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1.
Eur J Anaesthesiol ; 38(12): 1230-1241, 2021 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-34735395

RESUMO

BACKGROUND: Remifentanil is an effective drug in peri-operative pain therapy, but it can also induce and aggravate hyperalgesia. Supplemental administration of N2O may help to reduce remifentanil-induced hyperalgesia. OBJECTIVE: To evaluate the effect of 35 and 50% N2O on hyperalgesia and pain after remifentanil infusion. DESIGN: Single site, phase 1, double-blind, placebo-controlled, randomised crossover study. SETTING: University Hospital, Germany from January 2012 to April 2012. PARTICIPANTS: Twenty-one healthy male volunteers. INTERVENTIONS: Transcutaneous electrical stimulation induced spontaneous acute pain and stable areas of hyperalgesia. Each volunteer underwent the following four sessions in a randomised order: 50 to 50% N2-O2 and intravenous (i.v.) 0.9% saline infusion (placebo); 50 to 50% N2-O2 and i.v. remifentanil infusion at 0.1 µg kg-1 min-1 (remifentanil); 35 to 15 to 50% N2O-N2-O2 and i.v. remifentanil infusion at 0.1 µg kg-1 min-1 (tested drug) and 50 to 50% N2O-O2 and i.v. remifentanil infusion at 0.1 µg kg-1 min-1 (gas active control). Gas mixtures were inhaled for 60 min; i.v. drugs were administered for 30 min. MAIN OUTCOME MEASURES: Areas of pin-prick hyperalgesia, areas of touch-evoked allodynia and pain intensity on a visual analogue scale were assessed repeatedly for 160 min. RESULTS: Data from 20 volunteers were analysed. There were significant treatment and treatment-by-time effects regarding areas of hyperalgesia (P < 0.001). After the treatment period, the area of hyperalgesia was significantly reduced (P < 0.001) in the tested drug and in the gas active control (30.6 ±â€Š9.25 and 24.4 ±â€Š7.3 cm2, respectively) compared with remifentanil (51.0 ±â€Š17.0 cm2). There was also a significant difference between the gas active control and the tested drug sessions (P < 0.001). For the area of allodynia and pain rating, results were consistent with the results for hyperalgesia. CONCLUSIONS: Administration of 35% N2O significantly reduced hyperalgesia, allodynia and pain intensity induced after remifentanil. It might therefore be suitable in peri-operative pain relief characterised by hyperalgesia and allodynia, such as postoperative pain, and may help to reduce opioid demand. TRIAL REGISTRATION: EudraCT-No.: 2011-000966-37.


Assuntos
Óxido Nitroso , Piperidinas , Analgésicos Opioides , Método Duplo-Cego , Voluntários Saudáveis , Humanos , Hiperalgesia/induzido quimicamente , Hiperalgesia/diagnóstico , Hiperalgesia/tratamento farmacológico , Masculino , Dor Pós-Operatória , Piperidinas/efeitos adversos , Remifentanil
2.
Alcohol Res ; 41(1): 13, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34729286

RESUMO

People living with pain report drinking alcohol to relieve pain. Acute alcohol use reduces pain, and chronic alcohol use facilitates the emergence or exaggeration of pain. Recently, funding agencies and neuroscientists involved in basic research have turned their attention to understanding the neurobiological mechanisms that underlie pain-alcohol interactions, with a focus on circuit and molecular mediators of alcohol-induced changes in pain-related behavior. This review briefly discusses some examples of work being done in this area, with a focus on reciprocal projections between the midbrain and extended amygdala, as well as some neurochemical mediators of pain-related phenotypes after alcohol exposure. Finally, as more work accumulates on this topic, the authors highlight the need for the neuroscience field to carefully consider sex and age in the design and analysis of pain-alcohol interaction experiments.


Assuntos
Alcoolismo , Hiperalgesia , Alcoolismo/complicações , Tonsila do Cerebelo , Humanos , Hiperalgesia/induzido quimicamente , Mesencéfalo , Peptídeos
3.
Braz J Med Biol Res ; 54(12): e11071, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34730678

RESUMO

Kahweol is a compound derived from coffee with reported antinociceptive effects. Based on the few reports that exist in the literature regarding the mechanisms involved in kahweol-induced peripheral antinociceptive action, this study proposed to investigate the contribution of the endocannabinoid system to the peripheral antinociception induced in rats by kahweol. Hyperalgesia was induced by intraplantar injection of prostaglandin E2(PGE2) and was measured with the paw pressure test. Kahweol and the drugs to test the cannabinoid system were administered locally into the right hind paw. The endocannabinoids were purified by open-bed chromatography on silica and measured by LC-MS. Kahweol (80 µg/paw) induced peripheral antinociception against PGE2-induced hyperalgesia. This effect was reversed by the intraplantar injection of the CB1 cannabinoid receptor antagonist AM251 (20, 40, and 80 µg/paw), but not by the CB2 cannabinoid receptor antagonist AM630 (100 µg/paw). Treatment with the endocannabinoid reuptake inhibitor VDM11 (2.5 µg/paw) intensified the peripheral antinociceptive effect induced by low-dose kahweol (40 µg/paw). The monoacylglycerol lipase (MAGL) inhibitor, JZL184 (4 µg/paw), and the dual MAGL/fatty acid amide hydrolase (FAAH) inhibitor, MAFP (0.5 µg/paw), potentiated the peripheral antinociceptive effect of low-dose kahweol. Furthermore, kahweol increased the levels of the endocannabinoid anandamide, but not of the other endocannabinoid 2-arachidonoylglycerol nor of anandamide-related N-acylethanolamines, in the plantar surface of the rat paw. Our results suggested that kahweol induced peripheral antinociception via anandamide release and activation of CB1 cannabinoid receptors and this compound could be used to develop new drugs for pain relief.


