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1.
Eur J Neurosci ; 2018 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-29885271

RESUMO

Epidemiological studies have shown a close association between pain and depression. There is evidence showing this association as patients with depression show a high chronic pain prevalence and vice versa. Considering that social stress is critical for the development of depression in humans, we used a social defeat stress (SDS) model which induces depressive-like behavior in mice. In this model, mice are exposed to an aggressor mouse for ten days, suffering brief periods of agonistic contact and long periods of sensory contact. Some mice display social avoidance, a depressive-like behavior, and are considered susceptible, while some mice do not, and are considered resilient. Thus, we investigated the nociceptive behavior of mice submitted to SDS and the neuroplastic changes in dopaminergic mesolimbic system. Our results showed that the stressed mice (resilient and susceptible) presented a higher sensitivity to pain than the control mice in chemical and mechanical tests. We also verified that susceptible mice have higher Bdnf mRNA in the VTA compared to the resilient and control mice. The stressed mice had less mature BDNF and more truncated BDNF protein in the NAc compared with control mice. Although social stress may trigger the development of depression and hyperalgesia, these two conditions may manifest independently as social stress induced hyperalgesia even in mice that did not display depressive-like behavior. Also, increased Bdnf in the VTA seems to be associated with depressive-like behavior, whereas high levels of truncated BDNF and low mature BDNF appear to be associated with hyperalgesia induced by social defeat stress.

2.
PLoS One ; 15(10): e0240115, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33048957

RESUMO

Chronic pain affects significant portion of the world's population and physical exercise has been extensively indicated as non-pharmacological clinical intervention to relieve symptoms in chronic pain conditions. In general, studies on pain chronification and physical exercise intervention have focused on neuropathic pain, although chronic pain commonly results from an original inflammatory episode. Based on this, the objective of the present study was to investigate the therapeutic and preventive effect of the running wheel exercise on the persistent hyperalgesia induced by repetitive inflammatory stimulus, a rodent model that simulates clinical conditions of chronic pain that persist even with no more inflammatory stimulus present. To evaluate the therapeutic effect of physical exercise, we first induced persistent hyperalgesia through 14 days of PGE2 hind paw injections and, after that, mice have access to the regular voluntary running wheel. To evaluate the preventive effect of physical exercise, we first left the mice with access to the regular voluntary running wheel and, after that, we performed 14 days of PGE2 hind paw injection. Our results showed that voluntary running wheel exercise reduced persistent mechanical and chemical hyperalgesia intensity induced by repetitive inflammatory stimulus. In addition, we showed that this therapeutic effect is long-lasting and is observed even if started belatedly, i.e. two weeks after the development of hyperalgesia. Also, our results showed that voluntary running wheel exercise absolutely prevented persistent mechanical and chemical hyperalgesia induction. We can conclude that physical exercise has therapeutic and preventive effect on inflammatory stimulus-induced persistent hyperalgesia. Our data from animal experiments bypass placebo effects bias of the human studies and reinforce physical exercise clinical recommendations to treat and prevent chronic pain.


Assuntos
Terapia por Exercício , Hiperalgesia/etiologia , Hiperalgesia/terapia , Inflamação/complicações , Animais , Dor Crônica/etiologia , Dor Crônica/prevenção & controle , Dor Crônica/terapia , Modelos Animais de Doenças , Hiperalgesia/prevenção & controle , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Condicionamento Físico Animal , Corrida
3.
Neurosci Lett ; 729: 135006, 2020 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-32387758

RESUMO

Recently the voltage-gated sodium (Nav) channels began to be studied as possible targets for analgesic drugs. In addition, specific Nav 1.8 blockers are currently being used to treat some types of chronic pain pathologies such as neuropathies and fibromyalgia. Nav 1.8+ fibers convey nociceptive information to brain structures belonging to the limbic system, which is involved in the pathophysiology of major depressive disorders. From this, using a model of chronic social defeat stress (SDS) and intrathecal injections of Nav 1.8 antisense, this study investigated the possible involvement of Nav 1.8+ nociceptive fibers in SDS- induced hyperalgesia in C57/BL mice. Our results showed that SDS induced a depressive-like behavior of social avoidance and increased the sensitivity to mechanical (electronic von Frey test) and chemical (capsaicin test) nociceptive stimuli. We also showed that intrathecal injection of Nav 1.8 antisense reversed the SDS-induced hyperalgesia as demonstrated by both, mechanical and chemical nociceptive tests. We confirmed the antisense efficacy and specificity in a separate no-defeated cohort through real-time PCR, which showed a significant reduction of Nav 1.8 mRNA and no reduction of Nav 1.7 and Nav 1.9 in the L4, L5 and L6 dorsal root ganglia (DRG). The present study advances the understanding of SDS-induced hyperalgesia, which seems to be dependent on Nav 1.8+ nociceptive fibers.


