RESUMO
Neuroactive steroids (NASs) directly affect neuronal excitability. Despite their role in the nervous system is intimately linked to pain control, knowledge is currently limited. This study investigates the peripheral involvement of NASs in chronic ischemic pain by targeting the cytochrome P450 side-chain cleavage enzyme (P450scc). Using a rat model of hind limb thrombus-induced ischemic pain (TIIP), we observed an increase in P450scc expression in the ischemic hind paw skin. Inhibiting P450scc with intraplantar aminoglutethimide (AMG) administration from post-operative day 0 to 3 significantly reduced the development of mechanical allodynia. However, AMG administration from post-operative day 3 to 6 did not affect established mechanical allodynia. In addition, we explored the role of the peripheral sigma-1 receptor (Sig-1R) by co-administering PRE-084 (PRE), a Sig-1R agonist, with AMG. PRE reversed the analgesic effects of AMG during the induction phase. These findings indicate that inhibiting steroidogenesis with AMG alleviates peripheral ischemic pain during the induction phase via Sig-1Rs.
Assuntos
Modelos Animais de Doenças , Hiperalgesia , Isquemia , Ratos Sprague-Dawley , Receptores sigma , Animais , Hiperalgesia/tratamento farmacológico , Hiperalgesia/patologia , Hiperalgesia/complicações , Masculino , Isquemia/complicações , Isquemia/patologia , Receptores sigma/antagonistas & inibidores , Receptores sigma/metabolismo , Receptor Sigma-1 , Dor/tratamento farmacológico , Dor/complicações , Dor/etiologia , Dor/patologia , Membro Posterior/efeitos dos fármacos , Ratos , Sistema Enzimático do Citocromo P-450/metabolismoRESUMO
Spontaneous pain, a major complaint of patients with neuropathic pain, has eluded study because there is no reliable marker in either preclinical models or clinical studies. Here, we performed a comprehensive electroencephalogram/electromyogram analysis of sleep in several mouse models of chronic pain: neuropathic (spared nerve injury and chronic constriction injury), inflammatory (Freund's complete adjuvant and carrageenan, plantar incision) and chemical pain (capsaicin). We find that peripheral axonal injury drives fragmentation of sleep by increasing brief arousals from non-rapid eye movement sleep (NREMS) without changing total sleep amount. In contrast to neuropathic pain, inflammatory or chemical pain did not increase brief arousals. NREMS fragmentation was reduced by the analgesics gabapentin and carbamazepine, and it resolved when pain sensitivity returned to normal in a transient neuropathic pain model (sciatic nerve crush). Genetic silencing of peripheral sensory neurons or ablation of CGRP+ neurons in the parabrachial nucleus prevented sleep fragmentation, whereas pharmacological blockade of skin sensory fibers was ineffective, indicating that the neural activity driving the arousals originates ectopically in primary nociceptor neurons and is relayed through the lateral parabrachial nucleus. These findings identify NREMS fragmentation by brief arousals as an effective proxy to measure spontaneous neuropathic pain in mice.
Assuntos
Neuralgia , Nociceptores , Humanos , Ratos , Camundongos , Animais , Movimentos Oculares , Hiperalgesia/complicações , Ratos Sprague-Dawley , Sono , Modelos Animais de DoençasRESUMO
Pain is a major symptom in cancer patients, and cancer-induced bone pain (CIBP) is the most common type of moderate and severe cancer-related pain. The current available analgesic treatments for CIBP have adverse effects as well as limited therapeutic effects. Acupuncture is proved effective in pain management as a safe alternative therapy. We evaluated the analgesic effect of acupuncture in treatment of cancer pain and try to explore the underlying analgesic mechanisms. Nude mice were inoculated with cancer cells into the left distal femur to establish cancer pain model. Electroacupuncture (EA) treatment was applied for the xenograft animals. Pain behaviors of mice were evaluated, followed by the detections of neuropeptide-related and inflammation-related indicators in peripheral and central levels. EA treatment alleviated cancer-induced pain behaviors covering mechanical allodynia, thermal hyperalgesia and spontaneous pain, and also down-regulated immunofluorescence expressions of neuropeptide CGRP and p75 in the skin of affected plantar area in xenograft mice, and inhibited expressions of overexpressed neuropeptide-related and inflammation-related protein in the lumbar spinal cord of xenograft mice. Overall, our findings suggest that EA treatment ameliorated cancer-induced pain behaviors in the mouse xenograft model of cancer pain, possibly through inhibiting the expressions of neuropeptide-related and inflammation-related protein in central level following tumor cell xenografts.