Assuntos
Diterpenos , Endocanabinoides , Analgésicos/farmacologia , Animais , Café , Hiperalgesia/induzido quimicamente , Hiperalgesia/tratamento farmacológico , Ratos , Receptor CB1 de Canabinoide , Receptor CB2 de Canabinoide
4.
Zhonghua Yi Xue Za Zhi ; 101(43): 3581-3587, 2021 Nov 23.
Artigo em Chinês | MEDLINE | ID: mdl-34808752

RESUMO

Objective: To investigate the molecular mechanism of oxaliplatin-induced chemotherapy-induced peripheral neuropathic pain (CIPNP). Methods: A total of 16 male Sprague-Dawley rats of specific pathogen-free grade were randomly divided into two groups: oxaliplatin experimental group (2.4 mg/kg oxaliplatin dissolved in 5.0% glucose solution, n=8) and control group (equal volume 5% glucose solution, n=8). The rat model of CIPNP was established by continuous administration with oxaliplatin. In addition, mechanical allodynia, thermal hyperalgesia and cold hyperalgesia were measured and compared between the two groups. To explore the molecular mechanism of oxaliplatin-induced CIPNP, the gene expression of dorsal root ganglia (DRG) from the rat model of CIPNP was analyzed using RNA sequencing (RNA-Seq). Results: Mechanical and thermal hypersensitivity was exhibited on day 7 and a stronger hypersensitivity was observed on day 14. A total of 20 152 genes were quantified by RNA-Seq, and 379 differentially expressed genes (DEGs) were obtained with absolute fold change cut-offs ≥ 2 and P value<0.05. There were 7 genes (Npy, Car3, Cdkn1a, Nts, Prc1, Ms4a7 and Ecel1) that were involved in peripheral nerve injury-related neuropathic pain. Gene ontology (GO) functional enrichment analyses indicated that the DEGs induced by oxaliplatin were involved in oxygen transport, cell division, intermediate, centromere, oxygen transporter activity, oxygen binding. Moreover, the result of Kyoto Encyclopedia of genes and genomes (KEGG) analyses highlighted that the DEGs induced by oxaliplatin were involved in malaria, African trypanosomiasis, primary immunodeficiency, peroxisome proliferator activated receptor (PPAR) signaling pathway. Conclusion: Oxaliplatin induces CIPNP via pain-related genes and signaling pathways.


Assuntos
Neuralgia , Animais , Gânglios Espinais , Hiperalgesia/induzido quimicamente , Masculino , Neuralgia/induzido quimicamente , Oxaliplatina , Ratos , Ratos Sprague-Dawley
5.
Sci Rep ; 11(1): 17971, 2021 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-34504248

RESUMO

Rheumatoid arthritis (RA) is an autoimmune disease associated with advanced joint dysfunction. Madhuca indica J. F. Gmel, from the family Sapotaceae, is an Indian medicinal plant reported to have an array of pharmacological properties. The aim of present investigation was to determine the anti-arthritic potential of an isolated phytoconstituent from methanolic leaf extract of Madhuca indica (MI-ALC) against FCA-induced experimental arthritis. Polyarthritis was induced in female rats (strain: Wistar) via an intradermal injection of FCA (0.1 mL) into the tail. Polyarthritis developed after 32 days of FCA administration. Then rats were treated orally with an isolated phytoconstituent from MI-ALC at doses of 5, 10, and 20 mg/kg. Findings suggested that High-Performance Thin-Layer Chromatography, Fourier-Transform Infrared Spectroscopy, and Liquid Chromatography-Mass Spectrometry spectral analyses of the phytoconstituent isolated from MI-ALC confirmed the structure as 3,5,7,3',4'-Pentahydroxy flavone (i.e., QTN). Treatment with QTN (10 and 20 mg/kg) showed significant (p < 0.05) inhibition of increased joint diameter, paw volume, paw withdrawal threshold, and latency. The elevated synovial oxidative stress (Superoxide dismutase, reduced glutathione, and malondialdehyde) and protein levels of Tumor necrosis factor-α (TNF-α) and Interleukin (ILs) were markedly (p < 0.05) reduced by QTN. It also effectively (p < 0.05) ameliorated cyclooxygenase-2 (COX-2), Nuclear factor of kappa light polypeptide gene enhancer in B cells (NF-kß) and its inhibitor-α (Ikßα), and ATP-activated P2 purinergic receptors (P2X7) protein expressions as determined by western blot analysis. In conclusion, QTN ameliorates FCA-induced hyperalgesia through modulation of elevated inflammatory release (NF-kß, Ikßα, P2X7, and COX-2), oxido-nitrosative stress, and pro-inflammatory cytokines (ILs and TNF-α) in experimental rats.


Assuntos
Antirreumáticos/administração & dosagem , Artrite Experimental/tratamento farmacológico , Artrite Reumatoide/tratamento farmacológico , Flavonoides/administração & dosagem , Madhuca/química , Fitoterapia/métodos , Extratos Vegetais/administração & dosagem , Plantas Medicinais/química , Adjuvantes Imunológicos/efeitos adversos , Administração Oral , Animais , Antirreumáticos/química , Antirreumáticos/isolamento & purificação , Artrite Experimental/induzido quimicamente , Artrite Experimental/metabolismo , Artrite Reumatoide/induzido quimicamente , Artrite Reumatoide/metabolismo , Ciclo-Oxigenase 2/metabolismo , Citocinas/metabolismo , Feminino , Flavonoides/química , Flavonoides/isolamento & purificação , Adjuvante de Freund/efeitos adversos , Hiperalgesia/induzido quimicamente , Hiperalgesia/tratamento farmacológico , Hiperalgesia/metabolismo , Estrutura Molecular , NF-kappa B/metabolismo , Estresse Nitrosativo/efeitos dos fármacos , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Resultado do Tratamento
6.
Sci Rep ; 11(1): 17418, 2021 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-34465829