Assuntos
Transtorno Depressivo Maior/fisiopatologia , Hiperalgesia/tratamento farmacológico , Derrota Social , Bloqueadores dos Canais de Sódio/farmacologia , Animais , Transtorno Depressivo Maior/tratamento farmacológico , Gânglios Espinais/efeitos dos fármacos , Gânglios Espinais/fisiopatologia , Hiperalgesia/fisiopatologia , Masculino , Camundongos Endogâmicos C57BL , Tetrodotoxina/farmacologia
4.
Front Neurosci ; 13: 1453, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-32038148

RESUMO

Recent findings from rodent studies suggest that high-fat diet (HFD) increases hyperalgesia independent of obesity status. Furthermore, weight loss interventions such as voluntary physical activity (PA) for adults with obesity or overweight was reported to promote pain reduction in humans with chronic pain. However, regardless of obesity status, it is not known whether HFD intake and sedentary (SED) behavior is underlies chronic pain susceptibility. Moreover, differential gene expression in the nucleus accumbens (NAc) plays a crucial role in chronic pain susceptibility. Thus, the present study used an adapted model of the inflammatory prostaglandin E2 (PGE2)-induced persistent hyperalgesia short-term (PH-ST) protocol for mice, an HFD, and a voluntary PA paradigm to test these hypotheses. Therefore, we performed an analysis of differential gene expression using a transcriptome approach of the NAc. We also applied a gene ontology enrichment tools to identify biological processes associated with chronic pain susceptibility and to investigate the interaction between the factors studied: diet (standard diet vs. HFD), physical activity behavior (SED vs. PA) and PH-ST (PGE vs. saline). Our results demonstrated that HFD intake and sedentary behavior promoted chronic pain susceptibility, which in turn was prevented by voluntary physical activity, even when the animals were fed an HFD. The transcriptome of the NAc found 2,204 differential expression genes and gene ontology enrichment analysis revealed 41 biologic processes implicated in chronic pain susceptibility. Taking these biological processes together, our results suggest that genes related to metabolic and mitochondria stress were up-regulated in the chronic pain susceptibility group (SED-HFD-PGE), whereas genes related to neuroplasticity were up-regulated in the non-chronic pain susceptibility group (PA-HFD-PGE). These findings provide pieces of evidence that HFD intake and sedentary behavior provoked gene expression changes in the NAc related to promotion of chronic pain susceptibility, whereas voluntary physical activity provoked gene expression changes in the NAc related to prevention of chronic pain susceptibility. Finally, our findings confirmed previous literature supporting the crucial role of voluntary physical activity to prevent chronic pain and suggest that low levels of voluntary physical activity would be helpful and highly recommended as a complementary treatment for those with chronic pain.

5.
Neuroscience ; 398: 158-170, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30537520

RESUMO

Peripheral diabetic neuropathy (PDN) manifests in 50-60% of type I and II diabetic patients and is the major cause of limb amputation. Adequate therapy for PDN is a current challenge. There are evidences that the activation of the P2X4 receptor (P2X4R) expressed on microglial cells of the central nervous system takes part in the development of neuropathic pain. However, there is an open question: Is P2X4R activation on dorsal root ganglia (DRG) involved in the development of neuropathic pain? To answer this question, this study verified the involvement of P2X4R expressed in DRG cells on diabetes-induced neuropathic mechanical hyperalgesia in rats. We found that intrathecal or ganglionar (L5-DRG) administration of a novel P2X4R antagonist (PSB-15417) or intrathecal administration of oligodeoxynucleotides (ODN)-antisense against the P2X4R reversed diabetes-induced neuropathic mechanical hyperalgesia. The DRG of the diabetic neuropathic rats showed an increase in P2X4R expression, and the DRG immunofluorescence suggested that P2X4R is expressed mainly in satellite glial cells (SGC). Finally, our study showed a functional expression of P2X4R in SGCs of the rat's DRG, because the P2X4R agonist BzATP elicits an increase in intracellular calcium concentration in SGCs, which was reduced by PSB-15417. These findings indicate that P2X4R activation in DRG is essential to diabetes-induced neuropathic mechanical hyperalgesia. Therefore, this purinergic receptor in DRG could be an interesting therapeutic target for quaternary P2X4R antagonists that do not cross the hematoencephalic barrier, for the control of neuropathic pain, preserving central nervous system functions.


