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1.
Nat Commun ; 11(1): 2293, 2020 05 08.
Artigo em Inglês | MEDLINE | ID: mdl-32385249

RESUMO

The sodium channels Nav1.7, Nav1.8 and Nav1.9 are critical for pain perception in peripheral nociceptors. Loss of function of Nav1.7 leads to congenital insensitivity to pain in humans. Here we show that the spider peptide toxin called HpTx1, first identified as an inhibitor of Kv4.2, restores nociception in Nav1.7 knockout (Nav1.7-KO) mice by enhancing the excitability of dorsal root ganglion neurons. HpTx1 inhibits Nav1.7 and activates Nav1.9 but does not affect Nav1.8. This toxin produces pain in wild-type (WT) and Nav1.7-KO mice, and attenuates nociception in Nav1.9-KO mice, but has no effect in Nav1.8-KO mice. These data indicate that HpTx1-induced hypersensitivity is mediated by Nav1.9 activation and offers pharmacological insight into the relationship of the three Nav channels in pain signalling.


Assuntos
Hiperalgesia/induzido quimicamente , Hiperalgesia/metabolismo , Ativação do Canal Iônico , Canal de Sódio Disparado por Voltagem NAV1.7/metabolismo , Canal de Sódio Disparado por Voltagem NAV1.9/metabolismo , Peptídeos/efeitos adversos , Venenos de Aranha/efeitos adversos , Sequência de Aminoácidos , Animais , Feminino , Gânglios Espinais/patologia , Humanos , Hiperalgesia/complicações , Masculino , Camundongos Knockout , Canal de Sódio Disparado por Voltagem NAV1.7/química , Canal de Sódio Disparado por Voltagem NAV1.8/metabolismo , Canal de Sódio Disparado por Voltagem NAV1.9/química , Neurônios/efeitos dos fármacos , Neurônios/patologia , Dor/complicações , Dor/fisiopatologia , Ratos
2.
Sci Rep ; 10(1): 6569, 2020 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-32300146

RESUMO

Tenascin-X (TNX) is a member of the extracellular matrix glycoprotein tenascin family, and TNX deficiency leads to Ehlers-Danlos syndrome, a heritable human disorder characterized mostly by skin hyperextensibility, joint hypermobility, and easy bruising. TNX-deficient patients complain of chronic joint pain, myalgia, paresthesia, and axonal polyneuropathy. However, the molecular mechanisms by which TNX deficiency complicates pain are unknown. Here, we examined the nociceptive behavioral responses of TNX-deficient mice. Compared with wild-type mice, TNX-deficient mice exhibited mechanical allodynia but not thermal hyperalgesia. TNX deficiency also increased pain sensitivity to chemical stimuli and aggravated early inflammatory pain elicited by formalin. TNX-deficient mice were significantly hypersensitive to transcutaneous sine wave stimuli at frequencies of 250 Hz (Aδ fiber responses) and 2000 Hz (Aß fiber responses), but not to stimuli at frequency of 5 Hz (C fiber responses). In addition, the phosphorylation levels of extracellular signal-related kinase, an active neuronal marker, and the activity of NADPH-diaphorase, a neuronal nitric oxide activation marker, were enhanced in the spinal dorsal horns of TNX-deficient mice. These results suggest that TNX deficiency contributes to the development of mechanical allodynia and hypersensitivity to chemical stimuli, and it induces hypersensitization of myelinated A fibers and activation of the spinal dorsal horn.


Assuntos
Síndrome de Ehlers-Danlos/complicações , Hiperalgesia/complicações , Tenascina/deficiência , Analgésicos/farmacologia , Analgésicos/uso terapêutico , Animais , Formaldeído , Hiperalgesia/tratamento farmacológico , Hiperalgesia/fisiopatologia , Masculino , Camundongos Endogâmicos C57BL , Dor/complicações , Dor/patologia , Dor/fisiopatologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Corno Dorsal da Medula Espinal/efeitos dos fármacos , Corno Dorsal da Medula Espinal/patologia , Corno Dorsal da Medula Espinal/fisiopatologia , Tenascina/genética , Tenascina/metabolismo
3.
Eur J Pharmacol ; 866: 172835, 2020 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-31794708

RESUMO

Diabetes mellitus is characterized by metabolic dysregulation associated with a number of health complications. More than 50% of patients with diabetes mellitus suffer from diabetic polyneuropathy, which involves the presence of peripheral nerve dysfunction symptoms. The aim of this study was to evaluate the potential of a new synthetic arginine-rich exendin-4 (Peptide D) in the treatment of complications caused by diabetes, including peripheral neuropathy, in rats. Diabetes was induced by administering streptozotocin (STZ). Three groups of diabetic rats were treated with Peptide D (0.1, 1, and 10 µg/kg). One group of diabetic rats was treated with Byetta® (1 µg/kg) for 80 days. Neuropathic pain development was assessed by tactile allodynia. STZ-treated rats showed an increased level of tactile allodynia unlike naïve animals. A histological study revealed that the diameter of the sciatic nerve fibers in STZ-treated rats was smaller than that of the naïve animals. An IHC study demonstrated decreased expression of myelin basic protein (MBP) in the sciatic nerve of diabetic rats compared to that in the naïve animals. Peptide D reduced the severity of tactile allodynia. This effect was more pronounced in the Peptide D treated groups than in the group treated with Byetta®. Peptide D and Byetta® treatment resulted in increased MBP expression in the sciatic nerve and increased diameter of myelinated nerve fibers. These findings suggest that poly-arginine peptides are promising agents for the treatment of peripheral polyneuropathies.


