediators and neuropeptides. Dysregulation of this delicate physiological balance is implicated in the pathological mechanisms of various skin disorders and peripheral neuropathies. The skin is a highly complex biological structure within which peripheral sensory nerve terminals and immune cells colocalise. Herein, we provide an overview of the sensory innervation of the skin and immune cells resident to the skin. We discuss modulation of cutaneous immune response by sensory neurons and their mediators (e.g., nociceptor-derived neuropeptides), and sensory neuron regulation by cutaneous immune cells (e.g., nociceptor sensitization by immune-derived mediators). In particular, we discuss recent findings concerning neuroimmune communication in skin infections, psoriasis, allergic contact dermatitis and atopic dermatitis. We then summarize evidence of neuroimmune mechanisms in the skin in the context of peripheral neuropathic pain states, including chemotherapy-induced peripheral neuropathy, diabetic polyneuropathy, post-herpetic neuralgia, HIV-induced neuropathy, as well as entrapment and traumatic neuropathies. Finally, we highlight the future promise of emerging therapies associated with skin neuroimmune crosstalk in neuropathic pain.

Asunto(s)

Citocinas/inmunología , Mediadores de Inflamación/inmunología , Neuralgia/inmunología , Neuroinmunomodulación/inmunología , Células Receptoras Sensoriales/inmunología , Piel/inmunología , Animales , Citocinas/metabolismo , Humanos , Mediadores de Inflamación/metabolismo , Modelos Inmunológicos , Neuralgia/metabolismo , Neuralgia/fisiopatología , Nociceptores/inmunología , Nociceptores/metabolismo , Células Receptoras Sensoriales/metabolismo , Piel/inervación , Piel/metabolismo

RESUMEN

Chronic neuropathic pain (CNP) is caused by a lesion or disease of the somatosensory nervous system. It affects ~8% of the general population and negatively impacts a person's level of functioning and quality of life. Its resistance to available pain therapies makes CNP a major unmet medical need. Immune cells have been shown to play a role for development, maintenance and recovery of CNP and therefore are attractive targets for novel pain therapies. In particular, in neuropathic mice and humans, microglia are activated in the dorsal horn and peripheral immune cells infiltrate the nervous system to promote chronic neuroinflammation and contribute to the initiation and progression of CNP. Importantly, immunity not only controls pain development and maintenance, but is also essential for pain resolution. In particular, regulatory T cells, a subpopulation of T lymphocytes with immune regulatory function, and macrophages were shown to be important contributors to pain recovery. In this review we summarize the interactions of the peripheral immune system with the nervous system and outline their contribution to the development and recovery of pain.

Asunto(s)

Dolor Crónico/inmunología , Memoria Inmunológica , Macrófagos/inmunología , Neuralgia/inmunología , Linfocitos T Reguladores/inmunología , Animales , Dolor Crónico/patología , Dolor Crónico/terapia , Humanos , Macrófagos/patología , Neuralgia/patología , Neuralgia/terapia , Linfocitos T Reguladores/patología

RESUMEN

BACKGROUND: Human immunodeficiency virus (HIV)-associated distal symmetric peripheral neuropathy (DSPN) is one of the most frequent neurological complications of HIV infection, and causes pain and dysaesthesias in millions globally. Many individuals with this infection report using acupuncture to manage their symptoms, but evidence supporting the use of acupuncture is limited. This systematic review will assess the effectiveness and safety of acupuncture for patients with HIV-associated DSPN. METHODS: Databases including MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, Scopus, Web of science, AMED (Allied and Complementary Medicine), the Chinese Biomedical Literature Database, the China National Knowledge Infrastructure, Wanfang Database, VIP Database and clinical trials registers (the WHO International Clinical Trials Registry Platform portal and www.ClinicalTrials.gov) will be electronically searched from inception to December 1, 2020. All randomized controlled trials in English or Chinese without restriction on publication status will be included. Selection of studies, extraction of data, and assessment of studies quality will be independently performed by 2 reviewers. The primary outcome measure will be the change in pain intensity assessed by validated scales. Secondary outcomes include change in neurologic summary scores, quality of life, physical function evaluated by admitted tools, and adverse events related to acupuncture reported in the included trials. If possible, a meta-analysis will be conducted to provide an estimate of the pooled treatment effect using Review Manager 5.3 statistical software. Otherwise, qualitative descriptive analysis will be given. The results will be presented as the risk ratio for binary data and the mean difference (MD) or standardized MD for continuous data. RESULTS: The results of the systematic review will be disseminated via publication in a peer-reviewed journal and presented at a relevant conference. CONCLUSION: This review will be the first review entirely focused on assessing the effectiveness and safety of acupuncture for HIV-associated DSPN. PROSPERO REGISTRATION NUMBER: CRD42020210994.

