Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 4.477
Filtrar
1.
Eur J Med Chem ; 188: 111920, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31901745

RESUMO

γ-Aminobutyric acid (GABA) uptake transporters are membrane transport proteins that are involved in the pathophysiology of a number of neurological disorders. Some types of chronic pain appear to result from the dysfunction of the GABAergic system. The deficiency of mouse GAT1 transporter (mGAT1) abolishes the nociceptive response, which means that mGAT1 inhibition is an appropriate medical approach to achieve analgesia. The mGAT4 transporter is the second most abundant GAT subtype in the brain; however, its physiological role has not yet been fully understood in the central nervous system. In this study, we examined whether the combination of mGAT1 and mGAT3/mGAT4 inhibition in a single molecule might lead to potentially synergistic effects improving analgesic activity to relieve neuropathic pain. To study this hypothesis, new GABA uptake inhibitors were designed, synthesized, and evaluated in terms of their activity and subtype selectivity for mGAT1-4. Among new functionalized amino acid derivatives of serine and GABA analogs, compounds with preferential mGAT3/4 inhibitory activity were discovered. Two selected hits (19b and 31c) were subjected to in vivo tests. We found a statistically significant antiallodynic activity in the von Frey test in diabetic and oxaliplatin-induced neuropathic pain model. The novel compounds (4-hydroxybutanoic, 4-hydroxypentanoic, and 4-aminobutanoic acid derivatives and serine analogs) provide new insights into the structure-activity relationship of mGAT3/mGAT4 inhibitors and indicate a new direction in the search for potential treatment of neuropathic pain of various origin.


Assuntos
Analgésicos/uso terapêutico , Proteínas da Membrana Plasmática de Transporte de GABA/metabolismo , Inibidores da Captação de GABA/uso terapêutico , Hiperalgesia/tratamento farmacológico , Neuralgia/tratamento farmacológico , Limiar da Dor/efeitos dos fármacos , Analgésicos/síntese química , Analgésicos/metabolismo , Animais , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/complicações , Proteínas da Membrana Plasmática de Transporte de GABA/química , Inibidores da Captação de GABA/síntese química , Inibidores da Captação de GABA/metabolismo , Hiperalgesia/induzido quimicamente , Hiperalgesia/etiologia , Masculino , Camundongos , Simulação de Acoplamento Molecular , Estrutura Molecular , Neuralgia/induzido quimicamente , Neuralgia/etiologia , Oxaliplatina , Ligação Proteica , Estreptozocina , Relação Estrutura-Atividade
2.
Br J Anaesth ; 124(1): 92-100, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31711605

RESUMO

BACKGROUND: Intravenous dexamethasone is thought to prolong the duration of peripheral nerve block, but the dose-response relationship remains unclear. The aim of this volunteer study was to evaluate the dose-response effect of i.v. dexamethasone on the prolongation of median nerve block. METHODS: In a double-blind, randomised controlled study, 18 volunteer subjects received two median nerve blocks separated by a washout period. One block was conducted alongside an infusion of saline and the other alongside i.v. dexamethasone 2, 4, or 8 mg. The primary outcome was time to return of normal pinprick sensation. Secondary outcomes included thermal quantitative sensory testing (QST) for the time to return of cold detection threshold (CDT), warm detection threshold (WDT), cold pain threshold (CPT), heat pain threshold (HPT), area under QST curves, grip strength, and the incidence of adverse effects. RESULTS: The primary outcome, time to recovery of pinprick sensation, was similar between volunteers receiving saline or i.v. dexamethasone, regardless of dose (P=0.99). The time to recovery of QST milestones was similar between groups, although area under QST curves indicated prolongation of CDT (0 vs 8 mg, P=0.002) and WDT (0 vs 2 mg, P=0.008; 0 vs 4 mg, P=0.001; 0 vs 8 mg, P<0.001). There was no difference in motor recovery or adverse effects. CONCLUSIONS: Intravenous dexamethasone failed to significantly prolong the duration of pinprick anaesthesia regardless of dose. However, area under QST curve analysis indicated a dose-independent prolongation of CDT and WDT, the clinical significance of which is unclear. CLINICAL TRIAL REGISTRATION: NCT02864602 (clinicaltrials.gov).


Assuntos
Adjuvantes Anestésicos , Dexametasona , Bloqueio Nervoso/métodos , Nervos Periféricos , Adjuvantes Anestésicos/administração & dosagem , Adjuvantes Anestésicos/efeitos adversos , Administração Intravenosa , Adulto , Estudos Cross-Over , Dexametasona/administração & dosagem , Dexametasona/efeitos adversos , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Força da Mão , Voluntários Saudáveis , Humanos , Masculino , Nervo Mediano , Pessoa de Meia-Idade , Bloqueio Nervoso/efeitos adversos , Limiar da Dor/efeitos dos fármacos , Sensação/efeitos dos fármacos , Sensação Térmica/efeitos dos fármacos , Adulto Jovem
3.
World Neurosurg ; 132: e529-e534, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31449993

RESUMO

BACKGROUND: Spinal cord injury (SCI) is a common type of injury, and about half of patients affected by SCI will suffer from neuropathic pain within a year after injury. However, the treatment effect of neuropathic pain is far from satisfactory. Our study attempted to reveal whether salvianolic acid B (SalB) could relieve the neuropathic pain caused by SCI in mice by inhibiting the Toll-like receptor 4 (TLR4)/Myeloid differentiation factor 88 (MyD88) pathway. METHODS: The mice were randomly divided into a sham group, model group, high-dose treatment group, and low-dose treatment group. The high- and low-dose groups received varying doses of SalB after modeling. RESULTS: The increase of pain sensitivity was evaluated by detecting paw withdrawal mechanical threshold and withdrawal thermal latency. Messenger RNA and protein expression levels of TLR4 and myD88 were detected by using quantitative reverse-transcription polymerase chain reaction and western blot, respectively. Compared with the model group, there was a significant reduction in paw withdrawal mechanical threshold and withdrawal thermal latency after SalB treatment. CONCLUSIONS: SalB reduced the release of tumor necrosis factor-α and substance P by inhibiting the TLR4/MyD88 pathway in the SCI mouse model. This not only resulted in lower pain, but also contributed to long-term relief of mechanical hyperalgesia.