Assuntos
Arginina/química , Neuropatias Diabéticas/tratamento farmacológico , Exenatida/química , Exenatida/farmacologia , Animais , Glicemia/metabolismo , Neuropatias Diabéticas/sangue , Neuropatias Diabéticas/patologia , Neuropatias Diabéticas/fisiopatologia , Relação Dose-Resposta a Droga , Exenatida/uso terapêutico , Regulação da Expressão Gênica/efeitos dos fármacos , Hemoglobina A Glicada/metabolismo , Hiperalgesia/complicações , Insulina/metabolismo , Ilhotas Pancreáticas/efeitos dos fármacos , Ilhotas Pancreáticas/patologia , Locomoção/efeitos dos fármacos , Masculino , Tamanho do Órgão/efeitos dos fármacos , Ratos , Ratos Wistar , Nervo Isquiático/efeitos dos fármacos , Nervo Isquiático/patologia
4.
Support Care Cancer ; 28(6): 2891-2898, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31754834

RESUMO

PURPOSE: Medical treatment for head and neck cancer may induce the presence of inflammation, pain, and dysfunction. The purpose of the current study was to assess the presence of myofascial trigger points (TrPs) and their relationship with widespread pressure hypersensitivity and hyperalgesia in survivors of head and neck cancer (sHNC). METHODS: TrPs and pressure-pain thresholds (PPTs) were quantified in different muscles/joints in the head and neck of 30 sHNC (59.45 ± 13.13 years) and 28 age- and sex-matched controls (58.11 ± 12.67 years). RESULTS: The sHNC had more TrPs in all muscles on the affected side (p < 0.05) than did the healthy controls, and in the temporalis, masseter, and suboccipitalis muscles on the unaffected side (p < 0.05). They also had lower PPTs in all places (p < 0.05) except for the temporalis muscle (p = 0.114) and C5-C6 joint (p = 0.977). The intensity of cervical pain correlated positively with the presence of upper trapezius TrPs. CONCLUSIONS: sHNC suffering cervical and/or temporomandibular joint pain have multiple active TrPs and experience widespread pressure hypersensitivity and hyperalgesia, suggestive of peripheral and central sensitization.


Assuntos
Sobreviventes de Câncer/estatística & dados numéricos , Dor Facial/epidemiologia , Neoplasias de Cabeça e Pescoço , Hiperalgesia/epidemiologia , Síndromes da Dor Miofascial/epidemiologia , Cervicalgia/epidemiologia , Dor de Ombro/epidemiologia , Adulto , Idoso , Estudos de Casos e Controles , Face , Dor Facial/complicações , Feminino , Neoplasias de Cabeça e Pescoço/mortalidade , Neoplasias de Cabeça e Pescoço/reabilitação , Humanos , Hiperalgesia/complicações , Masculino , Pessoa de Meia-Idade , Síndromes da Dor Miofascial/etiologia , Cervicalgia/complicações , Limiar da Dor , Síndromes Paraneoplásicas/epidemiologia , Ombro , Dor de Ombro/complicações , Pontos-Gatilho
5.
Biochem Biophys Res Commun ; 522(2): 463-470, 2020 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-31780260

RESUMO

Long-term neuropathic pain can lead to anxiety, depression, and other issues, which seriously affect patients' quality of life. For this reason, it is important to find effective treatments. Studies have shown that glial cell-derived neurotrophic factor (GDNF) can relieve neuropathic pain. However, its mechanism of action is unknown. Our previous study of GDNF suggested that the N-cadherin-ß-catenin transmembrane signaling system might play a role in GDNF transmembrane signaling. Based on this, the current study aimed to produce a neuropathic pain model to confirm the activation of the N-cadherin-ß-catenin signaling system in the spinal dorsal horn under pain conditions and to study the impact of GDNF intrathecal injection on central sensitization of dorsal horn neurons. The results showed that N-cadherin expression, as well as the expression of membrane-associated ß-catenin, was reduced in the dorsal horn of the spinal cord in the chronic pain model. Intrathecal injection of GDNF could reactivate the N-cadherin-ß-catenin system, improve central sensitization, and relieve pain. Knockdown of N-cadherin or ß-catenin could significantly reduce the analgesic effect of GDNF. These results provide clear experimental evidence that the N-cadherin-ß-catenin signaling system participates in the analgesic effect of GDNF in neuropathic pain and help identify transmembrane and intracellular signal transduction mechanisms associated with GDNF's analgesic effects.


Assuntos
Analgésicos/uso terapêutico , Caderinas/metabolismo , Fator Neurotrófico Derivado de Linhagem de Célula Glial/uso terapêutico , Neuralgia/tratamento farmacológico , Transdução de Sinais , beta Catenina/metabolismo , Analgésicos/farmacologia , Animais , Constrição Patológica , Regulação para Baixo/genética , Fator Neurotrófico Derivado de Linhagem de Célula Glial/farmacologia , Hiperalgesia/complicações , Hiperalgesia/tratamento farmacológico , Masculino , Neuralgia/complicações , Ratos Sprague-Dawley , Corno Dorsal da Medula Espinal/metabolismo
6.
Artigo em Inglês | MEDLINE | ID: mdl-31837258

