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1.
Int J Mol Sci ; 22(17)2021 Aug 28.
Artículo en Inglés | MEDLINE | ID: mdl-34502257

RESUMEN

The catabolic and destructive activity of serine proteases in arthritic joints is well known; however, these enzymes can also signal pain and inflammation in joints. For example, thrombin, trypsin, tryptase, and neutrophil elastase cleave the extracellular N-terminus of a family of G protein-coupled receptors and the remaining tethered ligand sequence then binds to the same receptor to initiate a series of molecular signalling processes. These protease activated receptors (PARs) pervade multiple tissues and cells throughout joints where they have the potential to regulate joint homeostasis. Overall, joint PARs contribute to pain, inflammation, and structural integrity by altering vascular reactivity, nociceptor sensitivity, and tissue remodelling. This review highlights the therapeutic potential of targeting PARs to alleviate the pain and destructive nature of elevated proteases in various arthritic conditions.


Asunto(s)
Artritis/metabolismo , Receptores Proteinasa-Activados/fisiología , Animales , Humanos , Receptor PAR-1/fisiología , Receptor PAR-2/fisiología , Receptores de Trombina/fisiología , Transducción de Señal/fisiología
2.
Neurosci Lett ; 739: 135391, 2020 11 20.
Artículo en Inglés | MEDLINE | ID: mdl-32949662

RESUMEN

There is strong evidence showing that the activation of peripheral proteinase-activated receptors type 2 (PAR-2) can initiate hyperalgesic and inflammatory responses in the joint. However, to date, there is no report of functional spinal PAR-2 receptors in arthritis models. The primary aim of this study was to evaluate the activity of PAR-2 receptors at the spinal cord by using a potent agonist (FLIGRL) in naïve animals, and an antagonist (GB83) in different models of joint pain. Saline or FLIGRL (10 nmol) were injected intrathecally in naïve animals and nociceptive behaviour was evaluated over a 24 h time period by von Frey hair algesiometry. Paw withdrawal threshold decreased from 3 to 24 h and this allodynic effect was blocked by GB83 (90 nmol; i.p.). Acute inflammatory joint pain was induced by injecting 0.5 % kaolin/carrageenan (50 µL each) into the right knee joint of male Wistar rats (24 h recovery). Chronic inflammatory joint pain was modelled by intraarticular injection of Freund's complete adjuvant (FCA; 50 µL; 7 days recovery) or chronic osteoarthritis pain by sodium monoiodoacetate (MIA; 3 mg; 14 days recovery). Animals were then treated with either intrathecal vehicle or 10 nmol of GB83 (10 µL); joint pain was evaluated throughout the subsequent 3 h period. The acute inflammatory pain induced by kaolin/carrageenan was not affected by treatment with GB83. Conversely, both chronic arthritis models demonstrated increased hind paw withdrawal threshold after spinal injection of the PAR-2 antagonist. Based on these results, spinal PAR-2 receptors are involved in joint nociceptive processing in chronic but not acute arthritic conditions.


Asunto(s)
Artritis/fisiopatología , Hiperalgesia/fisiopatología , Nocicepción/fisiología , Receptor PAR-2/fisiología , Médula Espinal/fisiología , Animales , Artritis/complicaciones , Dipéptidos/administración & dosificación , Modelos Animales de Enfermedad , Hiperalgesia/complicaciones , Isoxazoles/administración & dosificación , Masculino , Umbral del Dolor/fisiología , Ratas Wistar , Receptor PAR-2/agonistas , Receptor PAR-2/antagonistas & inhibidores
3.
Life Sci ; 236: 116860, 2019 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-31518605