Assuntos
Benzofuranos/farmacologia , Fator 88 de Diferenciação Mieloide/efeitos dos fármacos , Neuralgia/metabolismo , Limiar da Dor/efeitos dos fármacos , Traumatismos da Medula Espinal/metabolismo , Receptor 4 Toll-Like/efeitos dos fármacos , Animais , Hiperalgesia/etiologia , Hiperalgesia/imunologia , Hiperalgesia/metabolismo , Masculino , Camundongos , Neuralgia/etiologia , Neuralgia/imunologia , Distribuição Aleatória , Traumatismos da Medula Espinal/complicações , Traumatismos da Medula Espinal/imunologia
4.
Eur J Med Chem ; 178: 544-551, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31212133

RESUMO

Nalbuphine, a partial agonist/antagonist opioid analgesic, is structurally related to morphine. It is equipotent to morphine and has no serious side effects. In the past few decades, studies focusing on morphine metabolism have indicated that one of its sugar-conjugated metabolites, morphine-6-glucuronide, exerts a higher analgesic effect than its parent drug. Considering that nalbuphine is a morphine analog that follows a similar metabolic scheme, nalbuphine glucuronides were synthesized in this study and their potential analgesic effects were assessed. Nalbuphine-3-glucuronide (N3G) and nalbuphine-6-glucuronide (N6G) were synthesized based on Schmidt's glycosylation with OPiv protections on the glycosyl donor. In a pharmacodynamic study, paw pressure and cold-ethanol tail-flick tests were conducted in rats to evaluate the analgesic response after intracisternal and intraperitoneal administrations of nalbuphine, N3G, or N6G. The antinociceptive response was evaluated for each compound by calculating the area under the curve and the duration spent at greater than 50% maximum possible analgesia. In conclusion, intracisternal administration of N6G exhibited a stronger analgesic response than nalbuphine in the pain tests after both cold and mechanical stimuli, but N3G had no obvious effect. Similar to that of morphine, the glucuronide metabolite of nalbuphine at the 6-O-position exerted at least three-fold higher antinociceptive potency and five-fold longer analgesic duration than nalbuphine.


Assuntos
Analgésicos Opioides/farmacologia , Limiar da Dor/efeitos dos fármacos , Dor/tratamento farmacológico , Analgésicos Opioides/síntese química , Analgésicos Opioides/química , Animais , Relação Dose-Resposta a Droga , Masculino , Estrutura Molecular , Medição da Dor , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade
5.
Vet J ; 249: 82-88, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31239171

RESUMO

There are few investigations relating anti-nociception to plasma concentrations of fentanyl in horses. The study objective was to evaluate analgesic efficacy and duration in horses and determine the minimum anti-nociceptive plasma concentrations. Eight horses were treated with saline (P) and fentanyl (F2.5=2.5µg/kg; F5=5µg/kg; F10=10µg/kg) given IV over 5min, with a wash-out period of 10 days. To evaluate thermal (°C) and mechanical (N) nociceptive threshold single stimulations were applied prior to (baseline) and 10, 30, 60, 90, 120, 180, 240, 300, 360, 420, 540min and 22.5h after treatment. Plasma fentanyl concentrations were measured at specific time points. Locomotor activity, heart rate, respiratory rate and gastrointestinal sounds were recorded. Two-way repeated measures ANOVA and pairwise comparisons were used for data analysis (P<0.05). With treatment F10, there was a significant increase in thermal threshold above baseline (47.2ö4.1°C) at t10 (53.7ö4.2°C) and t30 (52.1ö5.6°C), whereas mechanical threshold increased considerably above baseline (3.7ö1.3N) only at t10 (6.6ö3.6N). Estimated mean minimum anti-nociceptive plasma concentration determined by thermal stimulation was 6.1-6.8ng/mL. Dose-dependent increased locomotion occurred, but no significant changes in heart rate, respiratory rate and gastrointestinal sounds were observed. Fentanyl IV at 10µg/kg produced anti-nociception for 10-30min and fentanyl plasma concentrations of ≥6.1-6.8ng/mL appear necessary to induce thermal anti-nociception. Dose-dependent increased locomotion was the main side effect observed.


Assuntos
Analgésicos Opioides/farmacologia , Fentanila/farmacologia , Cavalos , Limiar da Dor/efeitos dos fármacos , Analgésicos Opioides/efeitos adversos , Analgésicos Opioides/sangue , Animais , Estudos Cross-Over , Relação Dose-Resposta a Droga , Feminino , Fentanila/efeitos adversos , Fentanila/sangue , Temperatura Alta , Masculino , Estimulação Física , Distribuição Aleatória , Receptores Opioides mu/antagonistas & inibidores , Fatores de Tempo
6.
J Coll Physicians Surg Pak ; 29(6): 528-531, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31133150

