Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 2.552
Filtrar
1.
Zhongguo Zhong Yao Za Zhi ; 47(9): 2533-2540, 2022 May.
Artigo em Chinês | MEDLINE | ID: mdl-35531701

RESUMO

Neuropathic pain is one of the common complications of diabetes. Tetrahydropalmatine(THP) is a main active component of Corydalis Rhizoma with excellent anti-inflammatory and pain-alleviating properties. This study aims to investigate the therapeutic effect of THP on diabetic neuropathic pain(DNP) and the underlying mechanism. High-fat and high-sugar diet(4 weeks) and streptozotocin(STZ, 35 mg·kg~(-1), single intraperitoneal injection) were employed to induce type-2 DNP in rats. Moreover, lipopolysaccharide(LPS) was used to induce the activation of BV2 microglia in vitro to establish an inflammatory cellular model. Fasting blood glucose(FBG) was measured by a blood glucose meter. Mechanical withdrawal threshold(MWT) was assessed with von Frey filaments, and thermal withdrawal latency(TWL) with hot plate apparatus. The protein expression levels of OX42, inducible nitric oxide synthase(iNOS), CD206, p38, and p-p38 were determined by Western blot, the fluorescence expression levels of OX42 and p-p38 in the dorsal horn of the rat spinal cord by immunofluorescence, the mRNA content of p38 and OX42 in rat spinal cord tissue by qRT-PCR, and levels of nitric oxide(NO), interleukin-1ß(IL-1ß), interleukin-6(IL-6), tumor necrosis factor-α(TNF-α), interleukin-10(IL-10), and serum fasting insulin(FINS) by enzyme-linked immunosorbent assay(ELISA). RESULTS:: showed that the mo-del group demonstrated significant decrease in MWT and TWL, with pain symptoms. THP significantly improved the MWT and TWL of DNP rats, inhibited the activation of microglia and p38 MAPK signaling pathway in rat spinal cord, and ameliorated its inflammatory response. Meanwhile, THP promoted the change of LPS-induced BV2 microglia from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype, suppressed the activation of the p38 MAPK signaling pathway, decreased the expression levels of inflammatory factors NO, IL-1ß, IL-6, and TNF-α, and increased the expression level of anti-inflammatory factor IL-10. The findings suggested that THP can significantly ameliorate the pain symptoms of DNP rats possibly by inhibiting the inflammatory response caused by M1 polarization of microglia via the p38 MAPK pathway.


Assuntos
Diabetes Mellitus , Neuropatias Diabéticas , Neuralgia , Animais , Alcaloides de Berberina , Glicemia/metabolismo , Neuropatias Diabéticas/tratamento farmacológico , Neuropatias Diabéticas/genética , Interleucina-10 , Interleucina-6/metabolismo , Lipopolissacarídeos/farmacologia , Microglia , Neuralgia/tratamento farmacológico , Neuralgia/genética , Neuralgia/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais , Medula Espinal/metabolismo , Estreptozocina/metabolismo , Estreptozocina/farmacologia , Estreptozocina/uso terapêutico , Fator de Necrose Tumoral alfa/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/genética , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
2.
Zhongguo Zhong Yao Za Zhi ; 47(8): 2187-2194, 2022 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-35531735

RESUMO

The present study investigated the effect of emodin on the serum metabolite profiles in the chronic constriction injury(CCI) model by non-target metabolomics and explored its analgesic mechanism. Twenty-four Sprague Dawley(SD) rats were randomly divided into a sham group(S), a CCI group(C), and an emodin group(E). The rats in the emodin group were taken emodin via gavage once a day for fifteen days(50 mg·kg~(-1)) on the first day after the CCI surgery. Mechanical withdrawal threshold(MWT) and thermal withdrawal threshold(TWL) in each group were performed before the CCI surgery and 3,7, 11, and 15 days after surgery. After 15 days, blood samples were collected from the abdominal aorta. The differential metabolites were screened out by non-target metabolomics and analyzed with Kyoto Encyclopedia of Genes and Genomes(KEGG) and ingenuity pathway analysis(IPA). From the third day after CCI surgery, the MWT and TWL values were reduced significantly in both CCI group and emodin group, compared with the sham group(P<0.01). At 15 days post-surgery, the MWT and TWL values in emodin group increased significantly compared with the CCI group(P<0.05). As revealed by non-target metabolomics, 72 differential serum metabolites were screened out from the C-S comparison, including 41 up-regulated and 31 down-regulated ones, while 26 differential serum metabolites from E-C comparison, including 10 up-regulated and 16 down-regulated ones. KEGG analysis showed that the differential metabolites in E-C comparison were enriched in the signaling pathways, such as sphingolipid metabolism, arginine biosynthesis, glycerophospholipid metabolism, and tryptophan metabolism. IPA showed that the differential metabolites were mainly involved in the lipid metabolism-molecular transport-small molecule biochemistry network. In conclusion, emodin can exert an analgesic role via regulating sphingolipid metabolism and arginine biosynthesis.