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Dor do Câncer , Eletroacupuntura , Neoplasias , Neuropeptídeos , Ratos , Humanos , Camundongos , Animais , Dor do Câncer/etiologia , Dor do Câncer/terapia , Dor do Câncer/metabolismo , Nociceptividade , Camundongos Nus , Ratos Sprague-Dawley , Dor/metabolismo , Hiperalgesia/complicações , Hiperalgesia/terapia , Hiperalgesia/induzido quimicamente , Analgésicos/metabolismo , Inflamação/metabolismo , Medula Espinal/metabolismoRESUMO
Neuropathic pain following nerve injury is a complex condition, which often puts a negative impact on life and remains a sustained problem. To make pain management better is of great significance and unmet need. RTA 408 (Omaveloxone) is a traditional Asian medicine with a valid anti-inflammatory property. Thus, we aim to investigate the therapeutic effect of RTA-408 on mechanical allodynia in chronic constriction injury (CCI) rats as well as the underlying mechanisms. Neuropathic pain was induced by using CCI of the rats' sciatic nerve (SN) and the behavior testing was measured by calibrated forceps testing. Activation of Nrf-2, the phosphorylation of nuclear factor-κB (NF-κB), and the inflammatory response were assessed by western blots. The number of apoptotic neurons and degree of glial cell reaction were examined by immunofluorescence assay. RTA-408 exerts an analgesic effect on CCI rats. RTA-408 reduces neuronal apoptosis and glial cell activation by increasing Nrf-2 expression and decreasing the inflammatory response (TNF-α/ p-NF-κB/ TSLP/ STAT5). These data suggest that RTA-408 is a candidate with potential to reduce nociceptive hypersensitivity after CCI by targeting TSLP/STAT5 signaling.
Assuntos
NF-kappa B , Neuralgia , Triterpenos , Ratos , Animais , NF-kappa B/metabolismo , Constrição , Fator de Transcrição STAT5/metabolismo , Nociceptividade , Ratos Sprague-Dawley , Neuralgia/complicações , Neuralgia/tratamento farmacológico , Neuralgia/metabolismo , Nervo Isquiático/metabolismo , Hiperalgesia/complicações , Hiperalgesia/tratamento farmacológico , Hiperalgesia/metabolismoRESUMO
We aimed to investigate the characteristics and longitudinal course of sensory phenotypes identified through quantitative sensory testing (QST) in the frame of diabetic sensorimotor polyneuropathy (DSPN). A total of 316 individuals with diabetes were examined (type 2 diabetes 78.8%), 250 of whom were undergoing follow-up visits at 1, 2, and/or 4 (2.88 ± 1.27) years. Allocation into four sensory phenotypes (healthy, thermal hyperalgesia [TH], mechanical hyperalgesia [MH], and sensory loss [SL]) at every time point was based on QST profiles of the right foot. Cross-sectional analysis demonstrated a gradual worsening of clinical and electrophysiological sensory findings and increased DSPN prevalence across the groups, culminating in SL. Motor nerve impairment was observed solely in the SL group. Longitudinal analysis revealed a distinct pattern in the developmental course of the phenotype (from healthy to TH, MH, and finally SL). Those with baseline MH exhibited the highest risk of transition to SL. Reversion to healthy status was uncommon and mostly observed in the TH group. Among those without DSPN initially, presence or future occurrence of SL was associated with a three- to fivefold higher likelihood of DSPN development. Our comprehensive longitudinal study of phenotyped patients with diabetes elucidates the natural course of DSPN. QST-based sensory examination together with other tools for phenotyping may be useful in determining the natural course of diabetic neuropathy to identify patients at high risk of DSPN and guide preventive and therapeutic interventions. ARTICLE HIGHLIGHTS: The course of diabetic sensorimotor polyneuropathy (DSPN) development, from healthy status to overt DSPN, is poorly understood. We studied the characteristics and longitudinal appearance of lower-extremity sensory phenotypes (healthy, thermal hyperalgesia [TH], mechanical hyperalgesia [MH], and sensory loss [SL]) identified through quantitative sensory testing in individuals with diabetes. There was an increasing severity and patterned order of longitudinal appearance across healthy, TH, MH, and SL phenotypes. SL was most strongly associated with formal DSPN. Our findings provide insight into the natural history of DSPN. Sensory phenotyping can be implemented to identify high-risk individuals and those most likely to benefit from therapeutic interventions.