Assuntos
Diabetes Mellitus Experimental/metabolismo , Neuropatias Diabéticas/metabolismo , Gânglios Espinais/metabolismo , Hiperalgesia/metabolismo , Neuralgia/metabolismo , Receptores Purinérgicos P2X4/metabolismo , Animais , Cálcio/metabolismo , Células Cultivadas , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/patologia , Neuropatias Diabéticas/tratamento farmacológico , Neuropatias Diabéticas/patologia , Gânglios Espinais/efeitos dos fármacos , Gânglios Espinais/patologia , Hiperalgesia/tratamento farmacológico , Hiperalgesia/patologia , Masculino , Neuralgia/tratamento farmacológico , Neuralgia/patologia , Neuroglia/efeitos dos fármacos , Neuroglia/metabolismo , Neuroglia/patologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Antagonistas do Receptor Purinérgico P2X , Distribuição Aleatória , Ratos Wistar , Tato
6.
Eur J Pharmacol ; 830: 87-94, 2018 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-29715452

RESUMO

Steroidal and non-steroidal anti-inflammatory drugs (NSAIDs) are widely used to control inflammatory pain, but there is a risk of gastrointestinal bleeding and increased heart failure risk. The search for new drugs remains ongoing, and natural products are a source for potential new compounds. Mangiferin, a natural xanthone C-glucoside, has demonstrated biological activity, including anti-inflammatory and analgesic properties, but it's mechanisms are poorly understood. In this study, we investigated the mechanisms underlying the anti-inflammatory and analgesic effects of local administration of mangiferin. We employed an electronic von Frey apparatus to evaluate mechanical hyperalgesia induced by carrageenan in rats. Mangiferin (150-1200 µg/paw), administered locally into the hindpaw, prevented hyperalgesia in a dose-dependent - 150 µg (- 9%), 300 µg (- 27%, P < 0.01), 600 µg (- 77%, P < 0.001) and 1000 µg (- 93%, P < 0.001) - and local manner. Mangiferin showed decreased levels of TNF-α (P < 0.001) and CINC-1 (P < 0.001), but not IL-1ß; it also prevented neutrophil migration (P < 0.01), but not the increased COX-2 expression in peripheral tissue challenged with carrageenan. To further explore the mechanisms of mangiferin actions, rats were injected with modulators of inflammation and nociception; mangiferin prevented hyperalgesia induced by IL-1ß (P < 0.01), CINC-1 (P < 0.01), epinephrine (P < 0.01), 8-Br-cAMP (P < 0.01) or capsaicin (P < 0.01), but not that induced by PGE2 or α,ß-MeATP. Our study shows that mangiferin has anti-inflammatory and analgesic properties when locally administrated. The control of the inflammatory response and mechanical hyperalgesia by mangiferin depends on the inhibition of TNF-α production/release and the CINC1/epinephrine/PKA pathway, supporting its marked inhibition of inflammatory mechanical hyperalgesia.


Assuntos
Analgésicos , Anti-Inflamatórios , Hiperalgesia , Xantonas , Analgésicos/farmacologia , Analgésicos/uso terapêutico , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Carragenina , Quimiocina CXCL1/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Dinoprostona/metabolismo , Epinefrina/metabolismo , Hiperalgesia/induzido quimicamente , Hiperalgesia/tratamento farmacológico , Hiperalgesia/imunologia , Hiperalgesia/metabolismo , Interleucina-1beta/metabolismo , Masculino , Neutrófilos/efeitos dos fármacos , Neutrófilos/imunologia , Ratos Wistar , Fator de Necrose Tumoral alfa/metabolismo , Xantonas/farmacologia , Xantonas/uso terapêutico
7.
Eur J Pharmacol ; 798: 113-121, 2017 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-28131783