Assuntos
Emodina , Neuralgia , Analgésicos/farmacologia , Animais , Arginina , Emodina/farmacologia , Neuralgia/tratamento farmacológico , Neuralgia/metabolismo , Ratos , Ratos Sprague-Dawley , Esfingolipídeos
3.
Eur J Pharmacol ; 923: 174935, 2022 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-35378102

RESUMO

Chronic neuropathic pain (CNP) can result from surgery or traumatic injury, but also from peripheral neuropathies caused by diseases, viral infections, or toxic treatments. Opioids, although very effective for acute pain, do not prevent the development of CNP, and are considered as insufficient treatment. Therefore, there is high need for effective and safe non-opioid options to treat, prevent and eventually reverse CNP. A more effective approach to alleviating CNP would constitute a treatment that acts concurrently on various mechanisms involved in relieving pain symptoms and preventing or reversing chronification by enhancing both neuroprotection and neuroregeneration. We have identified and characterized GRT-X (N-[(3-fluorophenyl)-methyl]-1-(2-methoxyethyl)-4-methyl-2-oxo-(7-trifluoromethyl)-1H-quinoline-3-caboxylic acid amide), a novel drug which is able to activate both voltage-gated potassium channels of the Kv7 family and the mitochondrial translocator protein 18 kDa (TSPO). The dual mode-of-action (MoA) of GRT-X was indicated in in vitro studies and in vivo in a rat model of diabetic neuropathy. In this model, mechanical hyperalgesia was dose-dependently inhibited. After severe crush lesion of cervical spinal nerves in rats, GRT-X promoted survival, speeded up regrowth of sensory and motor neurons, and accelerated recovery of behavioral and neuronal responses to heat, cold, mechanical and electrical stimuli. These properties may reduce the likelihood of chronification of acute pain, and even potentially relieve established CNP. The absence of a conditioned place preference in rats suggests lack of abuse potential. In conclusion, GRT-X offers a promising preclinical profile with a novel dual MoA.


Assuntos
Dor Aguda , Neuralgia , Dor Aguda/tratamento farmacológico , Animais , Hiperalgesia/metabolismo , Regeneração Nervosa , Neuralgia/metabolismo , Neuroproteção , Ratos
4.
J Clin Invest ; 132(8)2022 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-35426375

RESUMO

Mice with experimental nerve damage can display long­lasting neuropathic pain behavior. We show here that 4 months and later after nerve injury, male but not female mice displayed telomere length (TL) reduction and p53­mediated cellular senescence in the spinal cord, resulting in maintenance of pain and associated with decreased lifespan. Nerve injury increased the number of p53­positive spinal cord neurons, astrocytes, and microglia, but only in microglia was the increase male­specific, matching a robust sex specificity of TL reduction in this cell type, which has been previously implicated in male­specific pain processing. Pain hypersensitivity was reversed by repeated intrathecal administration of a p53­specific senolytic peptide, only in male mice and only many months after injury. Analysis of UK Biobank data revealed sex-specific relevance of this pathway in humans, featuring male­specific genetic association of the human p53 locus (TP53) with chronic pain and a male-specific effect of chronic pain on mortality. Our findings demonstrate the existence of a biological mechanism maintaining pain behavior, at least in males, occurring much later than the time span of virtually all extant preclinical studies.


Assuntos
Dor Crônica , Neuralgia , Animais , Senescência Celular , Dor Crônica/genética , Dor Crônica/metabolismo , Feminino , Hiperalgesia/metabolismo , Masculino , Camundongos , Microglia/metabolismo , Neuralgia/genética , Neuralgia/metabolismo , Medula Espinal/metabolismo , Telômero/genética , Telômero/metabolismo , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
5.
Sci Transl Med ; 14(639): eabh2557, 2022 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-35385340

RESUMO

Diabetic neuropathic pain (DNP) is a common and devastating complication in patients with diabetes. The mechanisms mediating DNP are not completely elucidated, and effective treatments are lacking. A-fiber sensory neurons have been shown to mediate the development of mechanical allodynia in neuropathic pain, yet the molecular basis underlying the contribution of A-fiber neurons is still unclear. Here, we report that the orphan G protein-coupled receptor 177 (GPR177) in A-fiber neurons drives DNP via WNT5a-mediated activation of transient receptor potential vanilloid receptor-1 (TRPV1) ion channel. GPR177 is mainly expressed in large-diameter A-fiber dorsal root ganglion (DRG) neurons and required for the development of DNP in mice. Mechanistically, we found that GPR177 mediated the secretion of WNT5a from A-fiber DRG neurons into cerebrospinal fluid (CSF), which was necessary for the maintenance of DNP. Extracellular perfusion of WNT5a induced rapid currents in both TRPV1-expressing heterologous cells and nociceptive DRG neurons. Computer simulations revealed that WNT5a has the potential to bind the residues at the extracellular S5-S6 loop of TRPV1. Using a peptide able to disrupt the predicted WNT5a/TRPV1 interaction suppressed DNP- and WNT5a-induced neuropathic pain symptoms in rodents. We confirmed GPR177/WNT5A coexpression in human DRG neurons and WNT5A secretion in CSF from patients with DNP. Thus, our results reveal a role for WNT5a as an endogenous and potent TRPV1 agonist, and the GPR177-WNT5a-TRPV1 axis as a driver of DNP pathogenesis in rodents. Our findings identified a potential analgesic target that might relieve neuropathic pain in patients with diabetes.