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Diabetes Mellitus Tipo 2 , Neuropatias Diabéticas , Polineuropatias , Humanos , Diabetes Mellitus Tipo 2/complicações , Hiperalgesia/complicações , Estudos Longitudinais , Estudos Transversais , Polineuropatias/etiologia , FenótipoRESUMO
The dopaminergic system is implicated in the pathophysiology of migraine. However, the underlying mechanisms remain unclear. We explored the effects and mechanisms of dopaminergic system modulation in the in vivo and in vitro rat models of migraine. Dopaminergic agonist apomorphine, D2 receptor antagonists metoclopramide and haloperidol and 5-HT3 receptor antagonist ondansetron alone and together were tested in nitroglycerin-induced migraine model, in vivo. Likewise, the combinations of drugs were also tested on basal calcitonin gene-related peptide (CGRP) release in vitro hemiskull preparations. Mechanical allodynia was tested by von Frey filaments. CGRP concentrations in trigeminovascular structures and in vitro superfusates and c-Fos levels in the brainstem were determined by enzyme-linked immunosorbent assay. Meningeal mast cells were evaluated with toluidine blue staining. Apomorphine further enhanced nitroglycerin-induced mechanical allodynia, brainstem c-fos expression, trigeminal ganglion and brainstem CGRP concentrations and meningeal mast cell degranulation, in vivo. Haloperidol completely antagonised all apomorphine-induced effects and also alleviated changes induced by nitroglycerin without apomorphine. Metoclopramide and ondansetron partially attenuated apomorphine- or nitroglycerin-induced effects. A combination of haloperidol and ondansetron decreased basal CGRP release, in vitro, whereas the other administrations were ineffective. Apomorphine-mediated dopaminergic activation exacerbated nitroglycerin-stimulated nociceptive reactions by further enhancing c-fos expression, CGRP release and mast cell degranulation in strategical structures associated with migraine pain. Metoclopramide partially attenuated the effects of apomorphine, most likely because it is also a 5-HT3 receptor antagonist. Haloperidol with pure D2 receptor antagonism feature appears to be more effective than metoclopramide in reducing migraine-related parameters in dopaminergic activation- and/or NTG-induced migraine-like conditions.
Assuntos
Hiperalgesia , Transtornos de Enxaqueca , Ratos , Animais , Hiperalgesia/induzido quimicamente , Hiperalgesia/tratamento farmacológico , Hiperalgesia/complicações , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Nitroglicerina/efeitos adversos , Apomorfina/efeitos adversos , Ondansetron/efeitos adversos , Haloperidol/efeitos adversos , Metoclopramida/efeitos adversos , Receptores 5-HT3 de Serotonina , Transtornos de Enxaqueca/induzido quimicamente , Transtornos de Enxaqueca/tratamento farmacológico , Transtornos de Enxaqueca/complicações , Modelos Teóricos , Receptores Dopaminérgicos/metabolismo , Modelos Animais de DoençasRESUMO
Chronic postoperative pain (CPSP) is a major issue after surgery, which may impact on patient's quality of life. Traditionally, CPSP is believed to rely on maladaptive hyperalgesia and risk factors have been identified that predispose to CPSP, including acute postoperative pain. Despite new models of prediction are emerging, acute pain is still a modifiable factor that can be challenged with perioperative analgesic strategies. In this review we present the issue of CPSP, focusing on molecular mechanism underlying the development of acute and chronic hyperalgesia. Also, we focus on how perioperative strategies can impact directly or indirectly (by reducing postoperative pain intensity) on the development of CPSP.