RESUMO

OBJECTIVE: To investigate the effects of parecoxib on pain threshold and inflammatory factors interleukin-1ß (IL-1ß), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) in spinal cord of rats with bone cancer pain. STUDY DESIGN: An experimental study. PLACE AND DURATION OF STUDY: Department of Oncology, Shengjing Hospital of China Medical University, China, from March 2017 to May 2018. METHODOLOGY: Twenty-four healthy female Sprague-Dawley rats were selected and the bone cancer pain model was inoculated with W256 breast cancer cell into the bone marrow. Rats with bone cancer pain were randomly divided into the model group and the parecoxib group on the 7th day postoperation, with 12 rats in each group. Another 12 rats were taken as the control group. Rats in the parecoxib group were given intraperitoneal injection of parecoxib (8 mg/kg) for 10 consecutive days since the 15th day after operation. Mechanical pain threshold, thermal pain threshold, and the levels of inflammatory factors IL-1ß, IL-6 and TNF-α in spinal cord of rats in each group were compared. RESULTS: On the 14th postoperative day, mechanical pain threshold and thermal pain threshold of rats in the model group and the parecoxib group were significantly decreased compared with those in the control group (p<0.001). After 5 and 10 days of administration, mechanical and thermal pain threshold of rats in the parecoxib group were significantly higher than those in the model group and the control group (p<0.001). After 10 days of administration, levels of IL-1ß, IL-6 and TNF-α in spinal cord of the model group were higher than those of the control group (p<0.001); and levels of IL-1ß, IL-6 and TNF-α in spinal cord of the parecoxib group were significantly lower than those in the model group and the control group (p<0.001). CONCLUSION: Parecoxib can alleviate hyperalgesia in rats with bone cancer pain, increase pain threshold and inhibit the up-regulation of inflammatory factors in the spinal cord. Parecoxib may achieve analgesic effects by down-regulating the expression of IL-1ß, IL-6 and TNF-α in the spinal cord.


Assuntos
Dor do Câncer/tratamento farmacológico , Inibidores de Ciclo-Oxigenase 2/farmacologia , Interleucina-1beta/efeitos dos fármacos , Interleucina-6/líquido cefalorraquidiano , Isoxazóis/farmacologia , Limiar da Dor/efeitos dos fármacos , Fator de Necrose Tumoral alfa/efeitos dos fármacos , Animais , Neoplasias Ósseas/patologia , Inibidores de Ciclo-Oxigenase 2/administração & dosagem , Regulação para Baixo , Feminino , Hiperalgesia , Inflamação , Interleucina-1beta/líquido cefalorraquidiano , Isoxazóis/administração & dosagem , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Medula Espinal , Fator de Necrose Tumoral alfa/líquido cefalorraquidiano
7.
Neuropharmacology ; 151: 127-135, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30980837

RESUMO

Growing nonmedical use of prescription opioids is a global problem, motivating research on ways to reduce use and combat addiction. Medical cannabis ("medical marijuana") legalization has been associated epidemiologically with reduced opioid harms and cannabinoids have been shown to modulate effects of opioids in animal models. This study was conducted to determine if Δ9-tetrahydrocannabinol (THC) enhances the behavioral effects of oxycodone. Male rats were trained to intravenously self-administer (IVSA) oxycodone (0.15 mg/kg/infusion) during 1 h, 4 h or 8 h sessions. Following acquisition rats were exposed to THC by vapor inhalation (1 h and 8 h groups) or injection (0-10 mg/kg, i.p.; all groups) prior to IVSA sessions. Fewer oxycodone infusions were obtained by rats following vaporized or injected THC compared with vehicle treatment prior to the session. Follow-up studies demonstrated parallel dose-dependent effects of THC, i.p., on self-administration of different per-infusion doses of oxycodone and a preserved loading dose early in the session. These patterns are inconsistent with behavioral suppression. Additional groups of male and female Wistar rats were assessed for nociception following inhalation of vaporized THC (50 mg/mL), oxycodone (100 mg/mL) or the combination. Tail withdrawal latency was increased more by the THC/oxycodone combination compared to either drug alone. Similar additive antinociceptive effects were produced by injection of THC (5.0 mg/kg, i.p.) and oxycodone (2.0 mg/kg, s.c.). Together these data demonstrate additive effects of THC and oxycodone and suggest the potential use of THC to enhance therapeutic efficacy, and to reduce the abuse, of opioids.


Assuntos
Analgésicos Opioides/administração & dosagem , Canabinoides/farmacologia , Dronabinol/farmacologia , Nociceptividade/efeitos dos fármacos , Oxicodona/administração & dosagem , Animais , Feminino , Masculino , Limiar da Dor/efeitos dos fármacos , Ratos , Ratos Wistar , Autoadministração
8.
Pain ; 160(5): 1059-1069, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31008815

RESUMO

The taste of sucrose is commonly used to provide pain relief in newborn humans and is innately analgesic to neonatal rodents. In adulthood, sucrose remains a strong motivator to feed, even in potentially hazardous circumstances (ie, threat of tissue damage). However, the neurobiological mechanisms of this endogenous reward-pain interaction are unclear. We have developed a simple model of sucrose drinking-induced analgesia in Sprague-Dawley rats (6-10 weeks old) and have undertaken a behavioral and pharmacological characterization using the Hargreaves' test of hind-paw thermal sensitivity. Our results reveal an acute, potent, and robust inhibitory effect of sucrose drinking on thermal nociceptive behaviour that unlike the phenomenon in neonates is independent of endogenous opioid signalling and does not seem to operate through classical descending inhibition of the spinal cord circuitry. Experience of sucrose drinking had a conditioning effect whereby the apparent expectancy of sucrose enabled water alone (in euvolemic animals) to elicit a short-lasting placebo-like analgesia. Sweet taste alone, however, was insufficient to elicit analgesia in adult rats intraorally perfused with sucrose. Instead, the sucrose analgesia phenomenon only appeared after conditioning by oral perfusion in chronically cannulated animals. This sucrose analgesia was completely prevented by systemic dosing of the endocannabinoid CB1 receptor antagonist rimonabant. These results indicate the presence of an endogenous supraspinal analgesic circuit that is recruited by the context of rewarding drinking and is dependent on endocannabinoid signalling. We propose that this hedonic sucrose-drinking model may be useful for further investigation of the supraspinal control of pain by appetite and reward.