RESUMO

Hyperalgesia has become a major problem restricting the clinical application of tooth bleaching. We hypothesized that transient receptor potential ankyrin 1 (TRPA1), a pain conduction tunnel, plays a role in tooth hyperalgesia and inflammation after bleaching. Dental pulp stem cells were seeded on the dentin side of the disc, which was cut from the premolar buccal tissue, with 15% (90 min) or 40% (3 × 15 min) bleaching gel applied on the enamel side, and treated with or without a TRPA1 inhibitor. The bleaching gel stimulated intracellular reactive oxygen species, Ca2+, ATP, and extracellular ATP in a dose-dependent manner, and increased the mRNA and protein levels of hyperalgesia (TRPA1 and PANX1) and inflammation (TNFα and IL6) factors. This increment was adversely affected by TRPA1 inhibitor. In animal study, the protein levels of TRPA1 (P = 0.0006), PANX1 (P < 0.0001), and proliferation factors [PCNA (P < 0.0001) and Caspase 3 (P = 0.0066)] increased significantly after treated rat incisors with 15% and 40% bleaching gels as detected by immunohistochemistry. These results show that TRPA1 plays a critical role in sensitivity and inflammation after tooth bleaching, providing a solid foundation for further research on reducing the complications of tooth bleaching.


Assuntos
Polpa Dentária/patologia , Hiperalgesia/patologia , Inflamação/patologia , Espécies Reativas de Oxigênio/metabolismo , Células-Tronco/patologia , Clareadores Dentários/efeitos adversos , Clareamento Dental/efeitos adversos , Animais , Cálcio/metabolismo , Polpa Dentária/efeitos dos fármacos , Polpa Dentária/metabolismo , Géis/efeitos adversos , Hiperalgesia/induzido quimicamente , Hiperalgesia/metabolismo , Inflamação/induzido quimicamente , Inflamação/metabolismo , Ratos , Ratos Sprague-Dawley , Células-Tronco/efeitos dos fármacos , Células-Tronco/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
7.
Int J Mol Sci ; 22(16)2021 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-34445514

RESUMO

Oxaliplatin, a well-known chemotherapeutic agent, can induce severe neuropathic pain, which can seriously decrease the quality of life of patients. JI017 is an herb mixture composed of Aconitum carmichaelii, Angelica gigas, and Zingiber officinale. Its anti-tumor effect has been reported; however, the efficacy of JI017 against oxaliplatin-induced allodynia has never been explored. Single oxaliplatin injection [6 mg/kg, intraperitoneal, (i.p.)] induced both cold and mechanical allodynia, and oral administration of JI017 (500 mg/kg) alleviated cold but not mechanical allodynia in mice. Real-time polymerase chain reaction (PCR) analysis demonstrated that the upregulation of mRNA of spinal transient receptor potential vanilloid 1 (TRPV1) and astrocytes following oxaliplatin injection was downregulated after JI017 treatment. Moreover, TRPV1 expression and the activation of astrocytes were intensely increased in the superficial area of the spinal dorsal horn after oxaliplatin treatment, whereas JI017 suppressed both. The administration of TRPV1 antagonist [capsazepine, intrathecal (i.t.), 10 µg] attenuated the activation of astrocytes in the dorsal horn, demonstrating that the functions of spinal TRPV1 and astrocytes are closely related in oxaliplatin-induced neuropathic pain. Altogether, these results suggest that JI017 may be a potent candidate for the management of oxaliplatin-induced neuropathy as it decreases pain, spinal TRPV1, and astrocyte activation.


Assuntos
Astrócitos/metabolismo , Hiperalgesia/tratamento farmacológico , Oxaliplatina/efeitos adversos , Compostos Fitoquímicos/administração & dosagem , Canais de Cátion TRPV/metabolismo , Aconitum/química , Administração Oral , Angelica/química , Animais , Astrócitos/efeitos dos fármacos , Temperatura Baixa , Modelos Animais de Doenças , Regulação para Baixo , Gengibre/química , Hiperalgesia/induzido quimicamente , Hiperalgesia/genética , Hiperalgesia/metabolismo , Camundongos , Compostos Fitoquímicos/farmacologia , Coluna Vertebral/metabolismo , Canais de Cátion TRPV/genética
8.
Neuropsychopharmacology ; 46(11): 1990-1999, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34341495

RESUMO

The anterior cingulate cortex (ACC) is implicated in many pathologies, including depression, anxiety, substance-use disorders, and pain. There is also evidence from brain imaging that the ACC is hyperactive during periods of opioid withdrawal. However, there are limited data contributing to our understanding of ACC function at the cellular level during opioid withdrawal. Here, we address this issue by performing ex vivo electrophysiological analysis of thick-tufted, putative dopamine D2 receptor expressing, layer V pyramidal neurons in the ACC (ACC L5 PyNs) in a mouse model of spontaneous opioid withdrawal. We found that escalating doses of morphine (20, 40, 60, 80, and 100 mg/kg, i.p. on days 1-5, respectively) injected twice daily into male C57BL/6 mice evoked withdrawal behaviors and an associated withdrawal-induced mechanical hypersensitivity. Brain slices prepared 24 h following the last morphine injection showed increases in ACC L5 thick-tufted PyN-intrinsic membrane excitability, increases in membrane resistance, reductions in the rheobase, and reductions in HCN channel-mediated currents (IH). We did not observe changes in intrinsic or synaptic properties on thin-tufted, dopamine D1-receptor-expressing ACC L5 PyNs recorded from male Drd1a-tdTomato transgenic mice. In addition, we found that chemogenetic inhibition of the ACC blocked opioid-induced withdrawal and withdrawal-induced mechanical hypersensitivity. These results demonstrate that spontaneous opioid withdrawal alters neuronal properties within the ACC and that ACC activity is necessary to control behaviors associated with opioid withdrawal and withdrawal-induced mechanical hypersensitivity. The ability of the ACC to regulate both withdrawal behaviors and withdrawal-induced mechanical hypersensitivity suggests overlapping mechanisms between two seemingly distinguishable behaviors. This commonality potentially suggests that the ACC is a locus for multiple withdrawal symptoms.