Assuntos
Diabetes Mellitus , Neuropatias Diabéticas , Peptídeos e Proteínas de Sinalização Intracelular , Neuralgia , Receptores Acoplados a Proteínas G , Canais de Cátion TRPV , Proteína Wnt-5a , Animais , Diabetes Mellitus/metabolismo , Neuropatias Diabéticas/metabolismo , Gânglios Espinais/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Camundongos , Neuralgia/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Células Receptoras Sensoriais/metabolismo , Canais de Cátion TRPV/metabolismo , Proteína Wnt-5a/metabolismo
6.
Biochem Biophys Res Commun ; 607: 60-66, 2022 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-35366545

RESUMO

Hepatocyte growth factor (HGF) is a secretory protein that is involved in various biological activities such as angiogenesis, neuroprotection, and anti-inflammatory effects. Intramuscular injection of an HGF-encoding plasmid DNA (pCK-HGF-X7) has been shown to produce pain-relieving effects in a rodent model and patients with neuropathic pain.To further investigate the underlying mechanism, we investigated the anti-inflammatory effects of HGF in the context of neuropathic pain. Consistent with previous data, intramuscular injection of pCK-HGF-X7 showed pain relieving effects up to 8 weeks and pharmacological blockade of the c-Met receptor hindered this effect, which suggest that the analgesic effect was c-Met receptor-dependent. At the histological level, macrophage infiltration in the dorsal root ganglion (DRG) was significantly decreased in the pCK-HGF-X7 injected group. Moreover, HGF treatment significantly downregulated the LPS-mediated induction of pro-inflammatory cytokines in primary cultured DRG neurons. Taken together, these data suggest that HGF-encoding plasmid DNA attenuates neuropathic pain via controlling the expression of pro-inflammatory cytokines.


Assuntos
Fator de Crescimento de Hepatócito , Neuralgia , Animais , Anti-Inflamatórios/metabolismo , DNA/metabolismo , Modelos Animais de Doenças , Gânglios Espinais/metabolismo , Terapia Genética , Fator de Crescimento de Hepatócito/metabolismo , Humanos , Injeções Intramusculares , Neuralgia/genética , Neuralgia/metabolismo , Neuralgia/terapia , Plasmídeos/genética
7.
Neurobiol Dis ; 168: 105716, 2022 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-35367629

RESUMO

The distinction between glial painful and protective pathways is unclear and the possibility to finely modulate the system is lacking. Focusing on painful neuropathies, we studied the role of interleukin 1α (IL-1α), an alarmin belonging to the larger family of damage-associated molecular patterns endogenously secreted to restore homeostasis. The treatment of rat primary neurons with increasing doses of the neurotoxic anticancer drug oxaliplatin (0.3-100µM, 48 h) induced the release of IL-1α. The knockdown of the alarmin in neurons leads to their higher mortality when co-cultured with astrocytes. This toxicity was related to increased extracellular ATP and decreased release of transforming growth factor ß1, mostly produced by astrocytes. In a rat model of neuropathy induced by oxaliplatin, the intrathecal treatment with IL-1α was able to reduce mechanical and thermal hypersensitivity both after acute injection (100 ng and 300 ng) and continuous infusion (100 and 300 ng/die-1). Ex vivo analysis on spinal purified astrocyte processes (gliosomes) and nerve terminals (synaptosomes) revealed the property of IL-1α to reduce the endogenous glutamate release induced by oxaliplatin. This protective effect paralleled with an increased number of GFAP-positive cells in the spinal cord, suggesting the ability of IL-1α to evoke a positive, conservative astrocyte phenotype. Endogenous IL-1α induced protective signals in the cross-talk between neurons and astrocytes. Exogenously administered in rats, IL-1α prevented neuropathic pain in the presence of spinal glutamate decrease and astrocyte activation.


Assuntos
Antineoplásicos , Neuralgia , Alarminas/efeitos adversos , Alarminas/metabolismo , Animais , Antineoplásicos/efeitos adversos , Astrócitos/metabolismo , Ácido Glutâmico/metabolismo , Hiperalgesia/metabolismo , Interleucina-1alfa/efeitos adversos , Interleucina-1alfa/metabolismo , Neuralgia/metabolismo , Neurônios/metabolismo , Oxaliplatina/toxicidade , Ratos , Ratos Sprague-Dawley , Medula Espinal/metabolismo
8.
Physiol Behav ; 251: 113807, 2022 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-35427673