Assuntos
Hiperalgesia/terapia , Limiar da Dor/efeitos dos fármacos , Medula Espinal/fisiologia , Sacarose/uso terapêutico , Edulcorantes/uso terapêutico , Animais , Antagonistas de Receptores de Canabinoides/farmacologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Comportamento de Ingestão de Líquido/efeitos dos fármacos , Adjuvante de Freund/toxicidade , Temperatura Alta/efeitos adversos , Hiperalgesia/induzido quimicamente , Injeções Espinhais/métodos , Masculino , Naloxona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos , Ratos Sprague-Dawley , Tempo de Reação/efeitos dos fármacos , Rimonabanto/farmacologia , Medula Espinal/efeitos dos fármacos , Privação de Água/fisiologia
9.
Musculoskelet Sci Pract ; 41: 55-63, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31010570

RESUMO

PURPOSE: Cold hyperalgesia is an indicator of widespread pain sensitivity and is associated with poor clinical outcomes. Menthol activates TRPM8, a cold-sensing receptor channel. This research evaluated topical menthol as a potential stimulus to be used in the clinical evaluation of cold hyperalgesia. METHODS: Participants were 59 pain free volunteers (17 male: 42 female). A blinded, repeated measures design was used. Participants received applications of menthol at different concentrations in a liquid (study 1) or gel (study 2) formulation with a 24-h interval between each application. Each menthol concentration was applied for 15 min and participants were asked to rate the sensation produced using a series of visual analogue scales and by selecting words from a descriptor list derived from the McGill pain questionnaire (MPQ). The menthol was applied to a site on the volar forearm. Participants also had their cold pain thresholds (CPT) evaluated at the same site using a contact thermode. RESULTS: There were significant concentration-dependent effects for intensity of cold, unpleasantness and pain VAS: cold F(2,62) = 8.67, p < 0.001; unpleasantness χ2(2) = 14.14, p < 0.001; χ2(2) = 11.74, p = 0.003, with moderate effect sizes for unpleasantness and pain. There were also significant concentration dependent effects for descriptor indices, pain rating index (PRI) F(2,62) = 26.33, p < 0.001; number of words chosen (NWC) F(2,62) = 19.62, p < 0.001, with large effect sizes for 10-20% and 10-30% comparisons. Significant correlations were seen between measures of unpleasantness, pain, PRI, NWC and CPT dependent on menthol concentration. CONCLUSION: Topical menthol has potential as a stimulus to evaluate cold hyperalgesia.


Assuntos
Hiperalgesia/diagnóstico , Mentol/administração & dosagem , Medição da Dor/métodos , Limiar da Dor/efeitos dos fármacos , Células Receptoras Sensoriais/efeitos dos fármacos , Adulto , Idoso , Feminino , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
10.
Int J Mol Sci ; 20(8)2019 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-30999611

RESUMO

Lysine-rich proteins are some of the most important proteins of neurons and it has become necessary to investigate the possible role of L-lysine as a brain functioning regulator. The purpose of our study is to identify the characteristics and the mechanisms of L-lysine effects on the different types of pain-induced behavior in the stimulation of tail and foot-shock models in 210 adult male Wistar rats. L-lysine was administered in intraperitoneal or intracerebroventricular injections in doses of 0.15-50.0 µg/kg. When a tail is irritated, L-lysine was found to enhance pain sensitivity and affective defense after both intraperitoneal and intracerebroventricular administration. In the case of unavoidable painful irritation of a pair of rats with both types of L-lysine administration, there was no direct correlation of the severity of pain with defensive reactions and outbursts of aggression. This indicates a more complex integration of the activity of brain structures in this situation of animal interaction, which was confirmed by the results of the direct amino acid action on the periventricular brain structures. Our findings show that L-lysine influences the selective brain activity in dependence on the biological significance of pain-induced behavior.


Assuntos
Agressão/efeitos dos fármacos , Ansiolíticos/farmacologia , Encéfalo/efeitos dos fármacos , Lisina/farmacologia , Limiar da Dor/efeitos dos fármacos , Dor/complicações , Animais , Ansiolíticos/administração & dosagem , Comportamento Animal/efeitos dos fármacos , Encéfalo/fisiologia , Lisina/administração & dosagem , Masculino , Ratos Wistar
11.
J Neuroinflammation ; 16(1): 78, 2019 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-30971286