RESUMO

Background Osteoarthritis (OA) is a chronic disease in the joints. One of the proinflammatory cytokines that is thought to have a major role in the inflammatory process, the emergence of pain, and cartilage damage in OA is tumor necrosis factor α (TNF-α). Meloxicam is a nonsteroidal anti-inflammatory drug class of drugs that is relatively selective in inhibiting the activity of cyclooxygenase 2 (COX-2) formation. This study is conducted to prove the change in TNF-α level in the use of meloxicam with model in animals suffering from OA. Methods The OA rat model was induced with sodium monoiodoacetate intra-articularly. Rats were divided into 5 groups: negative control group, positive control group, and treatment groups with various doses of meloxicam. Hyperalgesia effect was evaluated using a warm plate test, and TNF-α level was determined using enzyme-linked immunosorbent assay. Results The treatment groups that received meloxicam at a dose of 1.0, 3.0, or 10.0 mg/kg body weight (BW) did not show significant differences in rat knee joint diameter (p = 0.99), but showed a significant difference in sensitivity to heat stimulation (p = 0.02) compared to the control group. Osteoarthritis rats experienced a significant reduction in TNF-α level after being given meloxicam at a dose of 10 mg/kg BW compared with the control group. This shows that the 10 mg/kg BW of meloxicam is a potential dose in reducing the TNF-α level in OA rat models. Conclusions Based on these data, it can be concluded that the inhibition of pain and the development of OA by meloxicam in animal models may be assigned to a decreased level of TNF-α.


Assuntos
Meloxicam/uso terapêutico , Osteoartrite do Joelho/tratamento farmacológico , Fator de Necrose Tumoral alfa/efeitos dos fármacos , Animais , Anti-Inflamatórios não Esteroides/uso terapêutico , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Hiperalgesia/complicações , Hiperalgesia/tratamento farmacológico , Ácido Iodoacético , Masculino , Osteoartrite do Joelho/sangue , Osteoartrite do Joelho/induzido quimicamente , Osteoartrite do Joelho/complicações , Ratos , Fator de Necrose Tumoral alfa/sangue
7.
Int J Mol Sci ; 20(24)2019 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-31835716

RESUMO

Somatostatin released from the capsaicin-sensitive sensory nerves mediates analgesic and anti-inflammatory effects via the somatostatin sst4 receptor without endocrine actions. Therefore, sst4 is considered to be a novel target for drug development in pain including chronic neuropathy, which is an emerging unmet medical need. Here, we examined the in silico binding, the sst4-linked G-protein activation on stable receptor expressing cells (1 nM to 10 µM), and the effects of our novel pyrrolo-pyrimidine molecules in mouse inflammatory and neuropathic pain models. All four of the tested compounds (C1-C4) bind to the same binding site of the sst4 receptor with similar interaction energy to high-affinity reference sst4 agonists, and they all induce G-protein activation. C1 is the more efficacious (γ-GTP-binding: 218.2% ± 36.5%) and most potent (EC50: 37 nM) ligand. In vivo testing of the actions of orally administered C1 and C2 (500 µg/kg) showed that only C1 decreased the resiniferatoxin-induced acute neurogenic inflammatory thermal allodynia and mechanical hyperalgesia significantly. Meanwhile, both of them remarkably reduced partial sciatic nerve ligation-induced chronic neuropathic mechanical hyperalgesia after a single oral administration of the 500 µg/kg dose. These orally active novel sst4 agonists exert potent anti-hyperalgesic effect in a chronic neuropathy model, and therefore, they can open promising drug developmental perspectives.


Assuntos
Analgésicos/farmacologia , Analgésicos/uso terapêutico , Neuralgia/tratamento farmacológico , Receptores de Somatostatina/agonistas , Administração Oral , Analgésicos/química , Animais , Células CHO , Doença Crônica , Cricetinae , Cricetulus , Diterpenos/toxicidade , Hiperalgesia/induzido quimicamente , Hiperalgesia/complicações , Hiperalgesia/tratamento farmacológico , Inflamação/patologia , Ligantes , Masculino , Camundongos , Simulação de Dinâmica Molecular , Neuralgia/complicações , Neuralgia/patologia , Pirimidinas/química , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Pirróis/química , Pirróis/farmacologia , Pirróis/uso terapêutico , Receptores de Somatostatina/metabolismo
8.
Sci Rep ; 9(1): 15656, 2019 10 30.
Artigo em Inglês | MEDLINE | ID: mdl-31666661

RESUMO

Neuropathic pain (NeP) is commonly encountered in patients with diseases associated with spinal cord damage (e.g., spinal cord injury (SCI) and compressive myelopathy). Recent studies described persistent glial activation and neuronal hyperactivity in SCI, but the pathomechanisms of NeP in chronic compression of the spinal cord remains elusive. The purpose of the present study was to determine the roles of microglia and infiltrating macrophages in NeP. The study was conducted in chimeric spinal hyperostotic mice (ttw/ttw), characterized by chronic progressive compression of the spinal cord as a suitable model of human compressive myelopathy. The severity of spinal cord compression correlated with proportion of activated microglia and hematogenous macrophages. Spinal cord compression was associated with overexpression of mitogen-activated protein kinases (MAPKs) in infiltrating macrophages and reversible blood-spinal cord barrier (BSCB) disruption in the dorsal horns. Our results suggested that chronic neuropathic pain in long-term spinal cord compression correlates with infiltrating macrophages, activated microglial cells and the associated damage of BSCB, together with overexpression of p-38 MAPK and p-ERK1/2 in these cells. Our findings are potentially useful for the design of new therapies to alleviate chronic neuropathic pain associated with compressive myelopathy.