Assuntos
Dor Crônica , Hiperalgesia , Humanos , Hiperalgesia/complicações , Qualidade de Vida , Analgésicos , Dor Pós-Operatória/tratamento farmacológico , Dor Pós-Operatória/complicações , Dor Pós-Operatória/prevenção & controle , Sistema Nervoso CentralRESUMO
INTRODUCTION: Transversus abdominis plane (TAP) has been mentioned as having bene-ficial effects on chronic pain after hernioplasty. This study assessed the effects of TAP block on acute and persistent postoperative pain after inguinal hernia surgery, with or without buprenorphine. MATERIAL AND METHODS: 64 patients were allocated to group R ( n = 32) and received 20 mL of 0.25% ropivacaine for TAP block; group RB ( n = 32) received 20 mL of 0.25% ropivacaine containing 300 µg of buprenorphine for TAP block. The primary outcome was the analgesic and antihyperalgesic effect of buprenorphine. The duration of analgesia, analgesic consumption, postoperative pain scores at rest and sitting up to 48 hours, and the effect on wound hyperalgesia were evaluated. Secondary outcomes included the incidence of side effects and complications. RESULTS: The median (IQR) duration of analgesia in group R was 386.5 (37.25) minutes vs. 868 (41.3) minutes in the RB group. Median pain scores on sitting were found to be significantly better in group RB than in group R at 6, 12, and 24 hours ( P < 0.001). The wound hyperalgesia index showed a significant difference between groups ( P < 0.001). The incidence of persistent postoperative pain was 6.25% in the R group, as compared to 0% in the RB group. Otherwise, the patients did not have any further complications associated with the block. CONCLUSIONS: The results demonstrated that TAP block with buprenorphine reduced acute postoperative pain severity, but we did not find a difference between groups in persistent pain.
Assuntos
Buprenorfina , Hérnia Inguinal , Humanos , Ropivacaina/farmacologia , Buprenorfina/uso terapêutico , Buprenorfina/farmacologia , Hérnia Inguinal/cirurgia , Hérnia Inguinal/complicações , Hérnia Inguinal/tratamento farmacológico , Hiperalgesia/complicações , Hiperalgesia/tratamento farmacológico , Dor Pós-Operatória/tratamento farmacológico , Dor Pós-Operatória/etiologia , Músculos Abdominais , Analgésicos/uso terapêutico , Analgésicos Opioides/uso terapêuticoRESUMO
Neuropathy is a terrible disorder that has a wide range of etiologies. Drug-induced neuropathy, which happens whenever a chemical agent damages the peripheral nerve system, has been linked here to the iatrogenic creation of some drugs. It is potentially permanent and causes sensory impairments and paresthesia that typically affects the hands, feet, and stockings; motor participation is uncommon. It might appear suddenly or over time, and the long-term outlook varies. The wide range of chronic pain conditions experienced by people has been one of the main obstacles to developing new, more effective medications for the treatment of neuropathic pain. Animal models can be used to examine various neuropathic pain etiologies and symptoms. Several models investigate the peripheral processes of neuropathic pain, whereas some even investigate the central mechanisms, such as drug induce models like vincristine, cisplatin, bortezomib, or thalidomide, etc., and surgical models like sciatic nerve chronic constriction injury (CCI), sciatic nerve ligation through spinal nerve ligation (SNL), sciatic nerve damage caused by a laser, SNI (spared nerve injury), etc. The more popular animal models relying on peripheral nerve ligatures are explained. In contrast to chronic sciatic nerve contraction, which results in behavioral symptoms of less reliable stressful neuropathies, (SNI) spared nerve injury generates behavioral irregularities that are more feasible over a longer period. This review summarizes the latest methods models as well as clinical ideas concerning this mechanism. Every strongest current information on neuropathy is discussed, along with several popular laboratory models for causing neuropathy.