RESUMO

BACKGROUND: Cell therapy is a promising treatment method for relieving neuropathic pain caused by spinal cord injuries (SCI). Sertoli cells (SCs) are an attractive choice given their demonstrated secretion of growth factors and immunosuppressant effect. This study mechanistically characterizes the analgesic effect of SCs transplantation. METHODS: The clip compression SCI model was carried out on the T12-T13 level in male Wistar rats. One-week post-SCI, SCs were transplanted into the site of injury. Animals underwent Basso, Beattie, and Bresnahan locomotor scoring, mechanical allodynia, and thermal hyperalgesia on a weekly basis for a duration of six weeks. Histological examination of the spinal cord and molecular evaluation of Iba-1, P2Y4, TRPC6, and P-mTOR were performed. SCs survival, measured by anti-Müllerian hormone expression in the spinal cord. RESULTS: Animals that received SCs transplantation showed improvement in motor function recovery and pain relief. Furthermore, a cavity was significantly decreased in the transplanted animals (p = 0.0024), the expression level of TRPC6 and caspase3 and the number of activated microglia decreased compared to the SCI animals, and p-mTOR and P2Y4R expression remarkably increased compared to the SCI group. CONCLUSION: SCs transplantation produces an analgesic effect which may represent a promising treatment for SCI-induced chronic pain.


Assuntos
Neuralgia , Traumatismos da Medula Espinal , Analgésicos , Animais , Transplante de Células/efeitos adversos , Hiperalgesia/etiologia , Hiperalgesia/terapia , Masculino , Microglia/metabolismo , Neuralgia/etiologia , Neuralgia/metabolismo , Neuralgia/terapia , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Células de Sertoli/metabolismo , Células de Sertoli/patologia , Medula Espinal/patologia , Traumatismos da Medula Espinal/complicações , Traumatismos da Medula Espinal/terapia , Serina-Treonina Quinases TOR/metabolismo , Canais de Cátion TRPC , Canal de Cátion TRPC6/metabolismo
9.
Physiol Behav ; 251: 113818, 2022 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-35443199

RESUMO

BACKGROUND: Brain cortical areas are involved in processing of sensory, affective and cognitive aspects of pain. In the present study, microinjection effects of oxytocin and L-368,899 (an oxytocin receptor antagonist) into the primary somatosensory cortex (S1) and anterior cingulate cortex (ACC) were investigated on sensory and affective aspects of neuropathic pain. METHODS: Neuropathic pain was induced by partial sciatic nerve ligation (PSNL). Seven days later, right and left sides of S1 and ACC were surgically implanted with guide cannulas. Sensory (day 14) and affective (day 17) dimensions were recorded using von Frey filaments and place escape avoidance paradigm, respectively. The S1 and ACC oxytocin receptor protein expression were also determined. RESULTS: The S1 and ACC oxytocin suppressed PSNL-induced mechanical allodynia, whereas PSNL-induced aversion was attenuated by ACC oxytocin. In the S1, alone L-368,899 with no effect on aversion increased mechanical allodynia, whereas, in the ACC, this treatment increased both mechanical allodynia and aversion. Pre-treatment with L-368,899 prevented oxytocin-induced anti-allodynia and anti-aversion. Oxytocin and L-368,899 did not alter mechanical allodynia in intact and sham groups. All the above-mentioned treatments did not change crossing number. The density of oxytocin receptors in the S1 and ACC of PSNL group was increased 1.5-2 folds in comparison to intact and sham groups. CONCLUSIONS: The results of the present study explained that the ACC and S1 oxytocin ameliorated sensory component of neuropathic pain, whereas affective component was attenuated only by ACC oxytocin. These effects might be related to the PSNL-increased oxytocin receptor expression in the S1 and ACC.


Assuntos
Giro do Cíngulo , Neuralgia , Animais , Giro do Cíngulo/metabolismo , Hiperalgesia/tratamento farmacológico , Ligadura , Neuralgia/tratamento farmacológico , Neuralgia/metabolismo , Ocitocina/metabolismo , Ocitocina/farmacologia , Ocitocina/uso terapêutico , Ratos , Receptores de Ocitocina/metabolismo , Nervo Isquiático , Córtex Somatossensorial/metabolismo
10.
ACS Chem Neurosci ; 13(9): 1446-1455, 2022 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-35420781

RESUMO

Specific protein 1 (Sp1) is a member of the Sp/Kruppel-like factor family, which regulates cellular processes of neurons in the nervous system. This study was performed to examine the regulatory role and the underlying mechanism of transcription factor Sp1 in neuropathic pain (NP)-like behaviors after spinal nerve ligation (SNL). Sp1 and histone deacetylase 1(HDAC1) expressions were determined in the C57BL6 mouse model with NP-like behaviors after SNL, which demonstrated that Sp1 and HDAC1 elevation occurred in neurons in the spinal dorsal horn of SNL mice. The chromatin immunoprecipitation assay verified that Sp1 was bound to the HDAC1 promoter region and HDAC1 to the SRY-box-containing gene 10 (SOX10) promoter region in the spinal dorsal horn. Immunofluorescence was performed to determine Sp1, HDAC1, and SOX10 in the spinal dorsal horn neurons as well as the neuronal marker (NeuN), microglial marker (Iba-1), and astrocyte marker (GFAP). The nociceptive test was performed to characterize the hindlimb paw withdrawal threshold (PWT) and paw withdrawal latency (PWL) of mice 0-10 days after model establishment. Loss- and gain-of-function assays revealed that Sp1 promoted HDAC1 expression, and HDAC1 in turn promoted SOX10 expression. HDAC1 elevation reversed the effects of Sp1 silencing, and the increased PWT and PWL of SNL mice were negated after SOX10 overexpression. Meanwhile, SOX10 also restored the results by Sp1 knockdown. Collectively, downregulating Sp1 alleviates NP-like behaviors after SNL via the HDAC1/SOX10 axis.