RESUMO

Cannabinoid system is a potential target for pain control. Cannabinoid receptor 1 (CB1) activation play a role in the analgesic effect of cannabinoids once it is expressed in primary afferent neurons. This study investigates whether the anti-hyperalgesic effect of CB1 receptor activation involves P2X3 receptor in primary afferent neurons. Mechanical hyperalgesia was evaluated by electronic von Frey test. Cannabinoid effect was evaluated using anandamide or ACEA, a non-selective or a selective CB1 receptor agonists, respectively; AM251, a CB1 receptor antagonist, and antisense ODN for CB1 receptor. Calcium imaging assay was performed to evaluated α,ß-meATP-responsive cultured DRG neurons pretreated with ACEA. Anandamide or ACEA administered in peripheral tissue reduced the carrageenan-induced mechanical hyperalgesia. The reduction in the carrageenan-induced hyperalgesia induced by ACEA was completely reversed by administration of AM251 as well as by the intrathecal treatment with antisense ODN for CB1 receptor. Also, ACEA reduced the mechanical hyperalgesia induced by bradykinin and by α,ß-meATP, a P2X3 receptor non-selective agonist, but not by tumor necrosis factor alpha (TNF-α), interleukin-1 beta (IL-1ß) and chemokine-induced chemoattractant-1 (CINC-1). Finally, CB1 receptors are co-localized with P2X3 receptors in DRG small-diameter neurons and the treatment with ACEA reduced the number of α,ß-meATP-responsive cultured DRG neurons. Our data suggest that the analgesic effect of CB1 receptor activation is mediated by a negative modulation of the P2X3 receptor in the primary afferent neurons.


Assuntos
Hiperalgesia/metabolismo , Hiperalgesia/patologia , Neurônios Aferentes/efeitos dos fármacos , Neurônios Aferentes/metabolismo , Receptor CB1 de Canabinoide/metabolismo , Receptores Purinérgicos P2X3/metabolismo , Animais , Bradicinina/farmacologia , Carragenina/farmacologia , Tamanho Celular , Citocinas/metabolismo , Gânglios Espinais/patologia , Hiperalgesia/induzido quimicamente , Hiperalgesia/tratamento farmacológico , Masculino , Neurônios Aferentes/patologia , Oligodesoxirribonucleotídeos Antissenso/genética , Ratos , Ratos Wistar , Receptor CB1 de Canabinoide/genética
8.
Eur J Pharmacol ; 741: 124-31, 2014 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-25058903

RESUMO

Dipyrone (metamizole) is an analgesic pro-drug used to control moderate pain. It is metabolized in two major bioactive metabolites: 4-methylaminoantipyrine (4-MAA) and 4-aminoantipyrine (4-AA). The aim of this study was to investigate the participation of peripheral CB1 and CB2 cannabinoid receptors activation in the anti-hyperalgesic effect of dipyrone, 4-MAA or 4-AA. PGE2 (100ng/50µL/paw) was locally administered in the hindpaw of male Wistar rats, and the mechanical nociceptive threshold was quantified by electronic von Frey test, before and 3h after its injection. Dipyrone, 4-MAA or 4-AA was administered 30min before the von Frey test. The selective CB1 receptor antagonist AM251, CB2 receptor antagonist AM630, cGMP inhibitor ODQ or KATP channel blocker glibenclamide were administered 30min before dipyrone, 4-MAA or 4-AA. The antisense-ODN against CB1 receptor expression was intrathecally administered once a day during four consecutive days. PGE2-induced mechanical hyperalgesia was inhibited by dipyrone, 4-MAA, and 4-AA in a dose-response manner. AM251 or ODN anti-sense against neuronal CB1 receptor, but not AM630, reversed the anti-hyperalgesic effect mediated by 4-AA, but not by dipyrone or 4-MAA. On the other hand, the anti-hyperalgesic effect of dipyrone or 4-MAA was reversed by glibenclamide or ODQ. These results suggest that the activation of neuronal CB1, but not CB2 receptor, in peripheral tissue is involved in the anti-hyperalgesic effect of 4-aminoantipyrine. In addition, 4-methylaminoantipyrine mediates the anti-hyperalgesic effect by cGMP activation and KATP opening.


Assuntos
Analgésicos/administração & dosagem , Anti-Inflamatórios não Esteroides/administração & dosagem , Dipirona/administração & dosagem , Neurônios/metabolismo , Canais de Potássio/metabolismo , Receptor CB1 de Canabinoide/metabolismo , Analgésicos/metabolismo , Animais , Anti-Inflamatórios não Esteroides/metabolismo , Injeções Espinhais , Masculino , Neurônios/efeitos dos fármacos , Ratos , Ratos Wistar , Distribuição Tecidual/efeitos dos fármacos , Distribuição Tecidual/fisiologia , Resultado do Tratamento
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