Assuntos
Progressão da Doença , Macrófagos/citologia , Microglia/patologia , Neuralgia/complicações , Neuralgia/patologia , Compressão da Medula Espinal/complicações , Animais , Hiperalgesia/complicações , Camundongos , Proteínas Quinases Ativadas por Mitógeno/metabolismo
9.
Mol Cell Proteomics ; 18(12): 2447-2458, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31649062

RESUMO

Chronic use of opioids can produce opioid-induced hyperalgesia (OIH), and when used to treat migraine, these drugs can result in increased pain and headache chronicity. We hypothesized that overlapping mechanisms between OIH and chronic migraine occur through neuropeptide dysregulation. Using label-free, non-biased liquid chromatography-mass spectrometry to identify and measure changes in more than 1500 neuropeptides under these two conditions, we observed only 16 neuropeptides that were altered between the two conditions. The known pro-migraine molecule, calcitonin-gene related peptide, was among seven peptides associated with chronic migraine, with several pain-processing neuropeptides among the nine other peptides affected in OIH. Further, composite peptide complements Pituitary adenylate cyclase-activating polypeptide (PACAP), Vasoactive intestinal peptide (VIP) and Secretogranin (SCG) showed significant changes in both chronic migraine and OIH. In a follow-up pharmacological study, we confirmed the role of PACAP in models of these two disorders, validating the effectiveness of our peptidomic approach, and identifying PACAP as a mechanistic link between chronic migraine and OIH. Data are available via ProteomeXchange with identifier PXD013362.


Assuntos
Analgésicos Opioides/efeitos adversos , Hiperalgesia/induzido quimicamente , Transtornos de Enxaqueca/tratamento farmacológico , Neuropeptídeos/metabolismo , Neurotransmissores/metabolismo , Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/metabolismo , Analgésicos Opioides/uso terapêutico , Animais , Comportamento Animal , Cromatografia Líquida , Modelos Animais de Doenças , Transtornos da Cefaleia/complicações , Transtornos da Cefaleia/tratamento farmacológico , Hiperalgesia/complicações , Hiperalgesia/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Transtornos de Enxaqueca/complicações , Transtornos de Enxaqueca/metabolismo , Espectrometria de Massas em Tandem
10.
Biomed Pharmacother ; 118: 109276, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31377466

RESUMO

BACKGROUND: Paeonia lactiflora (PL) was widely used for pain relief, but its effects on migraine headaches remain unclear. PURPOSE: The aim of the present study was to investigate the effects of PL on migraine headaches. METHODS: First, we found that PL was frequently used in Taiwan for headache treatment based on data from Taiwan's National Health Insurance Research Database. Migraine was induced through the intraperitoneal injection (i.p.) of nitroglycerin (NTG, 10 mg/kg) in rats. Pretreatment with PL was administered orally 30 min prior to the NTG i.p. Migraine headache behavior was observed by video-recordings. Finally, the rats were sacrificed and brain was removed for immunohistochemistry staining analysis. RESULTS: The frequency and total time spent rearing up and sniffing in exploratory behavior, and walking in locomotor behavior, were reduced in the NTG group compared with the control group (all p <  0.001). This reduction could be ameliorated by pretreatment with PL 1.0 g/kg (all p <  0.05). Total time spent in the light chamber was lower in the NTG group compared with the control group (p <  0.05); this could be ameliorated by pretreatment with 1.0 g/kg PL (p <  0.05). The rats in the NTG group spent longer time on the smooth surface than those in the control group (p <  0.001); this could be shortened by pretreatment with 0.5 and 1.0 g/kg PL (both p <  0.01). The traveling distance of rats in the NTG group was shorter than in the control group (p <  0.001); rats given 1.0 g/kg PL had a longer traveling distance than those in the NTG group (p <  0.01). Both c-fos and CGRP immunoreactive cells increased in the TNC in the NTG group compared with that of the control group (both p <  0.001); this increased could be reduced by pretreatment with PL 0.5 and 1.0 g/kg (both p <  0.05). CONCLUSION: Pretreatment with PL ameliorated migraine headache behaviors in the NTG-induced migraine rat model, suggesting pretreatment with PL is beneficial for migraine headache treatment. This effect of PL is related to the decrease of c-fos and CGRP in the TNC. However, still there are too many methodological limitations which need to be overcome in further experiments to support the data.


Assuntos
Comportamento Animal , Medicamentos de Ervas Chinesas/uso terapêutico , Transtornos de Enxaqueca/tratamento farmacológico , Paeonia/química , Animais , Ansiedade/complicações , Ansiedade/tratamento farmacológico , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Depressão/complicações , Depressão/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Reação de Congelamento Cataléptica , Asseio Animal , Hiperalgesia/complicações , Hiperalgesia/tratamento farmacológico , Imobilização , Masculino , Transtornos de Enxaqueca/complicações , Transtornos de Enxaqueca/fisiopatologia , Atividade Motora/efeitos dos fármacos , Nitroglicerina , Dor/tratamento farmacológico , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos Sprague-Dawley , Sono , Núcleos do Trigêmeo/efeitos dos fármacos , Núcleos do Trigêmeo/patologia , Núcleos do Trigêmeo/fisiopatologia
11.
Biomed Pharmacother ; 118: 109299, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31387001