Assuntos
Neuralgia , Nervos Espinhais , Animais , Regulação para Baixo , Hiperalgesia/metabolismo , Ligadura , Camundongos , Camundongos Endogâmicos C57BL , Neuralgia/metabolismo , Fatores de Transcrição SOXE/genética , Fatores de Transcrição SOXE/metabolismo , Corno Dorsal da Medula Espinal/metabolismo , Nervos Espinhais/metabolismo , Sinapsinas/metabolismo
11.
J Healthc Eng ; 2022: 8313415, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35432830

RESUMO

Neuropathic pain since early diabetes swamps patients' lives, and diabetes mellitus has become an increasingly worldwide epidemic. No agent, so far, can terminate the ongoing diabetes. Therefore, strategies that delay the process and the further complications are preferred, such as diabetic neuropathic pain (DNP). Dysfunction of ion channels is generally accepted as the central mechanism of diabetic associated neuropathy, of which hyperpolarization-activated cyclic nucleotide-gated 2 (HCN2) ion channel has been verified the involvement of neuropathic pain in dorsal root ganglion (DRG) neurons. Riluzole is a benzothiazole compound with neuroprotective properties on intervention to various ion channels, including hyperpolarization-activated voltage-dependent channels. To investigate the effect of riluzole within lumbar (L3-5) DRG neurons from DNP models, streptozocin (STZ, 70 mg/kg) injection was recruited subcutaneously followed by paw withdrawal mechanical threshold (PWMT) and paw withdrawal thermal latency (PWTL), which both show significant reduction, whilst relieved by riluzole (4 mg/kg/d) administration, which was performed once daily for 7 consecutive days for 14 days. HCN2 expression was also decreased in line with alleviated behavioral tests. Our results indicate riluzole as the alleviator to STZ-induced DNP with involvement of downregulated HCN2 in lumbar DRG by continual systemic administration in rats.


Assuntos
Diabetes Mellitus , Neuropatias Diabéticas , Neuralgia , Animais , Neuropatias Diabéticas/complicações , Neuropatias Diabéticas/tratamento farmacológico , Neuropatias Diabéticas/metabolismo , Gânglios Espinais/metabolismo , Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização/metabolismo , Neuralgia/complicações , Neuralgia/tratamento farmacológico , Neuralgia/metabolismo , Neurônios , Nucleotídeos Cíclicos/metabolismo , Nucleotídeos Cíclicos/farmacologia , Canais de Potássio/metabolismo , Canais de Potássio/farmacologia , Ratos , Riluzol/metabolismo , Riluzol/farmacologia , Riluzol/uso terapêutico , Estreptozocina/metabolismo , Estreptozocina/farmacologia
12.
Neurosci Lett ; 778: 136615, 2022 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-35367570

RESUMO

BACKGROUND: Optimal neuropathic pain (NeP) therapy has still not been established despite great efforts to develop new strategies for NeP analgesia. One possible target might be calcitonin gene-related peptide (CGRP). This is because the expression of CGRP and its receptors in the dorsal horn of the spinal cord might be associated with the persistence of pain symptoms including symptoms of NeP. We previously developed αCGRP knockout mice, and we aimed in this study to clarify the roles of CGRP in NeP by partial sciatic nerve ligation (PSNL) using the knockout mice. METHODS: PSNL was performed in αCGRP knockout mice and wild-type (WT) mice, and spontaneous pain behavior and mechanical and thermal hyperalgesia were evaluated after PSNL. CGRP immunoreactivity (IR) was also observed in the superficial dorsal horn and deep dorsal horn of L4 to L5 segments of the spinal cord in WT mice after PSNL. RESULTS: Spontaneous pain behavior and mechanical and thermal hyperalgesia after PSNL were not different between αCGRP knockout mice and WT mice throughout the observation period. The expression of CGRP-IR was not different between the PSNL model and the sham operation model at 1 day and 7 days after surgery. CONCLUSION: The results suggest that the involvement of αCGRP may differ depending on the type and site of nerve injury, and clinical indications for anti-CGRP treatment of NeP should be carefully based on various pathophysiological conditions of NeP.