Assuntos
Neuralgia , Animais , Doença Crônica , Modelos Animais de Doenças , Hiperalgesia/complicações , Hiperalgesia/tratamento farmacológico , Neuralgia/tratamento farmacológico , Neuralgia/etiologia , Medição da Dor/métodos , Nervo Isquiático/lesõesRESUMO
Neuromodulation through magnetic fields irradiation with ait® (AT-04), a device that irradiates a mixed alternating magnetic fields (2 kHz and 83.3 MHz), has been shown to have high efficacy for fibromyalgia and low back pain in our previous clinical trials. The aim of this study was to elucidate the underlying analgesic mechanism of the AT-04 using the partial sciatic nerve ligation (PSL) model as an animal model of neuropathic pain. AT-04 was applied to PSL model rats with hyperalgesia and its pain-improving effect was verified by examining mechanical allodynia using the von Frey method. The results demonstrated a significant improvement in hyperalgesia in PSL model rats. We also examined the involvement of descending pain modulatory systems in the analgesic effects of AT-04 using antagonism by serotonin and noradrenergic receptor antagonists. These antagonists significantly reduced the analgesic effect of AT-04 on pain in PSL model rats by approximately 50%. We also measured the amount of serotonin and noradrenaline in the spinal fluid of PSL model rats using microdialysis during AT-04 treatment. Both monoamines were significantly increased by magnetic fields irradiation with AT-04. Furthermore, we evaluated the involvement of opioid analgesia in the analgesic effects of AT-04 using naloxone, the main antagonist of the opioid receptor, and found that it significantly antagonized the effects by approximately 60%. Therefore, the analgesic effects of AT-04 in PSL model rats involve both the endogenous pain modulation systems, including the descending pain modulatory system and the opioid analgesic system.
Assuntos
Analgesia , Neuralgia , Ratos , Animais , Hiperalgesia/complicações , Hiperalgesia/tratamento farmacológico , Analgésicos Opioides/uso terapêutico , Serotonina , Medição da Dor , Neuralgia/tratamento farmacológico , Analgésicos/farmacologia , Modelos Animais de DoençasRESUMO
Deficiency of an extracellular matrix glycoprotein tenascin-X (TNX) leads to a human heritable disorder Ehlers-Danlos syndrome, and TNX-deficient patients complain of chronic joint pain, myalgia, paresthesia, and axonal polyneuropathy. We previously reported that TNX-deficient (Tnxb-/-) mice exhibit mechanical allodynia and hypersensitivity to myelinated A-fibers. Here, we investigated the pain response of Tnxb-/- mice using pharmacological silencing of A-fibers with co-injection of N-(2,6-Dimethylphenylcarbamoylmethyl) triethylammonium bromide (QX-314), a membrane-impermeable lidocaine analog, plus flagellin, a toll-like receptor 5 (TLR5) ligand. Intraplantar co-injection of QX-314 and flagellin significantly increased the paw withdrawal threshold to transcutaneous sine wave stimuli at frequencies of 250 Hz (Aδ fiber responses) and 2000 Hz (Aß fiber responses), but not 5 Hz (C fiber responses) in wild-type mice. The QX-314 plus flagellin-induced silencing of Aδ- and Aß-fibers was also observed in Tnxb-/- mice. Co-injection of QX-314 and flagellin significantly inhibited the mechanical allodynia and neuronal activation of the spinal dorsal horn in Tnxb-/- mice. Interestingly, QX-314 alone inhibited the mechanical allodynia in Tnxb-/- mice, and it increased the paw withdrawal threshold to stimuli at frequencies of 250 Hz and 2000 Hz in Tnxb-/- mice, but not in wild-type mice. The inhibition of mechanical allodynia induced by QX-314 alone was blocked by intraplantar injection of a TLR5 antagonist TH1020 in Tnxb-/- mice. These results suggest that mechanical allodynia due to TNX deficiency is caused by the hypersensitivity of Aδ- and Aß-fibers, and it is induced by constitutive activation of TLR5.
Assuntos
Síndrome de Ehlers-Danlos , Hiperalgesia , Animais , Humanos , Camundongos , Síndrome de Ehlers-Danlos/complicações , Síndrome de Ehlers-Danlos/genética , Matriz Extracelular , Flagelina , Hiperalgesia/genética , Hiperalgesia/complicações , Fibras Nervosas Amielínicas , Tenascina/genética , Receptor 5 Toll-LikeRESUMO
Pain is the most significant impairment and debilitating challenge for patients with bone metastasis. Therefore, the primary objective of current therapy is to mitigate and prevent the persistence of pain. Thus, cancer-induced bone pain is described as a multifaceted form of discomfort encompassing both inflammatory and neuropathic elements. We have developed a novel non-addictive pain therapeutic, PNA6, that is a derivative of the peptide Angiotensin-(1-7) and binds the Mas receptor to decrease inflammation-related cancer pain. In the present study, we provide evidence that PNA6 attenuates inflammatory, chemotherapy-induced peripheral neuropathy (CIPN) and cancer pain confined to the long bones, exhibiting longer-lasting efficacious therapeutic effects. PNA6, Asp-Arg-Val-Tyr-Ile-His-Ser-(O-ß-Lact)-amide, was successfully synthesized using solid phase peptide synthesis (SPPS). PNA6 significantly reversed inflammatory pain induced by 2% carrageenan in mice. A second murine model of platinum drug-induced painful peripheral neuropathy was established using oxaliplatin. Mice in the oxaliplatin-vehicle treatment groups demonstrated significant mechanical allodynia compared to the oxaliplatin-PNA6 treatment group mice. In a third study modeling a complex pain state, E0771 breast adenocarcinoma cells were implanted into the femur of female C57BL/6J wild-type mice to induce cancer-induced bone pain (CIBP). Both acute and chronic dosing of PNA6 significantly reduced the spontaneous pain behaviors associated with CIBP. These data suggest that PNA6 is a viable lead candidate for treating chronic inflammatory and complex neuropathic pain.