RESUMEN

AIMS: Intrathecal injection of morphine presents analgesic and antiedematogenic effects in rats. However, it is unknown whether tramadol, which possess a mixed mechanism of action, can also produce analgesic and antiedematogenic effects similarly. MAIN METHODS: Male Wistar rats received carrageenan and LPS in the right knee joint. Tramadol (10 µg) was injected intrathecally 20 min before articular LPS injection. Incapacitation and articular edema were measured 5 h after LPS stimulation. Synovial fluid was collected for leukocyte counting and western blot analysis. Whole joint and lumbar spinal cord were also collected for histology and immunohistochemistry, respectively. Intrathecal pretreatments groups were with the NKCC1 blocker bumetanide, TRPV1 agonist resiniferatoxin, µ-opioid receptor antagonist CTOP and serotonergic neurotoxin 5,7-DHT, all previously to tramadol. KEY FINDINGS: Tramadol treatment caused the reduction of incapacitation and edema. It also reduced c-Fos protein expression in the spinal cord dorsal horn and slightly reduced TNF-α levels in synovial fluid, but neither reduced cell migration nor tissue damage. Bumetanide and resiniferatoxin prevented the analgesic and antiedematogenic effects of tramadol. CTOP prevented the analgesic and the antiedematogenic effects, but 5,7-DHT prevented only tramadol-induced analgesia. SIGNIFICANCE: Spinal NKCC1 cotransporter and peptidergic peripheral afferents seem to be important for the analgesic and antiedematogenic effects of tramadol, as well as µ-opioid receptor. However, the monoamine uptake inhibition effect of tramadol seems to be important only to the analgesic effect.


Asunto(s)
Analgésicos Opioides/administración & dosificación , Artralgia/prevención & control , Artritis Experimental/complicaciones , Artritis Reactiva/complicaciones , Edema/prevención & control , Lipopolisacáridos/toxicidad , Tramadol/administración & dosificación , Animales , Artralgia/etiología , Artralgia/patología , Artritis Experimental/inducido químicamente , Artritis Experimental/fisiopatología , Artritis Reactiva/inducido químicamente , Artritis Reactiva/fisiopatología , Modelos Animales de Enfermedad , Edema/etiología , Edema/patología , Inyecciones Espinales , Masculino , Ratas , Ratas Wistar
4.
Life Sci ; 166: 60-65, 2016 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-27729269

RESUMEN

AIMS: Rheumatoid arthritis brings great burdens to the patients. In addition to the highly expensive treatment, they are commonly associated with severe side effects. In such context, the research for safe and affordable treatments is needed. MAIN METHODS: Arthritis was induced by CFA (0.5mg/mL) in female wistar rats. Trypsin was given p.o. (2.95mg/kg; 2mL) 24h after the intra-articular CFA injection. Articular incapacitation was measured daily by counting the paw elevation time (PET; s) during 1-min periods of stimulated walk, throughout the 7-days after intra-articular CFA injection. Articular diameter (AD) was accessed just after each PET measurement, taken the difference between naïve and diseased knee-joint diameter (cm). KEY FINDINGS: The present study showed that orally administered trypsin was able to reduce nociception and edema, effects that could be observed throughout the evaluation period. These effect, however, were not observed in animals underwent subdiaphragmatic vagotomy, suggesting a vagal mediation for trypsin effects. Likewise, these effects were blocked in rats which received intrathecal injection of the neurotoxins 5,7-dihydroxytryptamine or 6-hydroxydopamine, suggesting the involvement of spinal amines from axon terminals. SIGNIFICANCE: The present study proposes that oral trypsin may cause vagal activation, followed by the activation of descending inhibitory pathways and such mechanism may lead to a novel approach for the treatment of arthritis.


Asunto(s)
Analgésicos/uso terapéutico , Artritis Experimental/tratamiento farmacológico , Artritis Reumatoide/tratamiento farmacológico , Edema/tratamiento farmacológico , Nocicepción/efectos de los fármacos , Tripsina/uso terapéutico , 5,7-Dihidroxitriptamina/administración & dosificación , 5,7-Dihidroxitriptamina/farmacología , Administración Oral , Adrenérgicos/administración & dosificación , Adrenérgicos/farmacología , Analgésicos/administración & dosificación , Analgésicos/farmacología , Animales , Artritis Experimental/complicaciones , Artritis Reumatoide/complicaciones , Edema/complicaciones , Femenino , Inyecciones Espinales , Oxidopamina/administración & dosificación , Oxidopamina/farmacología , Ratas Wistar , Serotoninérgicos/administración & dosificación , Serotoninérgicos/farmacología , Tripsina/administración & dosificación , Tripsina/farmacología , Vagotomía
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