Assuntos
Peptídeo Relacionado com Gene de Calcitonina , Neuralgia , Animais , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Hiperalgesia/metabolismo , Ligadura/efeitos adversos , Camundongos , Camundongos Knockout , Neuralgia/metabolismo , Nervo Isquiático/metabolismo , Corno Dorsal da Medula Espinal/metabolismo
13.
J Nutr Biochem ; 104: 108979, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35245654

RESUMO

Among different types of chronic pain, neuropathic pain (NP), arising from damage to the nervous system, including peripheral fibers and central neurons, is notoriously difficult to treat and affects 7-10% of the general population. Currently available treatment options for NP are limited and opioid analgesics have severe side effects and can result in opioid use disorder. Recent studies have exhibited the role of dietary bioactive compounds in the mitigation of NP. Here, we assessed the effects of commonly consumed bioactive compounds (ginger, curcumin, omega-3 polyunsaturated fatty acids, epigallocatechin gallate, resveratrol, soy isoflavones, lycopene, and naringin) on NP and NP-related neuroinflammation. Cellular studies demonstrated that these bioactive compounds reduce inflammation via suppression of NF-κB and MAPK signaling pathways that regulate apoptosis/cell survival, antioxidant, and anti-inflammatory responses. Animal studies strongly suggest that these regularly consumed bioactive compounds have a pronounced anti-NP effect as shown by decreased mechanical allodynia, mechanical hyperalgesia, thermal hyperalgesia, and cold hyperalgesia. The proposed molecular mechanisms include (1) the enhancement of neuron survival, (2) the reduction of neuronal hyperexcitability by activation of antinociceptive cannabinoid 1 receptors and opioid receptors, (3) the suppression of sodium channel current, and (4) enhancing a potassium outward current in NP-affected animals, triggering a cascade of chemical changes within, and between neurons for pain relief. Human studies administered in this area have been limited. Future randomized controlled trials are warranted to confirm the findings of preclinical efficacies using bioactive compounds in patients with NP.


Assuntos
Neuralgia , Analgésicos Opioides , Animais , Antioxidantes/uso terapêutico , Humanos , Hiperalgesia/metabolismo , Neuralgia/tratamento farmacológico , Neuralgia/metabolismo , Manejo da Dor
14.
J Chem Neuroanat ; 121: 102086, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35257878

RESUMO

INTRODUCTION: Our previous work has shown that somatostatin effectively inhibits neuropathic pain by activating its type 2 receptor (SSTR2) in the dorsal root ganglion (DRG) and spinal cord of mice. However, the underlying mechanism of this activation has not been elucidated. METHODS: To explore further mechanisms, we examined pain behavior and the expression of neuropeptides such as calcitonin gene-related peptide (CGRP) in dorsal root ganglion neurons(DRGs) as well as the changes of the number of CGRP-IR DRGs in the mouse model of sciatic pinch nerve injury. RESULTS: In this model, the number of medium and small DRG neurons in ipsilateral CGRP-IR was slightly increased, but not significantly, compared with sham animals at 3, 7, and 9 days after pinch nerve injury. This correlated with the behavioral readouts of hypersensitivity at the same time points. However, the magnitude of the painful behavior (Autotomy) was observed after application of SSTR2 antagonist (CYN154806, 5 mg/kg) in the injured nerve groups compared to the saline-treated injured group as well as the sham-operated group. Following pinch nerve injury, there was a significant decrease in the number of ipsilateral CGRP-IR small and medium DRG neurons in SSTR2 antagonist (anti-SSTR2)- but not saline-treated mice. These data also correlated with painful behavioral readouts where hypersensitivity was significantly increased by anti-SSTR2 but not saline treatment. DISCUSSION/CONCLUSION: In all, application of the SSTR2 antagonist to the pinched sciatic nerve suppressed CGRP expression and aggravated painful behavior, suggesting that CGRP expression in DRG neurons can be an important component of the pain mechanism and an indicator of pain behavior.


Assuntos
Gânglios Espinais , Neuralgia , Receptores de Somatostatina/metabolismo , Animais , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Gânglios Espinais/metabolismo , Camundongos , Neuralgia/metabolismo , Ratos Sprague-Dawley , Somatostatina/metabolismo
15.
Proc Natl Acad Sci U S A ; 119(14): e2117209119, 2022 04 05.
Artigo em Inglês | MEDLINE | ID: mdl-35353623

RESUMO

microRNA (miRNA)­mediated gene regulation has been studied as a therapeutic approach, but its functional regulatory mechanism in neuropathic pain is not well understood. Here, we identify that miRNA-32-5p (miR-32-5p) is a functional RNA in regulating trigeminal-mediated neuropathic pain. High-throughput sequencing and qPCR analysis showed that miR-32-5p was the most down-regulated miRNA in the injured trigeminal ganglion (TG) of rats. Intra-TG injection of miR-32-5p agomir or overexpression of miR-32-5p by lentiviral delivery in neurons of the injured TG attenuated established trigeminal neuropathic pain. miR-32-5p overexpression did not affect acute physiological pain, while miR-32-5p down-regulation in intact rats was sufficient to cause pain-related behaviors. Nerve injury increased the methylated histone occupancy of binding sites for the transcription factor glucocorticoid receptor in the miR-32-5p promoter region. Inhibition of the enzymes that catalyze H3K9me2 and H3K27me3 restored the expression of miR-32-5p and markedly attenuated pain behaviors. Further, miR-32-5p­targeted Cav3.2 T-type Ca2+ channels and decreased miR-32-5p associated with neuropathic pain caused an increase in Cav3.2 protein expression and T-type channel currents. Conversely, miR-32-5p overexpression in injured TG suppressed the increased expression of Cav3.2 and reversed mechanical allodynia. Together, we conclude that histone methylation-mediated miR-32-5p down-regulation in TG neurons regulates trigeminal neuropathic pain by targeting Cav3.2 channels.