Assuntos
Antineoplásicos , Neoplasias Ósseas , Neoplasias da Mama , Dor do Câncer , Neuralgia , Humanos , Camundongos , Feminino , Animais , Oxaliplatina/efeitos adversos , Dor do Câncer/tratamento farmacológico , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL , Neuralgia/induzido quimicamente , Neuralgia/tratamento farmacológico , Neuralgia/complicações , Hiperalgesia/induzido quimicamente , Hiperalgesia/tratamento farmacológico , Hiperalgesia/complicações , Neoplasias da Mama/tratamento farmacológico , Neoplasias Ósseas/complicações , Neoplasias Ósseas/tratamento farmacológico , Antineoplásicos/efeitos adversosRESUMO
To guide the treatment of malignant neuropathic pain (MNP) in clinical practice, by inoculating MADB-106 breast cancer cells into the right L4 nerve root in Sprague-Dawley rats, a rat model of MNP was established, providing basic conditions for the study of neuropathic pain and development and application of therapeutic drugs. As the tumor grew over time, it pressed the nerve roots, causing nerve damage. The spinal nerve ligation (SNL) model, which is a neuropathic pain model widely used in rats, was compared with the L4 nerve root SNL model, and histologic examination of the nerve tissue of both models was performed by electron microscopy. In addition to the infiltration and erosion of the L4 nerve by tumor cells, the tumor tissue gradually grew and compressed the L4 nerve roots, resulting in hyperalgesia of the rat's posterior foot on the operative side. Some spontaneous pain phenomena were also observed, such as constant lifting or licking of the posterior foot on the operative side under quiet conditions. Electron microscopy images showed that nerve injury was due to progressive compression by the tumor, cells of which were visualized, but the injury was lighter than that in SNL rats. Imaging showed a paravertebral tumor near the L4 nerve root in the carcinomatous neuropathic pain model rat. These results suggest that progressive compression of the nerve by a malignant tumor leads to nerve damage similar to the behavioral changes associated with chronic compression injury resulting from a loose ligature of the nerve. The cancer neuropathologic pain model at the L4 nerve root was successfully established in Sprague-Dawley rats.
Assuntos
Neoplasias , Neuralgia , Ratos , Animais , Ratos Sprague-Dawley , Neuralgia/patologia , Nervos Espinhais/patologia , Hiperalgesia/complicações , Neoplasias/complicações , Gânglios Espinais/patologia , Ligadura/efeitos adversosRESUMO
The present study was undertaken to explore the relative contributions of Cav3.2 T-type channels to mediating the antihyperalgesic activity of joint manipulation (JM) therapy. We used the chronic constriction injury model (CCI) to induce peripheral neuropathy and chronic pain in male mice, followed by JM. We demonstrate that JM produces long-lasting mechanical anti-hyperalgesia that is abolished in Cav3.2 null mice. Moreover, we found that JM displays a similar analgesic profile as the fatty acid amide hydrolase inhibitor URB597, suggesting a possible converging mechanism of action involving endocannabinoids. Overall, our findings advance our understanding of the mechanisms through which JM produces analgesia.