RESUMO

BACKGROUND: Central sensitization is an important mechanism of chronic migraine (CM) and is related to the inflammatory response of microglia. The NOD-like receptor protein 3 (NLRP3) inflammasome may regulate the inflammatory process of microglia in several neurological diseases, but its role in CM is largely unknown. Therefore, the aim of this study was to identify the precise role of microglial NLRP3 in CM. METHODS: An experimental CM mouse model was established by repeated intraperitoneal (i.p) injection with nitroglycerin (NTG). We evaluated the expression levels of NLRP3 and its downstream interleukin (IL)-1ß protein in the trigeminal nucleus caudalis (TNC; which is a central area relevant to migraine pain) at different time points. To further examine the effects of the NLRP3 inflammasome pathway on central sensitization of CM, we examined MCC950, an NLRP3 inflammasome-specific inhibitor, and IL-1ra, an IL-1ß antagonist, whether altered NTG-induced mechanical hyperalgesia of the periorbital area and hind paw. The effect of MCC950 and IL-1ra on c-Fos, phosphorylated extracellular signal-regulated kinase (p-ERK) and calcitonin gene-related peptide (CGRP) expression in the TNC were also analyzed. The cell localization of NLRP3 and IL-1ß in the TNC was evaluated by immunofluorescence staining. RESULTS: Repeated NTG administration induced acute and chronic mechanical hyperalgesia and increased expression of NLRP3 and IL-1ß. Blockade of NLRP3 or IL-1ß reduced NTG-induced hyperalgesia, and this effect was accompanied by a significant inhibition of the NTG-induced increase in p-ERK, c-Fos and CGRP levels in the TNC. Immunofluorescence staining revealed that NLRP3 and IL-1ß were mainly expressed in microglia in the TNC, and the IL-1ß receptor, IL-1R, was mainly expressed in neurons in the TNC. CONCLUSIONS: These results indicate that NLRP3 activation in the TNC participates in the microglial-neuronal signal by mediating the inflammatory response. This process contributes to the central sensitization observed in CM.


Assuntos
Sensibilização do Sistema Nervoso Central/fisiologia , Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico , Interleucina-1beta/metabolismo , Transtornos de Enxaqueca/tratamento farmacológico , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Sulfonas/uso terapêutico , Animais , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Proteínas de Ligação ao Cálcio/metabolismo , Sensibilização do Sistema Nervoso Central/efeitos dos fármacos , Modelos Animais de Doenças , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Hiperalgesia/induzido quimicamente , Injeções Intraventriculares , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Interleucina-1beta/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas dos Microfilamentos/metabolismo , Transtornos de Enxaqueca/induzido quimicamente , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Nitroglicerina/toxicidade , Medição da Dor , Limiar da Dor/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-fos/metabolismo , Vasodilatadores/toxicidade
12.
J Neuroinflammation ; 16(1): 83, 2019 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-30975172

RESUMO

BACKGROUND: Neuropathic pain is a serious clinical problem that needs to be solved urgently. ASK1 is an upstream protein of p38 and JNK which plays important roles in neuroinflammation during the induction and maintenance of chronic pain. Therefore, inhibition of ASK1 may be a novel therapeutic approach for neuropathic pain. Here, we aim to investigate the effects of paeoniflorin on ASK1 and neuropathic pain. METHODS: The mechanical and thermal thresholds of rats were measured using the Von Frey test. Cell signaling was assayed using western blotting and immunohistochemistry. RESULTS: Chronic constrictive injury (CCI) surgery successfully decreased the mechanical and thermal thresholds of rats and decreased the phosphorylation of ASK1 in the rat spinal cord. ASK1 inhibitor NQDI1 attenuated neuropathic pain and decreased the expression of p-p38 and p-JNK. Paeoniflorin mimicked ASK1 inhibitor NQDI1 and inhibited ASK1 phosphorylation. Paeoniflorin decreased the expression of p-p38 and p-JNK, delayed the progress of neuropathic pain, and attenuated neuropathic pain. Paeoniflorin reduced the response of astrocytes and microglia to injury, decreased the expression of IL-1ß and TNF-α, and downregulated the expression of CGRP induced by CCI. CONCLUSIONS: Paeoniflorin is an effective drug for the treatment of neuropathic pain in rats via inhibiting the phosphorylation of ASK1, suggesting it may be effective in patients with neuropathic pain.


Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Apoptose/efeitos dos fármacos , Encefalite/tratamento farmacológico , Glucosídeos/uso terapêutico , MAP Quinase Quinase Quinase 5/metabolismo , Monoterpenos/uso terapêutico , Neuropatia Ciática/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Regulação para Baixo/efeitos dos fármacos , Encefalite/complicações , Hidroxiquinolinas/uso terapêutico , Hiperalgesia/fisiopatologia , Interleucina-1beta/metabolismo , Masculino , Limiar da Dor/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Neuropatia Ciática/complicações
13.
Br J Anaesth ; 122(6): e114-e126, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30915985

RESUMO

BACKGROUND: Opioid-induced hyperalgesia (OIH) is well documented in preclinical studies, but findings of clinical studies are less consistent. The objective was to undertake a systematic review and meta-analysis of studies examining evidence for OIH in humans after opioid exposure. METHODS: Systematic electronic searches utilised six research databases (Embase, Medline, PubMed, CINAHL Plus, Web of Science, and OpenGrey). Manual 'grey' literature searches were also undertaken. The Population, Interventions, Comparators, Outcomes, and Study design (PICOS) framework was used to develop search strategies, and findings are reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement. Data synthesis and subgroup analyses were undertaken using a random effects model (DerSimonian-Laird method). RESULTS: A total of 6167 articles were identified. After abstract and full-text reviews, 26 articles (involving 2706 participants) were included in the review. There was evidence of OIH, assessed by pain tolerance, in response to noxious thermal (hot and cold) stimuli, but not electrical stimuli. There was no evidence of OIH when assessing pain detection thresholds. OIH was more evident in patients with opioid use disorder than in patients with pain, and in patient groups treated with N-methyl-d-aspartate receptor antagonists (primarily evidenced in methadone-maintained populations). CONCLUSIONS: OIH was evident in patients after chronic opioid exposure, but findings were dependent upon pain modality and assessment measures. Further studies should consider evaluating both pain threshold and pain tolerance across a range of modalities to ensure assessment validity. Significant subgroup findings suggest that potential confounders of pain judgements, such as illicit substance use, affective characteristics, or coping styles, should be rigorously controlled in future studies.