RESUMO

We have recently demonstrated that the neurosteroid-metabolizing enzyme, cytochrome P450c17 is increased in spinal astrocytes contributing to the development of mechanical allodynia in chronic constriction injury (CCI)-induced neuropathic mice. However, the mechanisms by which spinal P450c17 modulates pathological changes in astrocytes remain unclear. In this study we investigated whether P450c17 modulates astrocyte activation and whether this process is mediated by spinal p38 mitogen-activated protein kinase phosphorylation ultimately leading to the development of mechanical allodynia in CCI mice. Sciatic nerve injury induced a significant increase in glial fibrillary acidic protein (GFAP) expression in the superficial dorsal horn (SDH, laminae I-II) and nucleus proprius (NP, laminae III-IV) regions of the spinal cord dorsal horn. Repeated daily (from days 0-3 post-surgery) intrathecal administration of the P450c17 inhibitor, ketoconazole (10 nmol) significantly inhibited the CCI-induced increase in GFAP-immunoreactivity, but had no effect on the CCI-induced increase in Iba-1-immunoreactivity. In addition, intrathecal administration of ketoconazole significantly inhibited the CCI-induced increase in p38 phosphorylation, while the levels of ERK and JNK phosphorylation remained unchanged. The CCI-induced development of mechanical allodynia was attenuated by administration of either ketoconazole (10 nmol) or the p38 MAPK inhibitor, SB203580 (5 nmol). Administration of a sub-effective dose of SB203580 (0.5 nmol) potentiated the pharmacological effect of ketoconazole (1 nmol) on spinal GFAP-immunostaining, as well as, the development of mechanical allodynia following CCI. Collectively these data suggest that spinal P450c17 activates astrocytes via p38 phosphorylation, ultimately leading to the development of mechanical allodynia in a model of peripheral neuropathy.


Assuntos
Astrócitos/enzimologia , Neuralgia/enzimologia , Neuralgia/patologia , Medula Espinal/patologia , Esteroide 17-alfa-Hidroxilase/antagonistas & inibidores , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/patologia , Constrição Patológica , Modelos Animais de Doenças , Hiperalgesia/complicações , Hiperalgesia/patologia , Imidazóis/farmacologia , Cetoconazol/administração & dosagem , Cetoconazol/farmacologia , Vértebras Lombares/enzimologia , Vértebras Lombares/patologia , Masculino , Camundongos , Microglia/efeitos dos fármacos , Microglia/patologia , Fosforilação/efeitos dos fármacos , Piridinas/farmacologia , Corno Dorsal da Medula Espinal/enzimologia , Corno Dorsal da Medula Espinal/patologia , Esteroide 17-alfa-Hidroxilase/metabolismo
12.
BMC Neurosci ; 20(1): 36, 2019 07 31.
Artigo em Inglês | MEDLINE | ID: mdl-31366324

RESUMO

BACKGROUND: Postoperative pain (POP) is a severe acute pain encountered in patients suffering from an operation, and is less than adequately controlled by the currently available analgesics. Phosphatidylinositol 3-kinase (PI3K) has been reported to have an important role in neuropathic and inflammatory pain. Our previous research revealed that pre-surgical inhibition of spinal PI3K alleviated the pain behavior induced by plantar incision in mice. The aim of this study was to clarify whether post-surgical inhibition of PI3K would attenuate the POP and the underlying mechanisms. METHODS: A POP model was established by plantar incision in Kunming mice. A behavioral test was performed to determine mechanical allodynia, thermal hyperalgesia, and cumulative pain scores. The spinal Fos was detected by immunohistochemistry. The spinal expression of protein kinase B (Akt) or phosphorylated Akt (pAkt) was explored using western blot. The cellular location of pAkt was determined by immunofluorescence. RESULTS: Post-surgical inhibition of PI3K attenuated mechanical allodynia, thermal hyperalgesia, and cumulative pain scores induced by plantar incision significantly in male mice, and mildly in female mice. Post-surgical inhibition of PI3K attenuated the expression of spinal Fos in male mice. Plantar incision induced a time-dependent expression of spinal pAkt in male mice, which was primarily expressed in the spinal dorsal horn, and localized with the neuron and microglia's marker. Post-surgical inhibition of PI3K attenuated the activation of Akt induced by plantar incision in male mice as well. CONCLUSIONS: We concluded that post-surgical inhibition of PI3K could attenuate the pain-related behaviors induced by plantar incision, by suppressing the activation of spinal Akt in male mice. This finding might be used in clinical studies to reach a better understanding of POP mechanisms and optimal treatment.


Assuntos
Cromonas/farmacologia , Hiperalgesia/fisiopatologia , Morfolinas/farmacologia , Dor Pós-Operatória/prevenção & controle , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Wortmanina/farmacologia , Animais , Feminino , Traumatismos do Pé/complicações , Hiperalgesia/complicações , Hiperalgesia/prevenção & controle , Masculino , Camundongos , Medição da Dor/efeitos dos fármacos , Dor Pós-Operatória/complicações , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-fos/metabolismo , Caracteres Sexuais , Medula Espinal/metabolismo
13.
Eur J Pharmacol ; 859: 172555, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31326377

RESUMO

Complex regional pain syndrome I (CRPS-I) is a chronic painful pathology still undertreated. CTK 01512-2 is a recombinant version of the spider peptide Phα1ß, and it functions as a voltage-gated calcium channel blocker and a transient receptor potential ankyrin 1 (TRPA1) antagonist with antinociceptive effect in different pain models. Here, we investigate the mechanisms involved in the acute and chronic nociceptive phases of a model of CPRS-I in mice and assess the antinociceptive effect of CTK 01512-2 using this model. Adult male and female mice C57BL/6 (20-30 g) were used to determine mechanical (von Frey test) or cold (acetone test) allodynia induction. Inflammatory parameters (serum and tibial nerve lactate levels, hind paw temperature and edema, or tissue cell infiltration) were evaluated after chronic post-ischemia pain (CPIP, a model of CPRS-I) induction. Anti-inflammatory and anti-neuropathic drugs or CTK 01512-2 were tested. First, we detected that CPIP-induced mechanical and cold allodynia in male and female mice in a similar way. In the acute phase (1 day after CPIP), an increase in inflammatory parameters were observed, as well as the anti-allodynic effect of anti-inflammatory compounds. In the chronic phase (17 days after CPIP), mice exhibited mechanical and cold allodynia, and anti-neuropathic drugs induced antinociception, while no inflammatory alterations were found. CTK 01512-2 reversed the CPIP allodynic effect in both nociceptive phases. Thus, this CPRS-I model can be used to understand the mechanisms involved in CPRS-I induced pain and inflammation. Besides, we observed that CTK 01512-2 has a valuable antinociceptive effect in this pain model.