Assuntos
Analgesia , Canais de Cálcio Tipo T , Camundongos , Masculino , Animais , Dor , Hiperalgesia/complicações , Analgésicos/farmacologia , Analgésicos/uso terapêutico , Canais de Cálcio Tipo T/metabolismoRESUMO
Neuropathic pain (NP) is a prevalent clinical problem for which satisfactory treatment options are unavailable. Tetrandrine (TET), a bisbenzylisoquinoline alkaloid extracted from Stephania tetrandra S. Moore, possesses anti-inflammatory and immune-modulatory properties. Chemokine-like factor 1 (CKLF1) is known to play a crucial role in both peripheral and central inflammatory processes. This study aimed to investigate the potential anti-NP effects of TET and the involvement of CKLF1 in the action of TET. A male C57BL/6J mice model of NP caused by spared nerve injury (SNI) was established and mechanical withdrawal thresholds were measured using von Frey filaments. The results showed that TET improved mechanical allodynia in SNI mice and the propofol-induced sleep assay demonstrated that the TET group did not exhibit central inhibition, while the pregabalin (PGB) group showed significant central inhibition. Western blotting and immunofluorescence staining showed that TET significantly inhibited spinal protein expression levels of CKLF1, p-NF-κB/NF-κB, p-IKK/IKK, pro-inflammatory cytokines IL-1ß and TNF-α, and increased protein expression levels of the anti-inflammatory cytokine IL-10, while inhibiting the expression levels of microglia and astrocyte markers IBA-1 and GFAP of SNI mice. Moreover, immunofluorescence double-labeling results revealed that CKLF1 was predominantly colocalized with microglia of the spinal cord (SC) in SNI mice. C19 (an antagonism peptide of CKLF1) alleviated SNI-induced mechanical pain hypersensitivity, while C27 (an analog peptide of CKLF1) induced mechanical allodynia in normal mice. TET significantly attenuated mechanical allodynia induced by C27 in mice. TET may effectively alleviate NP by reducing neuroinflammation and decreasing CKLF1.
Assuntos
Benzilisoquinolinas , Neuralgia , Ratos , Masculino , Camundongos , Animais , NF-kappa B/metabolismo , Ratos Sprague-Dawley , Hiperalgesia/etiologia , Hiperalgesia/complicações , Camundongos Endogâmicos C57BL , Citocinas/metabolismo , Medula Espinal/metabolismo , Benzilisoquinolinas/farmacologia , Benzilisoquinolinas/uso terapêutico , Benzilisoquinolinas/metabolismo , Anti-Inflamatórios/farmacologia , Neuralgia/metabolismoRESUMO
This study aimed to assess the efficacy of ethanolic extract of Solanum torvum L. fruit (EESTF) containing solasodine in treating chronic constriction injury (CCI)-induced neuropathic pain in rats. Three-dimensional (3D) simulation studies of solasodine binding were conducted on the TRPV1 receptor, IL-6, and TNF-α structures. For in vivo justification, an assessment of behavioral, biochemical, and histological changes was designed after a CCI-induced neuropathic pain model in rats. On days 7, 14, and 21, CCI significantly increased mechanical, thermal, and cold allodynia while producing a functional deficit. IL-6, TNF-α, TBARS, and MPO levels also increased. SOD levels of catalase and reduced glutathione levels also decreased. Administration of pregabalin (30 mg/kg, oral), solasodine (25 mg/kg, oral), and EESTF (100 and 300 mg/kg, oral) significantly reduced CCI-induced behavioral and biochemical changes (P < 0.05). The protective nature of EESTF was also confirmed by histological analysis. Capsaicin, a TRPV1 receptor agonist, abolished the antinociceptive effects of EESTF when used previously. From the observations of the docking studies, solasodine acted as an antagonist at TRPV1, whereas the docking scores of solasodine against TNF-α and IL-6 were reported to be -11.2 and -6.04 kcal/mol, respectively. The attenuating effect of EESTF might be related to its antagonistic effects on TRPV1, suppression of cytokines, and anti-inflammatory and antioxidant properties.