Assuntos
Hiperalgesia , Síndrome de Abstinência a Substâncias , Analgésicos Opioides , Animais , Giro do Cíngulo , Hiperalgesia/induzido quimicamente , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Morfina , Ratos , Ratos Sprague-Dawley
9.
J Neurochem ; 159(3): 512-524, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34338322

RESUMO

Studies have verified that Fragile X mental retardation protein (FMRP), an RNA-binding protein, plays a potential role in the pathogenesis of formalin- and (RS)-3,5-dihydroxyphenylglycine-induced abnormal pain sensations. However, the role of FMRP in inflammatory pain has not been reported. Here, we showed an increase in FMRP expression in the spinal dorsal horn (SDH) in a rat model of inflammatory pain induced by complete Freund's adjuvant (CFA). Double immunofluorescence staining revealed that FMRP was mainly expressed in spinal neurons and colocalized with proinflammatory cytokines [tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6)]. After consecutive intrathecal injection of fragile X mental retardation 1 small interfering RNA for 3 days post-CFA injection, FMRP expression in the SDH was reduced, and CFA-induced hyperalgesia was decreased. In addition, the CFA-induced increase in spinal TNF-α and IL-6 production was significantly suppressed by intrathecal administration of fragile X mental retardation 1 small interfering RNA. Together, these results suggest that FMRP regulates TNF-α and IL-6 levels in the SDH and plays an important role in inflammatory pain.


Assuntos
Citocinas/biossíntese , Proteína do X Frágil de Retardo Mental/fisiologia , Inflamação/genética , Inflamação/patologia , Dor/patologia , Medula Espinal/metabolismo , Medula Espinal/patologia , Animais , Proteína do X Frágil de Retardo Mental/genética , Adjuvante de Freund , Hiperalgesia/induzido quimicamente , Hiperalgesia/patologia , Injeções Espinhais , Interleucina-6/metabolismo , Masculino , Dor/induzido quimicamente , Dor/genética , Células do Corno Posterior/metabolismo , RNA Interferente Pequeno/administração & dosagem , RNA Interferente Pequeno/farmacologia , Ratos , Ratos Sprague-Dawley , Fator de Necrose Tumoral alfa/metabolismo
10.
Biomed Pharmacother ; 139: 111653, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34243625

RESUMO

The clinical application of opioids may be accompanied by a series of adverse consequences, such as opioid tolerance, opioid-induced hyperalgesia, opioid dependence or addiction. In view of this issue, clinicians are faced with the dilemma of treating various types of pain with or without opioids. In this review, we discuss that Src protein tyrosine kinase plays an important role in these adverse consequences, and Src inhibitors can solve these problems well. Therefore, Src inhibitors have the potential to be used in combination with opioids to achieve synergy. How to combine them together to maximize the analgesic effect while avoiding unnecessary trouble provides a topic for follow-up research.


Assuntos
Analgésicos Opioides/farmacologia , Dor Crônica/tratamento farmacológico , Tolerância a Medicamentos/fisiologia , Hiperalgesia/induzido quimicamente , Inibidores de Proteínas Quinases/farmacologia , Transtornos Relacionados ao Uso de Substâncias/etiologia , Quinases da Família src/antagonistas & inibidores , Analgésicos Opioides/metabolismo , Animais , Dor Crônica/metabolismo , Humanos , Hiperalgesia/metabolismo
11.
J Neurosci ; 41(27): 5963-5978, 2021 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-34252037

RESUMO

Systemic treatment with resiniferatoxin (RTX) induces small-fiber sensory neuropathy by damaging TRPV1-expressing primary sensory neurons and causes distinct thermal sensory impairment and tactile allodynia, which resemble the unique clinical features of postherpetic neuralgia. However, the synaptic plasticity associated with RTX-induced tactile allodynia remains unknown. In this study, we found that RTX-induced neuropathy is associated with α2δ-1 upregulation in the dorsal root ganglion (DRG) and increased physical interaction between α2δ-1 and GluN1 in the spinal cord synaptosomes. RNAscope in situ hybridization showed that RTX treatment significantly increased α2δ-1 expression in DRG neurons labeled with calcitonin gene-related peptide, isolectin B4, NF200, and tyrosine hydroxylase. Electrophysiological recordings revealed that RTX treatment augmented the frequency of miniature excitatory postsynaptic currents (mEPSCs) and the amplitude of evoked EPSCs in spinal dorsal horn neurons, and these effects were reversed by blocking NMDA receptors with AP-5. Inhibiting α2δ-1 with gabapentin, genetically ablating α2δ-1, or targeting α2δ-1-bound NMDA receptors with α2δ-1Tat peptide largely normalized the baseline frequency of mEPSCs and the amplitude of evoked EPSCs potentiated by RTX treatment. Furthermore, systemic treatment with memantine or gabapentin and intrathecal injection of AP-5 or Tat-fused α2δ-1 C terminus peptide reversed allodynia in RTX-treated rats and mice. In addition, RTX-induced tactile allodynia was attenuated in α2δ-1 knock-out mice and in mice in which GluN1 was conditionally knocked out in DRG neurons. Collectively, our findings indicate that α2δ-1-bound NMDA receptors at presynaptic terminals of sprouting myelinated afferent nerves contribute to RTX-induced potentiation of nociceptive input to the spinal cord and tactile allodynia.SIGNIFICANCE STATEMENT Postherpetic neuralgia (PHN), associated with shingles, is a distinct form of neuropathic pain commonly seen in elderly and immunocompromised patients. The synaptic plasticity underlying touch-induced pain hypersensitivity in PHN remains unclear. Using a nonviral animal model of PHN, we found that glutamatergic input from primary sensory nerves to the spinal cord is increased via tonic activation of glutamate NMDA receptors. Also, we showed that α2δ-1 (encoded by Cacna2d1), originally considered a calcium channel subunit, serves as an auxiliary protein that promotes activation of presynaptic NMDA receptors and pain hypersensitivity. This new information advances our understanding of the molecular mechanism underlying PHN and suggests new strategies for treating this painful condition.