Asunto(s)

Terapia por Acupuntura/efectos adversos , Infecciones por VIH/complicaciones , Neuralgia/terapia , Parestesia/terapia , Polineuropatías/terapia , Infecciones por VIH/inmunología , Infecciones por VIH/virología , Humanos , Metaanálisis como Asunto , Neuralgia/diagnóstico , Neuralgia/inmunología , Neuralgia/virología , Dimensión del Dolor , Parestesia/diagnóstico , Parestesia/inmunología , Parestesia/virología , Polineuropatías/diagnóstico , Polineuropatías/inmunología , Polineuropatías/virología , Calidad de Vida , Ensayos Clínicos Controlados Aleatorios como Asunto , Índice de Severidad de la Enfermedad , Revisiones Sistemáticas como Asunto , Resultado del Tratamiento

RESUMEN

The A3 adenosine receptor (A3AR) has emerged as a therapeutic target with A3AR agonists to tackle the global challenge of neuropathic pain, and investigation into its mode of action is essential for ongoing clinical development. Immune cell A3ARs, and their activation during pathology, modulate cytokine release. Thus, the use of immune cells as a cellular substrate for the pharmacological action of A3AR agonists is enticing, but unknown. The present study discovered that Rag-KO mice lacking T and B cells, as compared with WT mice, are insensitive to the anti-allodynic effects of A3AR agonists. Similar findings were observed in interleukin-10 and interleukin-10 receptor knockout mice. Adoptive transfer of CD4+ T cells from WT mice infiltrated the dorsal root ganglion (DRG) and restored A3AR agonist-mediated anti-allodynia in Rag-KO mice. CD4+ T cells from Adora3-KO or Il10-KO mice did not. Transfer of CD4+ T cells from WT mice, but not Il10-KO mice, into Il10-KO mice or Adora3-KO mice fully reinstated the anti-allodynic effects of A3AR activation. Notably, A3AR agonism reduced DRG neuron excitability when cocultured with CD4+ T cells in an IL-10-dependent manner. A3AR action on CD4+ T cells infiltrated in the DRG decreased phosphorylation of GluN2B-containing N-methyl-D-aspartate receptors at Tyr1472, a modification associated with regulating neuronal hypersensitivity. Our findings establish that activation of A3AR on CD4+ T cells to release IL-10 is required and sufficient evidence for the use of A3AR agonists as therapeutics.

Asunto(s)

Agonistas del Receptor de Adenosina A3/farmacología , Linfocitos T CD4-Positivos/inmunología , Ganglios Espinales/inmunología , Interleucina-10/inmunología , Neuralgia/tratamiento farmacológico , Neuronas/inmunología , Receptor de Adenosina A3/inmunología , Animales , Linfocitos B/inmunología , Linfocitos B/patología , Linfocitos T CD4-Positivos/patología , Ganglios Espinales/patología , Interleucina-10/genética , Ratones , Ratones Noqueados , Neuralgia/genética , Neuralgia/inmunología , Neuralgia/patología , Neuronas/patología , Receptor de Adenosina A3/genética

RESUMEN

Mutations within the SCN11A gene which encodes the voltage-gated sodium channel NaV1.9 mainly expressed in small fiber sensory neurons have been associated with neuropathic disorders; however, suitable medications have not been fully investigated. To develop drug therapies against NaV1.9-related neuropathic pain, we aimed to establish a novel model using mice carrying the Scn11a p.R222S mutation initially identified in patients with familial episodic limb pain that is characterized by paroxysmal pain induced by fatigue or bad weather conditions. We investigated the influence of cold exposure (4 °C, overnight) on the behavioral and biochemical phenotypes of Scn11a p.R222S mutant (R222S) and wild type C57BL/6N (WT) mice. We also tested the effects of acetaminophen (125, 250 mg/kg, perorally, p.o.) and traditional Japanese medicine, goshajinkigan (0.5 or 1.0 g/kg, p.o.), which are analgesic drugs prescribed to patients with neuropathic pain, in this model of cold-induced mechanical allodynia in R222S mice.Cold-exposed R222S mice exhibited enhanced mechanical allodynia and thermal hypersensitivity compared with WT mice. The decrease of the mechanical withdrawal threshold in R222S mice was reversible 24 h after housing at room temperature. There was no significant change in the levels of interleukin-1ß, interleukin-6, tumor necrosis factor-α, or interferon-γ in the plasma or spinal cords of WT and R222S mice after cold exposure. Both acetaminophen (250 mg/kg) and goshajinkigan (1.0 g/kg) significantly attenuated mechanical allodynia in R222S mice. The model of cold-induced mechanical allodynia in mice with the Scn11a p.R222S mutation is novel and useful for evaluating analgesic drugs for intractable neuropathies related to NaV1.9.