Assuntos
MicroRNAs , Neuralgia , Animais , Regulação para Baixo , Gânglios Espinais/metabolismo , Histonas/genética , Histonas/metabolismo , Metilação , MicroRNAs/genética , MicroRNAs/metabolismo , Neuralgia/metabolismo , Ratos , Ratos Sprague-Dawley , Células Receptoras Sensoriais/metabolismo
16.
Diabetes Res Clin Pract ; 186: 109806, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35240228

RESUMO

AIMS: We aimed to explore the evidence of brain microglia activation in diabetic neuropathic pain (DNP) and the effect and mechanism of glucagon-like peptide-1 receptor agonist (GLP-RA) on DNP via brain microglia. METHODS: Brain microglia activation was observed in DNP rats by positron emission tomography/computed tomography. The behavior of neuropathic pain was assessed in DNP rats after intracerebroventricular administration of GLP-1RA or microglial inhibitor minocycline. RNA sequencing was performed to explore the target of GLP-1RA on brain microglia. NOD-like receptor protein 3 (NLRP3) expression in brain microglia was evaluated in mentioned-above DNP rats, and the activation of NLRP3 inflammasome was analyzed in microglia treated with GLP-1RA. RESULTS: Microglia were activated in the cortex and thalamus of DNP rats. The thermal and mechanical allodynia were alleviated in DNP rats via intracerebroventricular administration of GLP-1RA or minocycline. And the activation of brain microglia was attenuated in DNP rats by intracerebroventricular administration of GLP-1RA. The expression of NLRP3 in brain microglia, which was found by RNA sequencing, was reduced in DNP rats by administration of GLP-1RA. Furthermore, GLP-1RA attenuated NLRP3 inflammasome activation in microglia triggered by LPS. CONCLUSION: GLP-1RA could alleviate DNP, possibly mediated by the suppression of brain microglia NLRP3 inflammasome activation.


Assuntos
Diabetes Mellitus , Neuropatias Diabéticas , Neuralgia , Animais , Encéfalo/metabolismo , Diabetes Mellitus/metabolismo , Neuropatias Diabéticas/tratamento farmacológico , Neuropatias Diabéticas/metabolismo , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Humanos , Inflamassomos/metabolismo , Inflamassomos/farmacologia , Microglia/metabolismo , Minociclina/metabolismo , Minociclina/farmacologia , Minociclina/uso terapêutico , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteínas NLR/metabolismo , Neuralgia/tratamento farmacológico , Neuralgia/metabolismo , Ratos
17.
Int J Mol Sci ; 23(5)2022 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-35269822

RESUMO

Neuropathic pain indicates pain caused by damage to the somatosensory system and is difficult to manage and treat. A new treatment strategy urgently needs to be developed. Both autophagy and apoptosis are critical adaptive mechanisms when neurons encounter stress or damage. Recent studies have shown that, after nerve damage, both autophagic and apoptotic activities in the injured nerve, dorsal root ganglia, and spinal dorsal horn change over time. Many studies have shown that upregulated autophagic activities may help myelin clearance, promote nerve regeneration, and attenuate pain behavior. On the other hand, there is no direct evidence that the inhibition of apoptotic activities in the injured neurons can attenuate pain behavior. Most studies have only shown that agents can simultaneously attenuate pain behavior and inhibit apoptotic activities in the injured dorsal root ganglia. Autophagy and apoptosis can crosstalk with each other through various proteins and proinflammatory cytokine expressions. Proinflammatory cytokines can promote both autophagic/apoptotic activities and neuropathic pain formation, whereas autophagy can inhibit proinflammatory cytokine activities and further attenuate pain behaviors. Thus, agents that can enhance autophagic activities but suppress apoptotic activities on the injured nerve and dorsal root ganglia can treat neuropathic pain. Here, we summarized the evolving changes in apoptotic and autophagic activities in the injured nerve, dorsal root ganglia, spinal cord, and brain after nerve damage. This review may help in further understanding the treatment strategy for neuropathic pain during nerve injury by modulating apoptotic/autophagic activities and proinflammatory cytokines in the nervous system.


Assuntos
Hiperalgesia , Neuralgia , Apoptose , Autofagia , Citocinas/metabolismo , Gânglios Espinais/metabolismo , Humanos , Hiperalgesia/metabolismo , Neuralgia/metabolismo , Corno Dorsal da Medula Espinal/metabolismo
18.
Bioengineered ; 13(4): 8101-8114, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35313782