Assuntos
Canais de Cálcio Tipo L/metabolismo , Hiperalgesia/metabolismo , Neuralgia/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Células Receptoras Sensoriais/metabolismo , Animais , Diterpenos/toxicidade , Gânglios Espinais , Ácido Glutâmico/metabolismo , Hiperalgesia/induzido quimicamente , Masculino , Camundongos , Neuralgia/induzido quimicamente , Neuralgia Pós-Herpética , Neurotoxinas/toxicidade , Ratos , Ratos Sprague-Dawley , Regulação para Cima
12.
Exp Brain Res ; 239(9): 2873-2886, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34302514

RESUMO

Subpopulations of primary nociceptors (C- and Aδ-fibers), express the TRPV1 receptor for heat and capsaicin. During cutaneous inflammation, these afferents may become sensitized, leading to primary hyperalgesia. It is known that TRPV1+ nociceptors are involved in heat hyperalgesia; however, their involvement in mechanical hyperalgesia is unclear. This study explored the contribution of capsaicin-sensitive nociceptors in the development of mechanical and heat hyperalgesia in humans following ultraviolet-B (UVB) irradiation. Skin areas in 18 healthy volunteers were randomized to treatment with 8% capsaicin/vehicle patches for 24 h. After patches removal, one capsaicin-treated area and one vehicle area were irradiated with 2xMED (minimal erythema dose) of UVB. 1, 3 and 7 days post-UVB exposure, tests were performed to evaluate the development of UVB-induced cutaneous hyperalgesia: thermal detection and pain thresholds, pain sensitivity to supra-threshold heat stimuli, mechanical pain threshold and sensitivity, touch pleasantness, trans-epidermal water loss (TEWL), inflammatory response, pigmentation and micro-vascular reactivity. Capsaicin pre-treatment, in the UVB-irradiated area (Capsaicin + UVB area), increased heat pain thresholds (P < 0.05), and decreased supra-threshold heat pain sensitivity (P < 0.05) 1, 3 and 7 days post-UVB irradiation, while mechanical hyperalgesia resulted unchanged (P > 0.2). No effects of capsaicin were reported on touch pleasantness (P = 1), TEWL (P = 0.31), inflammatory response and pigmentation (P > 0.3) or micro-vascular reactivity (P > 0.8) in response to the UVB irradiation. 8% capsaicin ablation predominantly defunctionalizes TRPV1+-expressing cutaneous nociceptors responsible for heat pain transduction, suggesting that sensitization of these fibers is required for development of heat hyperalgesia following cutaneous UVB-induced inflammation but they are likely only partially necessary for the establishment of robust primary mechanical hyperalgesia.


Assuntos
Capsaicina , Hiperalgesia , Humanos , Hiperalgesia/induzido quimicamente , Nociceptores , Dor , Limiar da Dor
13.
J Headache Pain ; 22(1): 70, 2021 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-34256692

RESUMO

BACKGROUND: Migraine is a complex neurological disorder that is characterized by throbbing head pain, increased sensitivity to light, sound, and touch, as well as nausea and fatigue. It is one of the most common and most disabling disorders globally but mechanisms causing migraine are poorly understood. While head pain is a typical feature of attacks, they also often present with cutaneous hypersensitivity in the rest of the body. In contrast, primary pain conditions in the lower parts of the body are less commonly associated with cephalic hypersensitivity. Previous studies indicate that application of stimuli to the meninges of rodents causes cutaneous facial as well as hindpaw hypersensitivity. In the present study, we asked whether widespread hypersensitivity is a unique feature of dural stimulation or whether body-wide responses occur similarly when the same stimulus is given in other locations. METHODS: Rats were given the same dose of IL-6 either via dural, intraplantar, subcutaneous, intramuscular, intracisternal, or intrathecal injection. Cutaneous facial and hindpaw allodynia was assessed using Von Frey following injection into each location. RESULTS: Hindpaw allodynia was observed following dural and intraplantar injection of IL-6 in both males and females. Hindpaw allodynia was only observed in females following intracisternal and intrathecal IL-6 injections. In contrast, facial allodynia was only observed in either sex following dural and intracisternal injections, which would activate meningeal afferents and the trigeminal nucleus caudalis (TNC), respectively. CONCLUSIONS: Here we show that while stimulation of upper body regions with IL-6 including the meninges and brainstem can cause widespread hypersensitivity spreading to the paws, similar stimulation of the lower body does not cause the spread of hypersensitivity into the head. These data are consistent with the observations that whole body hypersensitivity is specific to conditions such as migraine where pain is present in the head and they may provide insight into co-morbid pain states associated with migraine.