Assuntos
Nociceptividade , Distrofia Simpática Reflexa/fisiopatologia , Doença Aguda , Animais , Doença Crônica , Modelos Animais de Doenças , Feminino , Hiperalgesia/complicações , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Distrofia Simpática Reflexa/complicações , Distrofia Simpática Reflexa/metabolismo
14.
Int J Mol Sci ; 20(13)2019 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-31269729

RESUMO

The stimulation of the AMP-activated kinase (AMPK) by 5-amino-1-ß-D-ribofuranosyl-imidazole-4-carboxamide (AICAR) has been associated with antihyperalgesia and the inhibition of nociceptive signaling in the spinal cord in models of paw inflammation. The attenuated nociception comes along with a strongly reduced paw edema, indicating that peripheral antiinflammatory mechanisms contribute to antinociception. In this study, we investigated the impact of AICAR on the immune cell composition in inflamed paws, as well as the regulation of inflammatory and resolving markers in macrophages. By using fluorescence-activated cell sorting (FACS) analysis and immunofluorescence, we found a significantly increased fraction of proresolving M2 macrophages and anti-inflammatory interleukin (IL)-10 in inflamed tissue, while M1 macrophages and proinflammatory cytokines such as IL-1 were decreased by AICAR in wild type mice. In AMPKα2 knock-out mice, the M2 polarization of macrophages in the paw was missing. The results were supported by experiments in primary macrophage cultures which also showed a shift to a proresolving phenotype with decreased levels of proinflammatory mediators and increased levels of antiinflammatory mediators. However, in the cell cultures, we did not observe differences between the AMPKα2+/+ and -/- cells, thus indicating that the AICAR-induced effects are at least partially AMPK-independent. In summary, our results indicate that AICAR has potent antiinflammatory and proresolving properties in inflammation which are contributing to a reduction of inflammatory edema and antinociception.


Assuntos
Aminoimidazol Carboxamida/análogos & derivados , Anti-Inflamatórios/uso terapêutico , Inflamação/tratamento farmacológico , Macrófagos/efeitos dos fármacos , Ribonucleotídeos/uso terapêutico , Aminoimidazol Carboxamida/uso terapêutico , Animais , Células Cultivadas , Edema/complicações , Edema/tratamento farmacológico , Edema/imunologia , Hiperalgesia/complicações , Hiperalgesia/tratamento farmacológico , Hiperalgesia/imunologia , Inflamação/complicações , Inflamação/imunologia , Macrófagos/imunologia , Masculino , Camundongos Endogâmicos C57BL
15.
J Leukoc Biol ; 106(3): 541-551, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31150565

RESUMO

The development of neuropathic pain after peripheral nerve injury involves neuroimmune-glial interactions in the spinal cord. However, whether the development of neuropathic pain depends on the infiltration of peripheral immune cells, such as monocytes, into the spinal cord parenchyma after peripheral nerve damage remains unclear. Here, we used a combination of different techniques such as transgenic reporter mouse (Cx3cr1GFP/+ and Ccr2RFP/+ mice), bone marrow chimeric mice, and parabiosis to investigate this issue in spared nerve injury (SNI) model. Herein, we provided robust evidence that, although microglial cells are activated/proliferate at the dorsal horn of the spinal cord after SNI, peripheral hematopoietic cells (including monocytes) are not able to infiltrate into the spinal cord parenchyma. Furthermore, there was no evidence of CCR2 expression in intrinsic cells of the spinal cord. However, microglial cells activation/proliferation in the spinal cord and mechanical allodynia after SNI were reduced in Ccr2-deficient mice. These results suggest that blood-circulating leukocytes cells are not able to infiltrate the spinal cord parenchyma after distal peripheral nerve injury. Nevertheless, they indicate that CCR2-expressing cells might be indirectly regulating microglia activation/proliferation in the spinal cord after SNI. In conclusion, our study supports that CCR2 inhibition could be explored as an interventional approach to reduce microglia activation and consequently neuropathic pain development after peripheral nerve injury.


Assuntos
Leucócitos/patologia , Traumatismos dos Nervos Periféricos/sangue , Traumatismos dos Nervos Periféricos/patologia , Medula Espinal/patologia , Animais , Proliferação de Células , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/sangue , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/patologia , Endotélio Vascular/patologia , Feminino , Células-Tronco Hematopoéticas/metabolismo , Hiperalgesia/sangue , Hiperalgesia/complicações , Hiperalgesia/imunologia , Hiperalgesia/patologia , Masculino , Camundongos Endogâmicos C57BL , Microglia/patologia , Monócitos/patologia , Neuralgia/sangue , Neuralgia/complicações , Neuralgia/imunologia , Neuralgia/patologia , Receptores CCR2/deficiência , Receptores CCR2/metabolismo
16.
Eur J Pharmacol ; 857: 172450, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31202805

RESUMO

Many areas of the brain along with neurotransmitters involve in processing of nociceptive, emotional and cognitive dimensions of neuropathic pain. Brian neuronal histamine through H1, H2, H3 and H4 receptors mediates many physiological functions such as cognition, emotion and pain. In the present study we investigated the effects of intra-agranular insular cortex microinjection of histamine and its H3 receptor agonist and antagonist on sensory and affective aspects of neuropathic pain. Spared nerve injury model of neuropathic pain was used. Two guide cannulas were surgically implanted in the right and left sides of agranular insular cortex. Sensory component (mechanical hyperalgesia) was recorded by application of von Frey filaments onto the plantar surface of the hind paw. Area under curve of mechanical hyperalgesia was calculated. Affective aspect (place escape avoidance paradigm) was recorded using an inverse white/black chamber. Histamine (0.5, 1 and 2 µg/site) and thioperamide (a histamine H3 receptor antagonist, 4 µg/site) decreased, whereas immepip (a histamine H3 receptor agonist, 2 µg/site) increased the percentages of paw withdrawal frequency and time spent in white side of white/black box. Prior administration of thioperamide (4 µg/site) increased the suppressive effects induced by histamine and inhibited immepip (2 µg/site)-induced hyperalgesia and aversion. Based on the present results, it is concluded that histamine and its H3 receptor at the agranular insular cortex level may involve in modulation of sensory and affective components of neuropathic pain.