RESUMO

Neuropeptide Y (NPY) is a highly conserved endogenous peptide in the central and peripheral nervous systems, which has been implicated in nociceptive signaling in neuropathic pain. However, downstream mechanistic actions remain uncharacterized. In this study, we sought to investigate the mechanism of NPY and its receptor NPY2R in the amygdala in rats with neuropathic pain-like behaviors induced by chronic constriction injury (CCI) of the sciatic nerve. The expression of NPY and NPY2R was found to be aberrantly up-regulated in neuropathic pain-related microarray dataset. Further, NPY was found to act on NPY2R in the basolateral amygdala (BLA). As reflected by the decrease in mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) as well as the increase of NPY expression in the amygdala of rats with neuropathic pain-like behaviors, NPY was closely related to the effect of amygdala nerve activity in neuropathic pain. Subsequently, mechanistic investigations indicated that NPY2R activated the MAPK signaling pathway in the amygdala. NPY2R-induced decrease of MWT and TWL were also restored in the presence of MAPK signaling pathway antagonist. Moreover, it was revealed that NPY2R overexpression promoted the viability while inhibiting the apoptosis of microglia. Taken together, NPY in the amygdala interacts with NPY2R to activate the MAPK signaling pathway, thereby promoting the occurrence of neuropathic pain.


Assuntos
Neuralgia , Neuropeptídeo Y , Tonsila do Cerebelo/metabolismo , Animais , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Neuralgia/genética , Neuralgia/metabolismo , Neuropeptídeo Y/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores de Neuropeptídeo Y/genética , Receptores de Neuropeptídeo Y/metabolismo
19.
Brain Res ; 1785: 147892, 2022 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-35341732

RESUMO

Inclinicalpractice, high-voltage, long-duration pulsed radiofrequency (HL-PRF) is effective for several types of intractable neuropathic pain (NP), but the mechanisms have not been well explored. Cav2.2 channels could increase neuronal excitability and neurotransmission accompanying NP. This study investigated the relationship of the efficacy of HL-PRF on NP with the levels of Cav2.2 in the spinal dorsal horn (SDH) and dorsal root ganglions (DRGs) of chronic constriction injury (CCI) in rats. Sham HL-PRF, GVIA (a specific Cav2.2 channel blocker), HL-PRF, or GVIA + HL-PRF was applied to CCI rats. The results showed: compared with the sham group, the PWT and PWL of CCI rats decreased significantly (P < 0.05), and Cav2.2 expression was elevated significantly in the SDH and DRGs (P < 0.05). Compared with the CCI group, both HL-PRF and ω-conotoxin GVIA treatment reversed the increased PWT and PWL (P < 0.05) and downregulated the overexpression of Cav2.2 in the SDH and DRGs (P < 0.05). Furthermore, PWT, PWL, and the expression of Cav2.2 in the SDH and DRGs were not significantly different among the 3 treatment groups. HL-PRF on L5 DRG reversed the hyperalgesia behavior of NP and reduced the levels of Cav2.2 in the ipsilateral SDH and DRGs in CCI rats. Moreover, the underlying mechanism may be related to the downregulation of CaV2.2 protein levels in both SDH and DRG.


Assuntos
Canais de Cálcio Tipo N/metabolismo , Lesões por Esmagamento , Neuralgia , Tratamento por Radiofrequência Pulsada , Animais , Lesões por Esmagamento/metabolismo , Gânglios Espinais/metabolismo , Hiperalgesia/metabolismo , Hiperalgesia/terapia , Neuralgia/metabolismo , Neuralgia/terapia , Tratamento por Radiofrequência Pulsada/métodos , Ratos , Ratos Sprague-Dawley , Corno Dorsal da Medula Espinal/metabolismo
20.
Phytother Res ; 36(4): 1678-1691, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35234314

RESUMO

Switching microglial polarization from the M1 to M2 phenotype is a promising therapeutic strategy for neuropathic pain (NP). Toll-like receptor 4 (TLR4) is activated by lipopolysaccharide (LPS). Uncontrolled activation of TLR4 has been proven to trigger chronic inflammation. Kaempferol, a dietary flavonoid, is known to have anti-inflammatory properties. This study is aimed to investigate the analgesic and anti-inflammatory effects and the underlying mechanisms of kaempferol, which were explored with an NP model in vivo and LPS-induced injury in microglial BV2 cells in vitro. The levels of proinflammatory cytokines were evaluated. H&E staining and immunohistochemistry were used to assess the sciatic nerve condition after chronic constriction injury surgery. Western blotting and immunofluorescence were used to determine whether TLR4/NF-ĸB signaling pathway plays a major role in kaempferol-mediated alleviation of neuroinflammation. Quantitative real-time polymerase chain reaction and flow cytometry were used to examine the modulator effect of kaempferol on microglial M1/M2 polarization. We found that kaempferol treatment can significantly reduce NP and proinflammatory cytokine production. Kaempferol attenuated the activation of TLR4/NF-κB pathways in LPS-activated BV2 cells. The analgesic effects of kaempferol on NP may be due to inhibition of microglia activation and switching the M1 to M2 phenotype.


Assuntos
Neuralgia , Fármacos Neuroprotetores , Anti-Inflamatórios/metabolismo , Anti-Inflamatórios/farmacologia , Linhagem Celular , Humanos , Quempferóis , Lipopolissacarídeos/farmacologia , Microglia , NF-kappa B/metabolismo , Neuralgia/tratamento farmacológico , Neuralgia/metabolismo , Fármacos Neuroprotetores/farmacologia , Transdução de Sinais , Receptor 4 Toll-Like/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...