Assuntos
Interleucina-6 , Transtornos de Enxaqueca , Animais , Dura-Máter , Feminino , Hiperalgesia/induzido quimicamente , Masculino , Transtornos de Enxaqueca/induzido quimicamente , Ratos , Ratos Sprague-Dawley
14.
J Am Assoc Lab Anim Sci ; 60(5): 539-548, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34266519

RESUMO

Due to their reduced frequency of dosing and ease of availability, NSAIDs are generally preferred over opioids for rodent analgesia. We evaluated the efficacy of the highly COX2-selective NSAID firocoxib as compared with meloxicam and buprenorphine for reducing allodynia and hyperalgesia in rats in a plantar incision model of surgical pain. After a preliminary pharmacokinetic study using firocoxib, Sprague-Dawley rats (n = 12 per group, 6 of each sex) were divided into 6 groups: no surgery (anesthesia only), saline (surgery but no analgesia), buprenorphine (0.05 mg/kg SC every 8 h), meloxicam (2 mg/kg SC every 24 h), and 2 dosages of firocoxib (10 and 20 mg/kg SC every 24 h). The nociception assays were performed by using von Frey and Hargreaves methodology to test mechanical allodynia and thermal hyperalgesia. These assays were performed at 24 h before and at 20, 28, 44, and 52 h after start of surgery. None of the analgesics used in this study produced significantly different responses in allodynia or hyperalgesia from those of saline-treated rats. In the Hargreaves assay, female saline-treated rats experienced significantly greater hyperalgesia than did males. These findings add to a growing body of literature suggesting that commonly used dosages of analgesics may not provide sufficient analgesia in rats experiencing incisional pain.


Assuntos
Buprenorfina , 4-Butirolactona/análogos & derivados , Animais , Feminino , Hiperalgesia/induzido quimicamente , Hiperalgesia/tratamento farmacológico , Hiperalgesia/veterinária , Masculino , Meloxicam , Nociceptividade , Dor Pós-Operatória/tratamento farmacológico , Dor Pós-Operatória/veterinária , Ratos , Ratos Sprague-Dawley , Sulfonas
15.
Front Immunol ; 12: 672498, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34122430

RESUMO

Inflammation-associated chronic pain is a global clinical problem, affecting millions of people worldwide. However, the underlying mechanisms that mediate inflammation-associated chronic pain remain unclear. A rat model of cutaneous inflammation induced by Complete Freund's Adjuvant (CFA) has been widely used as an inflammation-induced pain hypersensitivity model. We present the transcriptomics profile of CFA-induced inflammation in the rat dorsal root ganglion (DRG) via an approach that targets gene expression, DNA methylation, and post-transcriptional regulation. We identified 418 differentially expressed mRNAs, 120 differentially expressed microRNAs (miRNAs), and 2,670 differentially methylated regions (DMRs), which were all highly associated with multiple inflammation-related pathways, including nuclear factor kappa B (NF-κB) and interferon (IFN) signaling pathways. An integrated analysis further demonstrated that the activator protein 1 (AP-1) network, which may act as a regulator of the inflammatory response, is regulated at both the transcriptomic and epigenetic levels. We believe our data will not only provide drug screening targets for the treatment of chronic pain and inflammation but will also shed light on the molecular network associated with inflammation-induced hyperalgesia.


Assuntos
Hiperalgesia/metabolismo , Inflamação/metabolismo , Fator de Transcrição AP-1/metabolismo , Animais , Dor Crônica/induzido quimicamente , Dor Crônica/metabolismo , Modelos Animais de Doenças , Adjuvante de Freund/toxicidade , Gânglios Espinais/efeitos dos fármacos , Gânglios Espinais/metabolismo , Sequenciamento de Nucleotídeos em Larga Escala , Hiperalgesia/induzido quimicamente , Inflamação/induzido quimicamente , Masculino , Ratos , Ratos Sprague-Dawley
16.
Anesth Analg ; 133(3): 794-810, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34166321

RESUMO

BACKGROUND: Remifentanil can induce postinfusion cold hyperalgesia. N-methyl-d-aspartate receptor (NMDAR) activation and upregulation of transient receptor potential melastatin 8 (TRPM8) membrane trafficking in dorsal root ganglion (DRG) are critical to cold hyperalgesia derived from neuropathic pain, and TRPM8 activation causes NMDAR-dependent cold response. Contribution of P2Y1 purinergic receptor (P2Y1R) activation in DRG to cold pain hypersensitivity and NMDAR activation induced by P2Y1R upregulation in neurons are also unraveled. This study explores whether P2Y1R contributes to remifentanil-induced cold hyperalgesia via TRPM8-dependent regulation of NMDAR phosphorylation in DRG. METHODS: Rats with remifentanil-induced cold hyperalgesia were injected with TRPM8 antagonist or P2Y1R antagonist at 10 minutes before remifentanil infusion. Cold hyperalgesia (paw lift number and withdrawal duration on cold plate) was measured at -24, 2, 6, 24, and 48 hours following remifentanil infusion. After the last behavioral test, P2Y1R expression, TRPM8 expression and membrane trafficking, and NMDAR subunit (NR1 and NR2B) expression and phosphorylation in DRG were detected by western blot, and colocalization of P2Y1R with TRPM8 was determined by double-labeling immunofluorescence. Two-way repeated measures analysis of variance (ANOVA) or 2 × 2 factorial design ANOVA with repeated measures was used to analyze behavioral data of cold hyperalgesia. One-way ANOVA followed by Bonferroni post hoc comparisons was used to analyze the data in western blot and immunofluorescence. RESULTS: Remifentanil infusion (1 µg·kg-1·min-1 for 60 minutes) induced cold hyperalgesia (hyperalgesia versus control, paw lift number and withdrawal duration on cold plate at 2-48 hours, P < .0001) with upregulated NR1 (hyperalgesia versus naive, 48 hours, mean ± standard deviation [SD], 114.00% ± 12.48% vs 41.75% ± 5.20%, P < .005) and NR2B subunits expression (104.13% ± 8.37% vs 24.63% ± 4.87%, P < .005), NR1 phosphorylation at Ser896 (91.88% ± 7.08% vs 52.00% ± 7.31%, P < .005) and NR2B phosphorylation at Tyr1472 (115.75% ± 8.68% vs 59.75% ± 7.78%, P < .005), TRPM8 expression (115.38% ± 9.27% vs 40.50% ± 4.07%, P < .005) and membrane trafficking (112.88% ± 5.62% vs 48.88% ± 6.49%, P < .005), and P2Y1R expression (128.25% ± 14.86% vs 45.13% ± 7.97%, P < .005) in DRG. Both TRPM8 and P2Y1R antagonists attenuated remifentanil-induced cold hyperalgesia and downregulated increased NR1 and NR2B expression and phosphorylation induced by remifentanil (remifentanil + RQ-00203078 versus remifentanil + saline, NR1 phosphorylation, 69.38% ± 3.66% vs 92.13% ± 4.85%; NR2B phosphorylation, 72.25% ± 6.43% vs 111.75% ± 11.00%, P < .0001). NMDAR activation abolished inhibition of TRPM8 and P2Y1R antagonists on remifentanil-induced cold hyperalgesia. P2Y1R antagonist inhibited remifentanil-evoked elevations in TRPM8 expression and membrane trafficking and P2Y1R-TRPM8 coexpression (remifentanil + 2'-deoxy-N6-methyl adenosine 3',5'-diphosphate [MRS2179] versus remifentanil + saline, coexpression, 8.33% ± 1.33% vs 22.19% ± 2.15%, P < .0001). CONCLUSIONS: Attenuation of remifentanil-induced cold hyperalgesia by P2Y1R inhibition is attributed to downregulations in NMDAR expression and phosphorylation via diminishing TRPM8 expression and membrane trafficking in DRG.