Asunto(s)

Modelos Animales de Enfermedad , Hiperalgesia , Canal de Sodio Activado por Voltaje NAV1.9/genética , Neuralgia , Acetaminofén/uso terapéutico , Analgésicos/uso terapéutico , Animales , Frío , Citocinas/sangre , Citocinas/inmunología , Medicamentos Herbarios Chinos/uso terapéutico , Miembro Posterior/patología , Hiperalgesia/tratamiento farmacológico , Hiperalgesia/genética , Hiperalgesia/inmunología , Hiperalgesia/patología , Masculino , Ratones Endogámicos C57BL , Ratones Mutantes , Mutación Missense , Neuralgia/tratamiento farmacológico , Neuralgia/genética , Neuralgia/inmunología , Neuralgia/patología , Médula Espinal/inmunología , Tacto

RESUMEN

BACKGROUND: MicroRNAs play a crucial role in diabetic peripheral neuropathic pain (DPNP). miR-590-3p is a novel miRNA and involved in multiple diseases. However, the pathological mechanism of miR-590-3p in DPNP needs to be elucidated. MATERIALS AND METHODS: The db/db mice and db/m mice were selected to mimic diabetes and control, respectively, for in vivo studies. The miR-590-3p agomir was injected into db/db mice and pain-related behavioral tests were performed. The interaction of miR-590-3p with target gene was confirmed by dual-luciferase reporter assay. The expression of target gene was determined by qRT-PCR and western blot assay. The levels of inflammatory cytokines were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: miR-590-3p was down-regulated in diabetic peripheral neuropathy mice. More importantly, miR-590-3p agomir alleviated pain-related behavior, reduced TNF-α, IL-1ß and IL-6 concentrations, and inhibited neural infiltration by immune cells in db/db mice. Interestingly, RAP1A was predicted to be the target of miR-590-3p by Targetscan, and was actually regulated by miR-590-3p. Finally, the rescue experiments proved that overexpression of RAP1A partially abrogated the suppressive impact of miR-590-3p on T cells proliferation and migration. CONCLUSION: miR-590-3p ameliorates DPNP via targeting RAP1A and inhibiting T cells infiltration, indicating that exogenous miR-590-3p may be a potential candidate for clinical treatment of DPNP.

Asunto(s)

Diabetes Mellitus Tipo 2/genética , Neuropatías Diabéticas/genética , MicroARNs/genética , Neuralgia/genética , Linfocitos T/inmunología , Proteínas de Unión al GTP rap1/genética , Animales , Antagomirs/genética , Antagomirs/metabolismo , Emparejamiento Base , Secuencia de Bases , Movimiento Celular , Proliferación Celular , Diabetes Mellitus Tipo 2/inmunología , Diabetes Mellitus Tipo 2/patología , Neuropatías Diabéticas/inmunología , Neuropatías Diabéticas/patología , Modelos Animales de Enfermedad , Ganglios Espinales/inmunología , Ganglios Espinales/patología , Regulación de la Expresión Génica , Genes Reporteros , Interleucina-1beta/genética , Interleucina-1beta/inmunología , Interleucina-6/genética , Interleucina-6/inmunología , Luciferasas/genética , Luciferasas/metabolismo , Masculino , Ratones , MicroARNs/agonistas , MicroARNs/antagonistas & inhibidores , MicroARNs/inmunología , Neuralgia/inmunología , Neuralgia/patología , Neuralgia/prevención & control , Oligorribonucleótidos/genética , Oligorribonucleótidos/metabolismo , Transducción de Señal , Linfocitos T/patología , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/inmunología , Proteínas de Unión al GTP rap1/inmunología