Assuntos
Analgésicos Opioides/efeitos adversos , Hiperalgesia/induzido quimicamente , Analgésicos Opioides/administração & dosagem , Dor Crônica/tratamento farmacológico , Esquema de Medicação , Humanos , Medição da Dor/métodos , Limiar da Dor/efeitos dos fármacos
14.
Br J Anaesth ; 122(6): e146-e156, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30916003

RESUMO

BACKGROUND: The marked increase in mis-use of prescription opioids has greatly affected our society. One potential solution is to develop improved analgesics which have agonist action at both mu opioid peptide (MOP) and nociceptin/orphanin FQ peptide (NOP) receptors. BU10038 is a recently identified bifunctional MOP/NOP partial agonist. The aim of this study was to determine the functional profile of systemic or spinal delivery of BU10038 in primates after acute and chronic administration. METHODS: A series of behavioural and physiological assays have been established specifically to reflect the therapeutic (analgesia) and side-effects (abuse potential, respiratory depression, itch, physical dependence, and tolerance) of opioid analgesics in rhesus monkeys. RESULTS: After systemic administration, BU10038 (0.001-0.01 mg kg-1) dose-dependently produced long-lasting antinociceptive and antihypersensitive effects. Unlike the MOP agonist oxycodone, BU10038 lacked reinforcing effects (i.e. little or no abuse liability), and BU10038 did not compromise the physiological functions of primates including respiration, cardiovascular activities, and body temperature at antinociceptive doses and a 10-30-fold higher dose (0.01-0.1 mg kg-1). After intrathecal administration, BU10038 (3 µg) exerted morphine-comparable antinociception and antihypersensitivity without itch scratching responses. Unlike morphine, BU10038 did not cause the development of physical dependence and tolerance after repeated and chronic administration. CONCLUSIONS: These in vivo findings demonstrate the translational potential of bifunctional MOP/NOP receptor agonists such as BU10038 as a safe, non-addictive analgesic with fewer side-effects in primates. This study strongly supports that bifunctional MOP/NOP agonists may provide improved analgesics and an alternative solution for the ongoing prescription opioid crisis.


Assuntos
Analgésicos Opioides/efeitos adversos , Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/farmacologia , Animais , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos/métodos , Tolerância a Medicamentos , Hiperalgesia/tratamento farmacológico , Injeções Espinhais , Macaca mulatta , Masculino , Nociceptividade/efeitos dos fármacos , Transtornos Relacionados ao Uso de Opioides/etiologia , Limiar da Dor/efeitos dos fármacos
15.
Pain ; 160(5): 1146-1155, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30920428

RESUMO

Oxytocin reduces primary sensory afferent excitability and produces analgesia in part through a peripheral mechanism, yet its actions on physiologically characterized, mechanically sensitive afferents in normal and neuropathic conditions are unknown. We recorded intracellularly from L4 dorsal root ganglion neurons characterized as low-threshold mechanoreceptors (LTMRs) or high-threshold mechanoreceptors (HTMRs) in female rats 1 week after L5 partial spinal nerve injury or sham control (n = 24 rats/group) before, during, and after ganglionic perfusion with oxytocin, 1 nM. Nerve injury desensitized and hyperpolarized LTMRs (membrane potential [Em] was -63 ± 1.8 mV in sham vs -76 ± 1.4 mV in nerve injury; P < 0.001), and sensitized HTMRs without affecting Em. In nerve-injured rats, oxytocin depolarized LTMRs towards normal (Em = -69 ± 1.9 mV) and, in 6 of 21 neurons, resulted in spontaneous action potentials. By contrast, oxytocin hyperpolarized HTMRs (Em = -68 ± 2.7 mV before vs -80 ± 3.2 mV during oxytocin exposure; P < 0.01). These effects were reversed after removal of oxytocin, and oxytocin had minimal effects in neurons from sham surgery animals. Sensory afferent neurons immunopositive for the vasopressin 1a receptor were larger (34 ± 6.3 µm, range 16-57 µm) than immunonegative neurons (26 ± 3.4 µm, range 15-43 µm; P < 0.005). These data replicate findings that neuropathic injury desensitizes LTMRs while sensitizing HTMRs and show rapid and divergent oxytocin effects on these afferent subtypes towards normal, potentially rebalancing input to the central nervous system. Vasopressin 1a receptors are present on medium to large diameter afferent neurons and could represent oxytocin's target.


Assuntos
Gânglios Espinais/patologia , Nociceptores/efeitos dos fármacos , Ocitocina/uso terapêutico , Traumatismos dos Nervos Periféricos/patologia , Células Receptoras Sensoriais/efeitos dos fármacos , Tato , Potenciais de Ação/efeitos dos fármacos , Vias Aferentes/fisiopatologia , Animais , Modelos Animais de Doenças , Estimulação Elétrica , Feminino , Mecanorreceptores/efeitos dos fármacos , Nociceptores/fisiologia , Ocitocina/farmacologia , Limiar da Dor/efeitos dos fármacos , Traumatismos dos Nervos Periféricos/fisiopatologia , Ratos , Ratos Sprague-Dawley , Receptores de Vasopressinas/metabolismo , Células Receptoras Sensoriais/fisiologia
16.
Behav Brain Funct ; 15(1): 5, 2019 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-30909927