Assuntos
Córtex Cerebral/efeitos dos fármacos , Agonistas dos Receptores Histamínicos/farmacologia , Antagonistas dos Receptores Histamínicos/farmacologia , Histamina/farmacologia , Neuralgia/tratamento farmacológico , Neuralgia/fisiopatologia , Receptores Histamínicos H3/metabolismo , Animais , Histamina/administração & dosagem , Histamina/uso terapêutico , Agonistas dos Receptores Histamínicos/administração & dosagem , Agonistas dos Receptores Histamínicos/uso terapêutico , Antagonistas dos Receptores Histamínicos/administração & dosagem , Antagonistas dos Receptores Histamínicos/uso terapêutico , Hiperalgesia/complicações , Masculino , Microinjeções , Neuralgia/complicações , Neuralgia/metabolismo , Ratos , Ratos Wistar , Sensação/efeitos dos fármacos
17.
Sci Rep ; 9(1): 9297, 2019 06 26.
Artigo em Inglês | MEDLINE | ID: mdl-31243320

RESUMO

Neuropathic pain is characterized by an uncertain etiology and by a poor response to common therapies. The ineffectiveness and the frequent side effects of the drugs used to counteract neuropathic pain call for the discovery of new therapeutic strategies. Laser therapy proved to be effective for reducing pain sensitivity thus improving the quality of life. However, its application parameters and efficacy in chronic pain must be further analyzed. We investigated the pain relieving and protective effect of Photobiomodulation Therapy in a rat model of compressive mononeuropathy induced by Chronic Constriction Injury of the sciatic nerve (CCI). Laser (MLS-MiS) applications started 7 days after surgery and were performed ten times over a three week period showing a reduction in mechanical hypersensitivity and spontaneous pain that started from the first laser treatment until the end of the experiment. The ex vivo analysis highlighted the protective role of laser through the myelin sheath recovery in the sciatic nerve, inhibition of iNOS expression and enhancement of EAAT-2 levels in the spinal cord. In conclusion, this study supports laser treatment as a future therapeutic strategy in patients suffering from neuropathic pain induced by trauma.


Assuntos
Lasers , Terapia com Luz de Baixa Intensidade/métodos , Bainha de Mielina/efeitos da radiação , Neuralgia/radioterapia , Animais , Comportamento Animal , Transportador 2 de Aminoácido Excitatório/metabolismo , Hiperalgesia/complicações , Inflamação , Masculino , Proteína Básica da Mielina/metabolismo , Óxido Nítrico Sintase Tipo II/antagonistas & inibidores , Limiar da Dor , Pressão , Qualidade de Vida , Ratos , Ratos Sprague-Dawley , Nervo Isquiático/lesões , Medula Espinal/efeitos da radiação
18.
Mol Med Rep ; 20(2): 1279-1287, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31173269

RESUMO

Obesity is associated with increased sensitivity to pain, including neuropathic pain, but the precise mechanisms are not fully understood. Recent evidence has revealed that AMP­activated protein kinase (AMPK) in the central nervous system (CNS) regulates the neuropeptide calcitonin gene­related peptide (CGRP), a principal neurotransmitter of the class C nerve fiber, which serves an important role in initiating and maintaining neuropathic pain. AMPK has been demonstrated to be downregulated in the CNS in obesity. The present study hypothesized that obesity may lead to increased sensitivity to neuropathic pain by downregulating AMPK and upregulating CGRP expression levels in the CNS. Sprague­Dawley rats consuming a high­fat diet (HF) for 12 weeks developed obesity; they exhibited significantly decreased levels of phospho (p)­AMPK and increased CGRP expression levels in the spinal cord (SC) and dorsal root ganglion (DRG), respectively, compared with rats consuming a low­fat (LF) diet. HF­fed rats that underwent spared nerve injury (SNI) also exhibited lower p­AMPK and higher CGRP expression levels in the SC and DRG, compared with the corresponding LF­diet rats. The 50% paw withdrawal threshold (PWT; as measured by Von Frey testing) was significantly lower in HF­fed compared with LF­fed rats, with or without SNI. Through intrathecal treatment, the AMPK activator 5­aminoimidazole­4­carboxamide riboside (AICAR) or the CGRP antagonist CGRP8­37 decreased CGRP expression levels and increased the 50% PWT; however, the AMPK inhibitor dorsomorphin augmented CGRP expression levels and further reduced the 50% PWT in HF­fed rats, but not LF­fed rats, with or without SNI. The results indicated that blocking the AMPK­CGRP pathway may enhance neuropathic pain in HF­induced obesity, with or without nerve injury. Targeting AMPK in the CNS may be a novel strategy for the prevention and treatment of obesity­associated neuropathic pain.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Sistema Nervoso Central/metabolismo , Dieta Hiperlipídica , Tecido Nervoso/lesões , Neuralgia/metabolismo , Obesidade/metabolismo , Transdução de Sinais , Proteínas Quinases Ativadas por AMP/antagonistas & inibidores , Animais , Peso Corporal , Sistema Nervoso Central/patologia , Hiperalgesia/complicações , Masculino , Camundongos Obesos , Tecido Nervoso/metabolismo , Tecido Nervoso/patologia , Neuralgia/complicações , Obesidade/complicações , Limiar da Dor , Fosforilação , Ratos Sprague-Dawley
19.
Mol Neurobiol ; 56(11): 7408-7419, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31037647