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Citocinas , Neuralgia , Ratos , Animais , Fator de Necrose Tumoral alfa/metabolismo , Interleucina-6 , Frutas/metabolismo , Constrição , Neuralgia/complicações , Neuralgia/tratamento farmacológico , Neuralgia/prevenção & controle , Hiperalgesia/complicações , Hiperalgesia/tratamento farmacológico , Hiperalgesia/metabolismoRESUMO
Irritable bowel syndrome (IBS) is a common chronic functional gastrointestinal disorder defined by disturbances in bowel habits and abdominal pain, in the absence of known organic pathology that affects between 5 to 10% of healthy populations. Despite improvements in detection and treatment, the pathogenesis of IBS has not been clarified. Several microRNAs (miRNAs) are involved in the pathogenesis of IBS through increased intestinal permeability, inflammation, and modulation of visceral hyperalgesia, and they may have the potential to be used as biomarkers and therapeutic targets. Here, we have summarized the recent advances about the role of miRNAs in the development of IBS symptoms and the possibility to use them as therapeutic targets to mitigate symptoms in IBS.
Assuntos
Síndrome do Intestino Irritável , MicroRNAs , Humanos , Síndrome do Intestino Irritável/diagnóstico , Síndrome do Intestino Irritável/genética , Síndrome do Intestino Irritável/terapia , MicroRNAs/genética , Intestinos , Hiperalgesia/complicações , InflamaçãoRESUMO
Background: Propofol is an intravenous anaesthetic drug that has been shown to reduce inflammatory pain. Complex regional pain syndrome (CRPS) type I is a pain condition characterized by autonomic, motor and sensory disturbance. The chronic post-ischaemic pain (CPIP) model is a well-established model to recapture CRPS-I syndromes pre-clinically by non-invasive ischaemic-reperfusion (IR) injury. In this study, we investigated the analgesic effects of propofol and underlying mechanisms in mitigating CRPS pain using the CPIP model. Methods: Sub-anaesthetic dose of propofol (25 mg/kg) was intravenously delivered to the CPIP model and sham control. Nociceptive behavioural changes were assayed by the von Frey test. Molecular assays were used to investigate expression changes of PTEN, PI3K, AKT and IL-6 underlying propofol-mediated analgesic effects. Pharmacological inhibition was applied for PTEN/PI3K/AKT pathway manipulation. Results: Both pre- and post-operative administration of propofol attenuated mechanical allodynia induced by CPIP. Propofol could modulate PTEN/PI3K/AKT signalling pathway by increasing active PTEN and reducing phosphorylated PI3K, phosphorylated AKT and IL-6 expression in the spinal dorsal horn, which promoted pain relief in the CPIP model. Inhibition of PTEN with bpV abolished the analgesic effects produced by propofol in CPIP mice. Conclusion: Sub-anaesthetic dose of propofol administration resulted in the activation of PTEN, inhibition of both PI3K/AKT signalling and IL-6 production in the spinal cord, which dramatically reduced CPIP-induced pain. Our findings lay the foundation in using propofol for the treatment of CRPS with great therapeutic implications.
Assuntos
Dor Crônica , Síndromes da Dor Regional Complexa , Propofol , Distrofia Simpática Reflexa , Camundongos , Animais , Hiperalgesia/complicações , Hiperalgesia/tratamento farmacológico , Hiperalgesia/metabolismo , Propofol/farmacologia , Propofol/uso terapêutico , Interleucina-6 , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Distrofia Simpática Reflexa/metabolismo , Isquemia , Anestésicos Intravenosos , Corno Dorsal da Medula Espinal/metabolismo , Analgésicos/uso terapêutico , Modelos Animais de DoençasRESUMO
Chronic pain, along with comorbid psychiatric disorders, is a common problem worldwide. A growing number of studies have focused on non-opioid-based medicines, and billions of funds have been put into digging new analgesic mechanisms. Peripheral inflammation is one of the critical causes of chronic pain, and drugs with anti-inflammatory effects usually alleviate pain hypersensitivity. Sophoridine (SRI), one of the most abundant alkaloids in Chinese herbs, has been proved to exert antitumor, antivirus and anti-inflammation effects. Here, we evaluated the analgesic effect of SRI in an inflammatory pain mouse model induced by complete Freund's adjuvant (CFA) injection. SRI treatment significantly decreased pro-inflammatory factors release after LPS stimuli in microglia. Three days of SRI treatment relieved CFA-induced mechanical hypersensitivity and anxiety-like behavior, and recovered abnormal neuroplasticity in the anterior cingulate cortex of mice. Therefore, SRI may be a candidate compound for the treatment of chronic inflammatory pain and may serve as a structural basis for the development of new drugs.