Assuntos
Gânglios Espinais/metabolismo , Hiperalgesia/metabolismo , Limiar da Dor , Receptores de N-Metil-D-Aspartato/metabolismo , Receptores Purinérgicos P2Y1/metabolismo , Canais de Cátion TRPM/metabolismo , Analgésicos/farmacologia , Animais , Comportamento Animal , Temperatura Baixa , Modelos Animais de Doenças , Gânglios Espinais/efeitos dos fármacos , Gânglios Espinais/fisiopatologia , Hiperalgesia/induzido quimicamente , Hiperalgesia/fisiopatologia , Hiperalgesia/prevenção & controle , Masculino , Limiar da Dor/efeitos dos fármacos , Fosforilação , Transporte Proteico , Antagonistas do Receptor Purinérgico P2Y/farmacologia , Ratos Sprague-Dawley , Receptores Purinérgicos P2Y1/efeitos dos fármacos , Remifentanil , Transdução de Sinais , Canais de Cátion TRPM/antagonistas & inibidores
17.
Toxicon ; 200: 3-12, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34153310

RESUMO

Scorpionism is a public health burden in Brazil. Tityus bahiensis is responsible for most accidents in the Southeastern region of Brazil. Here, the hyperalgesic mechanisms of Tityus bahiensis venom were investigated, focusing on the role of pro-inflammatory cytokines (tumor necrosis factor alpha [TNF-α] and interleukin 1 beta [IL-1ß]) and activation of the transcription factor NFκB. Intraplantar (i.pl.) administration of Tityus bahiensis venom (0.2, 0.6, 1.2 and 2.4 µg/20 µL i.pl.) induced mechanical hyperalgesia and thermal hyperalgesia. The 2.4 µg dose of Tityus bahiensis venom induced overt pain-like behavior and increased myeloperoxidase (MPO) and N-acetyl-beta-D-glucosaminidase (NAG) activities, TNF-α and IL-1ß levels in the paw tissue. Systemic pre-treatment with etanercept (soluble TNF-α receptor; 10 mg/kg), IL-1ra (IL-1 receptor antagonist; 30 mg/kg) and pyrrolidine dithiocarbamate (PDTC, nuclear factor kappa B [NFκB] inhibitor; 100 mg/kg) inhibited Tityus bahiensis venom-induced mechanical and thermal hyperalgesia, MPO and NAG activity and overt pain-like behavior. These data demonstrate the involvement of TNF-α and IL-1ß signaling as well as NFκB activation in Tityus bahiensis venom-induced mechanical and thermal hyperalgesia, overt pain-like behavior, and MPO activity and NAG activity, indicating thus, that targeting these mechanisms might contribute to reducing the pain in this scorpionism.


Assuntos
Dor , Peçonhas , Animais , Hiperalgesia/induzido quimicamente , Dor/induzido quimicamente , Dor/tratamento farmacológico , Escorpiões , Fator de Necrose Tumoral alfa
18.
Muscle Nerve ; 64(2): 225-234, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34036599

RESUMO

INTRODUCTION/AIMS: Clinically, the chemotherapeutic agent oxaliplatin can cause peripheral neuropathy, impaired balance, and muscle wastage. Using a preclinical model, we investigated whether exercise intervention could improve these adverse conditions. METHODS: Mice were chronically treated with oxaliplatin alone or in conjunction with exercise. Behavioral studies, including mechanical allodynia, rotarod, open-field, and grip-strength tests, were performed. After euthanasia, multiple organs and four different muscle types were dissected and weighed. The cross-sectional area (CSA) of muscle fibers in the gastrocnemius muscle was assessed and gene expression analysis performed on the forelimb triceps muscle. RESULTS: Oxaliplatin-treated mice displayed reduced weight gain, mechanical allodynia, and exploratory behavior deficits that were not significantly improved by exercise. Oxaliplatin-treated exercised mice showed modest evidence of reduced muscle wastage compared with mice treated with oxaliplatin alone, and exercised mice demonstrated evidence of a mild increase in CSA of muscle fibers. DISCUSSION: Exercise intervention did not improve signs of peripheral neuropathy but moderately reduced the negative impact of oxaliplatin chemotherapy related to muscle morphology, suggesting the potential for exploring the impact of exercise on reducing oxaliplatin-induced neuromuscular toxicity in cancer patients.