RESUMO

Chemotherapy-induced peripheral neuropathy (CIPN) adversely impacts quality of life and a challenge to treat with existing drugs used for neuropathic pain. Losartan, an angiotensin II type 1 receptor (AT1R) antagonist widely used to treat hypertension, has been reported to have analgesic effects in several pain models. In this study, we assessed losartan's analgesic effect on paclitaxel-induced neuropathic pain (PINP) in rats and its mechanism of action in dorsal root ganglion (DRG). Rats received intraperitoneal injections of 2 mg/kg paclitaxel on days 0, 2, 4, and 6 and received single or multiple intraperitoneal injections of losartan potassium dissolved in phosphate-buffered saline at various times. The mechanical thresholds, protein levels of inflammatory cytokines, and cellular location of AT1R and interleukin 1ß (IL-1ß) in the DRG were assessed with behavioral testing, Western blotting, and immunohistochemistry, respectively. Data were analyzed by two-way repeated-measures analysis of variance for the behavioral test or the Mann-Whitney U test for the Western blot analysis and immunohistochemistry. Single and multiple injections of losartan ameliorated PINP, and losartan delayed the development of PINP. Paclitaxel significantly increased, and losartan subsequently decreased, the expression levels of inflammatory cytokines, including IL-1ß and tumor necrosis factor α (TNF-α), in the lumbar DRG. AT1R and IL-1ß were expressed in both neurons and satellite cells and losartan decreased the intensity of IL-1ß in the DRG. Losartan ameliorates PINP by decreasing inflammatory cytokines including IL-1ß and TNF-α in the DRG. Our findings provide a new or add-on therapy for CIPN patients.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Citocinas/metabolismo , Gânglios Espinais/metabolismo , Hiperalgesia/tratamento farmacológico , Mediadores da Inflamação/metabolismo , Losartan/uso terapêutico , Neuralgia/induzido quimicamente , Neuralgia/tratamento farmacológico , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Animais , Modelos Animais de Doenças , Gânglios Espinais/efeitos dos fármacos , Proteína Glial Fibrilar Ácida/metabolismo , Hiperalgesia/complicações , Hiperalgesia/patologia , Hipnóticos e Sedativos/farmacologia , Hipnóticos e Sedativos/uso terapêutico , Losartan/farmacologia , Masculino , NF-kappa B/metabolismo , Neuralgia/complicações , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Paclitaxel/efeitos adversos , Fosforilação/efeitos dos fármacos , Ratos Sprague-Dawley
20.
Mol Pain ; 15: 1744806919850383, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31041873

RESUMO

Preoperative anxiety is common in patients undergoing elective surgery and is closely related to postoperative hyperalgesia. In this study, a single prolonged stress model was used to induce preoperative anxiety-like behavior in rats 24 h before the surgery. We found that single prolonged stress exacerbated the postoperative pain and elevated the level of serum corticosterone. Previous studies have shown that glucocorticoid is associated with synaptic plasticity, and decreased spinal GABAergic activity can cause hyperalgesia in rodents. Here, single prolonged stress rats' lumbar spinal cord showed reduced glutamic acid decarboxylase-65, glutamic acid decarboxylase-67, GABA type A receptor alpha 1 subunit, and GABA type A receptor gamma 2 subunit, indicating an impairment of GABAergic system. Furthermore, neuronal PAS domain protein 4 was also reduced in rats after single prolonged stress stimulation, which has been reported to promote GABAergic synapse development. Then, intraperitoneal injection of RU486 (a glucocorticoid receptor antagonist) rather than spironolactone (a mineralocorticoid receptor antagonist) was found to relieve single prolonged stress-induced hyperalgesia and reverse neuronal PAS domain protein 4 reduction and the impairment of GABAergic system. Furthermore, overexpressing neuronal PAS domain protein 4 could also restore the damage of GABAergic system caused by single prolonged stress while interfering with neuronal PAS domain protein 4 caused an opposite effect. Finally, after stimulation of rat primary spinal cord neurons with exogenous corticosterone in vitro, neuronal PAS domain protein 4 and GABAergic markers were also downregulated, and RU486 reversed that. Together, our results demonstrated that preoperative anxiety led to GABAergic system impairment in spinal cord and thus caused hyperalgesia due to glucocorticoid-induced downregulation of neuronal PAS domain protein 4.


Assuntos
Ansiedade/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Biomarcadores/metabolismo , Glucocorticoides/metabolismo , Hiperalgesia/psicologia , Transdução de Sinais , Medula Espinal/metabolismo , Ácido gama-Aminobutírico/metabolismo , Animais , Ansiedade/complicações , Corticosterona/sangue , Dependovirus/metabolismo , Regulação para Baixo/efeitos dos fármacos , Hiperalgesia/complicações , Hiperalgesia/metabolismo , Injeções Espinhais , Masculino , Mifepristona/farmacologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Cuidados Pós-Operatórios , Cuidados Pré-Operatórios , Interferência de RNA , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Espironolactona/farmacologia , Estresse Psicológico/sangue , Regulação para Cima/efeitos dos fármacos
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