RESUMEN

Adaptor molecule downstream of kinase-3 (DOK3) is a vital regulator of innate immune responses in macrophages and B cells, and G-protein-coupled receptor 84 (GPR84) is significant in mediating the biosynthesis and maintenance of inflammatory mediators that are induced by neuropathic pain in microglia. In the present study, we determined the role of DOK3 in activating microglia-induced neuropathic pain and investigated the underlying mechanisms associated with GPR84. We found that knockdown of DOK3 in microglial cells dramatically reduced the levels of inflammatory factors, and we uncovered a physical association between DOK3 and GPR84 in the induction of inflammatory responses. We also observed that neuropathic pain and inflammatory responses induced by chronic constriction injury (CCI) of the sciatic nerve or intrathecal injection of a GPR84 agonist were compromised in DOK3-/- mice in vivo. Finally, enforced expression of DOK3 provoked inflammatory responses, and administration of pregabalin relieved neuropathic pain via inhibition of DOK3 expression. In conclusion, DOK3 induced neuropathic pain in mice by interacting with GPR84 in microglia. We hypothesize that targeting the adaptor protein DOK3 may open new avenues for pharmaceutical approaches to the alleviation of neuropathic pain in the spinal cord.

Asunto(s)

Proteínas Adaptadoras Transductoras de Señales/genética , Microglía/metabolismo , Neuralgia/genética , Receptores Acoplados a Proteínas G/metabolismo , Proteínas Adaptadoras Transductoras de Señales/efectos de los fármacos , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Analgésicos/farmacología , Animales , Línea Celular , Técnicas de Silenciamiento del Gen , Inflamación , Ratones , Ratones Noqueados , Microglía/inmunología , Neuralgia/inmunología , Neuralgia/metabolismo , Pregabalina/farmacología , Receptores Acoplados a Proteínas G/agonistas , Nervio Ciático/lesiones

RESUMEN

Cathepsin S (CatS) is a cysteine protease found in lysosomes of hematopoietic and microglial cells and in secreted form in the extracellular space. While CatS has been shown to contribute significantly to neuropathic pain, the precise mechanisms remain unclear. In this report, we describe JNJ-39641160, a novel non-covalent, potent, selective and orally-available CatS inhibitor that is peripherally restricted (non-CNS penetrant) and may represent an innovative class of immunosuppressive and analgesic compounds and tools useful toward investigating peripheral mechanisms of CatS in neuropathic pain. In C57BL/6 mice, JNJ-39641160 dose-dependently blocked the proteolysis of the invariant chain, and inhibited both T-cell activation and antibody production to a vaccine antigen. In the spared nerve injury (SNI) model of chronic neuropathic pain, in which T-cell activation has previously been demonstrated to be a prerequisite for the development of pain hypersensitivity, JNJ-39641160 fully reversed tactile allodynia in wild-type mice but was completely ineffective in the same model in CatS knockout mice (which exhibited a delayed onset in allodynia). By contrast, in the acute mild thermal injury (MTI) model, JNJ-39641160 only weakly attenuated allodynia at the highest dose tested. These findings support the hypothesis that blockade of peripheral CatS alone is sufficient to fully reverse allodynia following peripheral nerve injury and suggest that the mechanism of action likely involves interruption of T-cell activation and peripheral cytokine release. In addition, they provide important insights toward the development of selective CatS inhibitors for the treatment of neuropathic pain in humans.

Asunto(s)

Analgésicos/uso terapéutico , Catepsinas/antagonistas & inhibidores , Hiperalgesia/tratamiento farmacológico , Inmunosupresores/uso terapéutico , Neuralgia/tratamiento farmacológico , Traumatismos de los Nervios Periféricos/tratamiento farmacológico , Inhibidores de Proteasas/uso terapéutico , Analgésicos/farmacocinética , Analgésicos/farmacología , Animales , Encéfalo/metabolismo , Catepsinas/genética , Catepsinas/metabolismo , Línea Celular , Citocinas/inmunología , Calor , Humanos , Hiperalgesia/inmunología , Inmunoglobulina E/inmunología , Inmunoglobulina G/inmunología , Inmunosupresores/farmacocinética , Inmunosupresores/farmacología , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Neuralgia/inmunología , Traumatismos de los Nervios Periféricos/inmunología , Inhibidores de Proteasas/farmacocinética , Inhibidores de Proteasas/farmacología , Nervio Ciático/lesiones , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunología , Toxoide Tetánico/administración & dosificación , Tacto