RESUMO

Motor cortex stimulation (MCS) is an effective therapy for refractory neuropathic pain. MCS increases the nociceptive threshold in healthy rats via endogenous opioids, inhibiting thalamic nuclei and activating the periaqueductal gray. It remains unclear how the motor cortex induces top-down modulation of pain in the absence of persistent pain. Here, we investigated the main nuclei involved in the descending analgesic pathways and the spinal nociceptive neurons in rats that underwent one session of MCS and were evaluated with the paw pressure nociceptive test. The pattern of neuronal activation in the dorsal raphe nucleus (DRN), nucleus raphe magnus (NRM), locus coeruleus (LC), and dorsal horn of the spinal cord (DHSC) was assessed by immunoreactivity (IR) for Egr-1 (a marker of activated neuronal nuclei). IR for serotonin (5HT) in the DRN and NRM, tyrosine hydroxylase (TH) in the LC, and substance P (SP) and enkephalin (ENK) in the DHSC was also evaluated. MCS increased the nociceptive threshold of the animals; this increase was accompanied by activation of the NRM, while DRN activation was unchanged. However, cortical stimulation induced an increase in 5HT-IR in both serotonergic nuclei. MCS did not change the activation pattern or TH-IR in the LC, and it inhibited neuronal activation in the DHSC without altering SP or ENK-IR. Taken together, our results suggest that MCS induces the activation of serotonergic nuclei as well as the inhibition of spinal neurons, and such effects may contribute to the elevation of the nociceptive threshold in healthy rats. These results allow a better understanding of the circuitry involved in the antinociceptive top-down effect induced by MCS under basal conditions, reinforcing the role of primary motor cortex in pain control.


Assuntos
Analgésicos/farmacologia , Córtex Motor/fisiologia , Limiar da Dor/efeitos dos fármacos , Dor/fisiopatologia , Animais , Hiperalgesia/metabolismo , Masculino , Neuralgia/terapia , Neurônios/efeitos dos fármacos , Nociceptores/efeitos dos fármacos , Substância Cinzenta Periaquedutal/metabolismo , Ratos , Ratos Wistar , Medula Espinal/efeitos dos fármacos , Coluna Vertebral/efeitos dos fármacos
17.
Neuropharmacology ; 151: 171-179, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30904478

RESUMO

The emergence of several fentanyl-related substances in the recreational drug marketplace has resulted in a surge of opioid overdose deaths in the United States. Many of these substances have never been examined in living organisms under controlled conditions. In the present study, seven fentanyl-related substances were tested in adult male Swiss Webster mice for their effects on locomotion and antinociception and compared to those of fentanyl and morphine. In locomotor activity tests, fentanyl (1, 10 mg/kg), morphine (100, 180 mg/kg), isobutyrylfentanyl (10 mg/kg), crotonylfentanyl (10 mg/kg), para-fluorobutyrylfentanyl (10, 100 mg/kg), para-methoxybutyrylfentanyl (10 mg/kg), thiophenefentanyl (100 mg/kg), and benzodioxolefentanyl (0.1 mg/kg) produced significant (p ≤ 0.05) dose-dependent increases in locomotion. Valerylfentanyl, however, was without effects on locomotion up to 100 mg/kg. In warm-water tail-withdrawal tests, all substances produced significant (p ≤ 0.05) dose-dependent increases in antinociception with increasing ED50 values (CI) of isobutyrylfentanyl [0.0768 mg/kg (0.044-0.128)] > fentanyl [0.0800 mg/kg (0.0403-0.164)] > para-methoxybutyrylfentanyl [0.106 mg/kg (0.0516-0.195)] > crotonylfentanyl [0.226 mg/kg (0.176-0.292)] > para-fluorobutyrylfentanyl [0.908 mg/kg (0.459-1.58)] > thiophenefentanyl [4.66 mg/kg (3.65-5.95)] > valerylfentanyl [6.43 mg/kg (3.91-10.5)] > morphine [7.82 mg/kg (5.42-11.0)] > benzodioxolefentanyl [46.3 mg/kg (25.8-83.4)]. Naltrexone (1 mg/kg) increased antinociceptive ED50 values several fold in decreasing magnitudes of isobutyrylfentanyl (233x) > para-methoxybutyrylfentanyl (37.7x) > thiophenefentanyl (34.6x) > valerylfentanyl (11.9x) > para-fluorobutyrylfentanyl (10.9x) > benzodioxolefentanyl (8.42x) > crotonylfentanyl (6.27x) > fentanyl (3.95x) > morphine (1.48x). These findings establish that locomotor and antinociceptive effects of several fentanyl-related substances are similar to those of morphine and fentanyl and are mediated by opioid receptors.


Assuntos
Fentanila/farmacologia , Atividade Motora/efeitos dos fármacos , Entorpecentes/farmacologia , Nociceptividade/efeitos dos fármacos , Limiar da Dor/efeitos dos fármacos , Animais , Relação Dose-Resposta a Droga , Masculino , Camundongos , Morfina/farmacologia
18.
Biomed Pharmacother ; 111: 882-890, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30841467