Assuntos
Hiperalgesia/terapia , Doenças do Sistema Nervoso Periférico/terapia , Condicionamento Físico Animal/fisiologia , Animais , Antineoplásicos/farmacologia , Modelos Animais de Doenças , Hiperalgesia/induzido quimicamente , Masculino , Camundongos Endogâmicos C57BL , Oxaliplatina/farmacologia , Limiar da Dor/efeitos dos fármacos , Doenças do Sistema Nervoso Periférico/induzido quimicamente
19.
Neurochem Res ; 46(8): 2181-2191, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34032956

RESUMO

Application of chemotherapeutic oxaliplatin represses gene transcription through induction of DNA methylation, which may contribute to oxaliplatin-induced chronic pain. Here, Ddr1, which showed an increased methylation in the promoter, was screened from the SRA methylation database (PRJNA587622) after oxaliplatin treatment. qPCR and MeDIP assays verified that oxaliplatin treatment increased the methylation in Ddr1 promoter region and decreased the expression of DDR1 in the neurons of spinal dorsal horn. In addition, overexpression of DDR1 by intraspinal injection of AAV-hSyn-Ddr1 significantly alleviated the mechanical allodynia induced by oxaliplatin. Furthermore, we found that oxaliplatin treatment increased the expression of DNMT3b and ZEB1 in dorsal horn neurons, and promoted the interaction between DNMT3b and ZEB1. Intrathecal injection of ZEB1 siRNA inhibited the enhanced recruitment of DNMT3b and the hypermethylation in Ddr1 promoter induced by oxaliplatin. Finally, ZEB1 siRNA rescued the DDR1 downregulation and mechanical allodynia induced by oxaliplatin. In conclusion, these results suggested that the ZEB1 recruited DNMT3b to the Ddr1 promoter, which induced the DDR1 downregulation and contributed to the oxaliplatin-induced chronic pain.


Assuntos
Dor Crônica/metabolismo , Metilação de DNA/fisiologia , Receptor com Domínio Discoidina 1/genética , Oxaliplatina/efeitos adversos , Corno Dorsal da Medula Espinal/metabolismo , Homeobox 1 de Ligação a E-box em Dedo de Zinco/metabolismo , Animais , Dor Crônica/induzido quimicamente , DNA/metabolismo , DNA (Citosina-5-)-Metiltransferases/metabolismo , Metilação de DNA/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Hiperalgesia/induzido quimicamente , Hiperalgesia/metabolismo , Masculino , Neuralgia/induzido quimicamente , Neuralgia/metabolismo , Regiões Promotoras Genéticas/fisiologia , RNA Interferente Pequeno/farmacologia , Ratos Sprague-Dawley , Corno Dorsal da Medula Espinal/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos
20.
Eur J Pain ; 25(9): 1971-1993, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34051016

RESUMO

BACKGROUND: Mechanical hyperalgesia and allodynia incidence varies considerably amongst neuropathic pain patients. This study explored whether sensory or psychological factors associate with mechanical hyperalgesia and brush allodynia in a human experimental model. METHODS: Sixty-six healthy volunteers (29 male) completed psychological questionnaires and participated in two quantitative sensory testing (QST) sessions. Warmth detection threshold (WDT), heat pain threshold (HPT) and suprathreshold mechanical pain (STMP) ratings were measured before exposure to a capsaicin-heat pain model (C-HP). After C-HP exposure, brush allodynia and STMP were measured in one session, whilst mechanical hyperalgesia was measured in another session. RESULTS: WDT and HPT measured in sessions separated by 1 month demonstrated significant but moderate levels of reliability (WDT: ICC = 0.5, 95%CI [0.28, 0.77]; HPT: ICC = 0.62, 95%CI [0.40, 0.77]). Brush allodynia associated with lower WDT (z = -3.06, p = 0.002; ϕ = 0.27). Those with allodynia showed greater hyperalgesia intensity (F = 7.044, p = 0.010, ηp 2  = 0.107) and area (F = 9.319, p = 0.004, ηp 2  = 0.163) than those without allodynia. No psychological self-report measures were significantly different between allodynic and nonallodynic groups. Intensity of hyperalgesia in response to lighter mechanical stimuli was associated with lower HPT, higher STMP ratings and higher Pain Sensitivity Questionnaire scores at baseline. Hyperalgesia to heavier probe stimuli associated with state anxiety and to a lesser extent somatic awareness. Hyperalgesic area associated with lower baseline HPT and higher STMP ratings. Hyperalgesic area was not correlated with allodynic area across individuals. CONCLUSIONS: These findings support research in neuropathic pain patients and human experimental models that peripheral sensory input and individual sensibility are related to development of mechanical allodynia and hyperalgesia during central sensitization, whilst psychological factors play a lesser role. SIGNIFICANCE: We evaluated differential relationships of psychological and perceptual sensitivity to the development of capsaicin-induced mechanical allodynia and hyperalgesia. Fifty percent of healthy volunteers failed to develop mechanical allodynia. Baseline pain sensitivity was greater in those developing allodynia and was related to the magnitude and area of hyperalgesia. State psychological factors, whilst unrelated to allodynia, were related to mechanical hyperalgesia. This supports that the intensity of peripheral sensory input and individual sensibility are related to development of mechanical allodynia and hyperalgesia during central sensitization, whilst psychological factors play a lesser role.


Assuntos
Hiperalgesia , Neuralgia , Ansiedade/induzido quimicamente , Capsaicina , Sensibilização do Sistema Nervoso Central , Humanos , Hiperalgesia/induzido quimicamente , Masculino , Neuralgia/induzido quimicamente , Limiar da Dor , Reprodutibilidade dos Testes
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