RESUMO

BACKGROUND AND PURPOSE: Chemotherapy-induced peripheral neuropathy (CIPN) is a pharmacoresistant neurological complication induced by some antitumor drugs. This study aimed to assess antiallodynic properties of aripiprazole and ceftriaxone used alone or in combination to attenuate neuropathic pain related to CIPN caused by oxaliplatin. METHODS: Neuropathic pain was induced in mice by a single intraperitoneal dose of oxaliplatin (10 mg/kg). Aripiprazole and ceftriaxone were used in a single- or repeated dosing protocol. Their antiallodynic activity was assessed using von Frey and cold plate tests on the day of oxaliplatin injection and after 7 days. The influence of aripiprazole and ceftriaxone on animals' locomotor activity and motor coordination was also assessed. RESULTS: Single-dose and repeated-dose aripiprazole 10 mg/kg and ceftriaxone 200 mg/kg used alone and in combination attenuated early-phase and late-phase tactile allodynia in oxaliplatin-treated mice. Repeated administrations of ceftriaxone 200 mg/kg prevented the development of late-phase tactile allodynia. Both drugs showed no antiallodynic properties in the cold plate test. Single-dose aripiprazole 1 and 10 mg/kg but not its repeated administration significantly decreased locomotor activity of oxaliplatin-treated mice. Single-dose aripiprazole 1 and 10 mg/kg, aripiprazole 1 mg/kg + ceftriaxone 50 mg/kg and aripiprazole 1 mg/kg + ceftriaxone 200 mg/kg impaired motor coordination in the rotarod test. CONCLUSIONS: In mice, neither ceftriaxone nor aripiprazole attenuated cold allodynia. Ceftriaxone alone could attenuate tactile allodynia caused by oxaliplatin without inducing motor adverse effects. Although the administration of aripiprazole reduced tactile allodynia, this effect seems to be limited considering severe motor deficits induced by this drug.


Assuntos
Aripiprazol/farmacologia , Ceftriaxona/farmacologia , Hiperalgesia/induzido quimicamente , Hiperalgesia/tratamento farmacológico , Oxaliplatina/farmacologia , Animais , Quimioterapia Combinada/métodos , Masculino , Camundongos , Neuralgia/tratamento farmacológico , Medição da Dor/métodos , Limiar da Dor/efeitos dos fármacos
19.
Pharmacol Rep ; 71(2): 306-310, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30826571

RESUMO

BACKGROUND: We hypothesized that renin-angiotensin system and neprilysin (NEP) inhibition can modulate the nociceptive parameters on hypertensive rats. The aim of this study is to assess the preventive and therapeutic effects of ramipril and sacubitril on the pain hypersensitivities, and their interaction mechanisms with high blood pressure. METHODS: Antinociceptive effects of ramipril and sacubitril were compared with those of diclofenac. Threshold of pain assesments were recorded before drugs administration. After a 18 days treatment, normotensive and dexamethasone-induced hypertensive rats were evaluated on thermal hyperalgesia and mechanical allodynia tests. Blood pressure of rats were verified by mean arterial pressure measurement. RESULTS: Hypertensive rats showed significantly high pain threshold on thermal plantar test compared to that of normotensives. Among hypertensive rats, pain hypersensitivity was lowest in diclofenac group, followed by sacubitril group, while ramipril caused increased thermal and mechanical hypersensitivities. CONCLUSION: We found that NEP inhibition may play a role in nociception in hypertensive rats. NEP inhibitors may be suitable choice for the management of hypertension and pain because of their therapeutic and preventive effects on nociception and arterial blood pressure.


Assuntos
Aminobutiratos/farmacologia , Hipertensão/tratamento farmacológico , Dor/tratamento farmacológico , Ramipril/farmacologia , Tetrazóis/farmacologia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Animais , Anti-Hipertensivos/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Dexametasona/toxicidade , Modelos Animais de Doenças , Hipertensão/complicações , Masculino , Neprilisina/metabolismo , Dor/etiologia , Limiar da Dor/efeitos dos fármacos , Peptidil Dipeptidase A/efeitos dos fármacos , Peptidil Dipeptidase A/metabolismo , Ratos , Ratos Wistar , Sistema Renina-Angiotensina/efeitos dos fármacos
20.
Life Sci ; 220: 147-155, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30731141

RESUMO

AIMS: Neuroinflammatory changes in the central nervous system are widely involved in the initiation and maintenance of neuropathic pain after peripheral nerve injury. The present study investigated how losartan treatment may affect the development of neuropathic pain and neuroinflammation. MAIN METHODS: The effect of losartan treatment on the development of peripheral neuropathy was studied in L5 spinal nerve ligation (SNL) model in rats with systemic (100 mg/kg) or intrathecal (10 µl/ 20 µM solution) application of losartan. Electronic von Frey filament and plantar test were used to determine pain thresholds to mechanical and thermal stimulations. At the 7th post-operative day, CD68-positive cells in DRG and dorsal roots were quantified by immunohistochemistry and western blot analyses were used to compare the expression levels of neuroinflammatory markers in lumbar spinal cord (SC). KEY FINDINGS: Our data confirmed the presence of SNL-evoked heat hyperalgesia and mechanical allodynia. Losartan application blocked the SNL-induced hypersensitivity to thermal stimuli but failed to prevent mechanical allodynia. No significant difference between systemic and i.t. administration of losartan was observed. Immunohistochemistry confirmed the presence of infiltrated macrophages in the ipsilateral DRG that was significantly attenuated with the losartan treatment. Western blot SC tissue analysis revealed that systemic treatment with losartan prevented SNL-induced upregulation of CCR2, TNFα, TNFR1, and OX42 while its effect on CCL2 and AT1R expression was not significant. SIGNIFICANCE: Our results show that losartan treatment attenuates neuroinflammation and neuropathic pain after SNL. These effects of losartan represent an interesting direction for the development of novel treatments of peripheral neuropathy.


Assuntos
Hiperalgesia/tratamento farmacológico , Hiperalgesia/prevenção & controle , Losartan/farmacologia , Animais , Modelos Animais de Doenças , Gânglios Espinais/efeitos dos fármacos , Losartan/metabolismo , Masculino , Neuralgia/metabolismo , Medição da Dor/métodos , Limiar da Dor/efeitos dos fármacos , Traumatismos dos Nervos Periféricos/tratamento farmacológico , Ratos , Ratos Wistar , Medula Espinal/efeitos dos fármacos , Nervos Espinhais/efeitos dos fármacos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA