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1.
Biomed Res Int ; 2019: 6593125, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31467905

RESUMO

Methanolic extract of Clinacanthus nutans Lindau leaves (MECN) has been reported to exert antinociceptive activity. The present study aimed to elucidate the possible antinociceptive mechanisms of a lipid-soluble fraction of MECN, which was obtained after sequential extraction in petroleum ether. The petroleum ether fraction of C. nutans (PECN), administered orally to mice, was (i) subjected to capsaicin-, glutamate-, phorbol 12-myristate 13-acetate-, bradykinin-induced nociception model; (ii) prechallenged (intraperitoneal (i.p.)) with 0.15 mg/kg yohimbine, 1 mg/kg pindolol, 3 mg/kg caffeine, 0.2 mg/kg haloperidol, or 10 mg/kg atropine, which were the respective antagonist of α 2-adrenergic, ß-adrenergic, adenosinergic, dopaminergic, or muscarinic receptors; and (iii) prechallenged (i.p.) with 10 mg/kg glibenclamide, 0.04 mg/kg apamin, 0.02 mg/kg charybdotoxin, or 4 mg/kg tetraethylammonium chloride, which were the respective inhibitor of ATP sensitive-, small conductance Ca2+-activated-, large conductance Ca2+-activated-, or nonselective voltage-activated-K+ channel. Results obtained demonstrated that PECN (100, 250, and 500 mg/kg) significantly (P<0.05) inhibited all models of nociception described earlier. The antinociceptive activity of 500 mg/kg PECN was significantly (P<0.05) attenuated when prechallenged with all antagonists or K+ channel blockers. However, only pretreatment with apamin and charybdotoxin caused full inhibition of PECN-induced antinociception. The rest of the K+ channel blockers and all antagonists caused only partial inhibition of PECN antinociception, respectively. Analyses on PECN's phytoconstituents revealed the presence of antinociceptive-bearing bioactive compounds of volatile (i.e., derivatives of γ-tocopherol, α-tocopherol, and lupeol) and nonvolatile (i.e., cinnamic acid) nature. In conclusion, PECN exerts a non-opioid-mediated antinociceptive activity involving mainly activation of adenosinergic and cholinergic receptors or small- and large-conductance Ca2+-activated-K+ channels.


Assuntos
Acanthaceae/química , Analgésicos/farmacologia , Dor Nociceptiva/tratamento farmacológico , Extratos Vegetais/farmacologia , Alcanos/química , Analgésicos/química , Analgésicos não Entorpecentes/química , Analgésicos não Entorpecentes/farmacologia , Animais , Bradicinina/toxicidade , Capsaicina/toxicidade , Ácido Glutâmico/toxicidade , Humanos , Metanol/química , Camundongos , Dor Nociceptiva/induzido quimicamente , Dor Nociceptiva/patologia , Extratos Vegetais/química , Folhas de Planta/química , Canais de Potássio/genética , Acetato de Tetradecanoilforbol/análogos & derivados , Acetato de Tetradecanoilforbol/toxicidade
2.
Prim Care ; 46(3): 319-333, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31375184

RESUMO

The intent of this article is to help clinicians to have practical knowledge and skills related to both assessment and pharmacotherapy of chronic pain in the seriously ill patients. Treating patients with chronic pain and progressive disease should include assessment of "total pain" (physical, psychological, and spiritual suffering) and the care givers as part of treatment team. Effective management of chronic pain starts with thorough assessment and diagnosis of the pain syndrome. A worldwide consensus endorses use of multimodal approach and opioid pharmacotherapy as the mainstay approach to moderate to severe pain in cancer and pain associated with serious illness.


Assuntos
Analgésicos Opioides/uso terapêutico , Dor Crônica/tratamento farmacológico , Manejo da Dor/métodos , Atenção Primária à Saúde/organização & administração , Analgésicos/uso terapêutico , Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/efeitos adversos , Dor Crônica/diagnóstico , Dor Crônica/terapia , Estado Terminal , Quimioterapia Combinada , Humanos , Neuralgia/diagnóstico , Neuralgia/terapia , Dor Nociceptiva/diagnóstico , Dor Nociceptiva/terapia , Medição da Dor , Cuidados Paliativos/métodos , Planejamento de Assistência ao Paciente , Dor Visceral/diagnóstico , Dor Visceral/terapia
4.
PLoS Comput Biol ; 15(7): e1007106, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31295266

RESUMO

Experimental studies show that human pain sensitivity varies across the 24-hour day, with the lowest sensitivity usually occurring during the afternoon. Patients suffering from neuropathic pain, or nerve damage, experience an inversion in the daily modulation of pain sensitivity, with the highest sensitivity usually occurring during the early afternoon. Processing of painful stimulation occurs in the dorsal horn (DH), an area of the spinal cord that receives input from peripheral tissues via several types of primary afferent nerve fibers. The DH circuit is composed of different populations of neurons, including excitatory and inhibitory interneurons, and projection neurons, which constitute the majority of the output from the DH to the brain. In this work, we develop a mathematical model of the dorsal horn neural circuit to investigate mechanisms for the daily modulation of pain sensitivity. The model describes average firing rates of excitatory and inhibitory interneuron populations and projection neurons, whose activity is directly correlated with experienced pain. Response in afferent fibers to peripheral stimulation is simulated by a Poisson process generating nerve fiber spike trains at variable firing rates. Model parameters for fiber response to stimulation and the excitability properties of neuronal populations are constrained by experimental results found in the literature, leading to qualitative agreement between modeled responses to pain and experimental observations. We validate our model by reproducing the wind-up of pain response to repeated stimulation. We apply the model to investigate daily modulatory effects on pain inhibition, in which response to painful stimuli is reduced by subsequent non-painful stimuli. Finally, we use the model to propose a mechanism for the observed inversion of the daily rhythmicity of pain sensation under neuropathic pain conditions. Underlying mechanisms for the shift in rhythmicity have not been identified experimentally, but our model results predict that experimentally-observed dysregulation of inhibition within the DH neural circuit may be responsible. The model provides an accessible, biophysical framework that will be valuable for experimental and clinical investigations of diverse physiological processes modulating pain processing in humans.


Assuntos
Ritmo Circadiano/fisiologia , Modelos Neurológicos , Dor/fisiopatologia , Corno Dorsal da Medula Espinal/fisiopatologia , Biologia Computacional , Gânglios Espinais/fisiopatologia , Humanos , Interneurônios/fisiologia , Rede Nervosa/fisiologia , Neuralgia/fisiopatologia , Nociceptividade/fisiologia , Dor Nociceptiva/fisiopatologia , Percepção da Dor/fisiologia
5.
Int J Behav Med ; 26(4): 427-436, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31236873

RESUMO

BACKGROUND: The associations between family strain, depression, and chronic pain interference vary across individuals, suggesting moderated relations, and one possible moderator is somatic amplification. The current study examined a moderated mediation model that investigated (a) whether depression mediated the relation between non-spouse family strain and chronic pain interference and (b) whether somatic amplification moderated the association between depression and chronic pain interference. METHODS: Data came from 933 adults who participated in the National Survey of Midlife Development in the USA. Participants completed telephone interviews or self-report measures. RESULTS: The relationship between non-spouse family strain and chronic pain interference was mediated by depression, and this mediation depended on the degree of somatic amplification. Specifically, individuals who experienced more non-spouse family strain were more likely to experience depression and higher levels of chronic pain interference. Somatic amplification significantly moderated the effect of depression on chronic pain, such that individuals with higher levels of somatic amplification and depression were likely to experience higher levels of chronic pain interference. The indirect effect of non-spouse family strain on chronic pain through depression was significant for low, middle, and high levels of somatic amplification. CONCLUSIONS: The presence of chronic pain has been associated with family dynamics changing, which may be linked with higher levels of non-spouse family strain. A negative family environment may be related to the development of depression, which may be associated with the severity and inability to cope with chronic pain. Somatic amplification may strengthen the association between depression and pain intensity.


Assuntos
Dor Crônica/psicologia , Depressão/psicologia , Relações Familiares/psicologia , Dor Nociceptiva/psicologia , Adaptação Psicológica , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Autorrelato
6.
Science ; 364(6443): 852-859, 2019 05 31.
Artigo em Inglês | MEDLINE | ID: mdl-31147513

RESUMO

Noxious substances, called algogens, cause pain and are used as defensive weapons by plants and stinging insects. We identified four previously unknown instances of algogen-insensitivity by screening eight African rodent species related to the naked mole-rat with the painful substances capsaicin, acid (hydrogen chloride, pH 3.5), and allyl isothiocyanate (AITC). Using RNA sequencing, we traced the emergence of sequence variants in transduction channels, like transient receptor potential channel TRPA1 and voltage-gated sodium channel Nav1.7, that accompany algogen insensitivity. In addition, the AITC-insensitive highveld mole-rat exhibited overexpression of the leak channel NALCN (sodium leak channel, nonselective), ablating AITC detection by nociceptors. These molecular changes likely rendered highveld mole-rats immune to the stings of the Natal droptail ant. Our study reveals how evolution can be used as a discovery tool to find molecular mechanisms that shut down pain.


Assuntos
Evolução Molecular , Ratos-Toupeira/fisiologia , Canal de Sódio Disparado por Voltagem NAV1.7/genética , Dor Nociceptiva/genética , Limiar da Dor , Canal de Cátion TRPA1/genética , Animais , Sítios de Ligação , Capsaicina/farmacologia , Ácido Clorídrico/farmacologia , Mordeduras e Picadas de Insetos/genética , Mordeduras e Picadas de Insetos/imunologia , Isotiocianatos/farmacologia , Ratos-Toupeira/genética , Ratos-Toupeira/imunologia , Dor Nociceptiva/induzido quimicamente , Nociceptores/efeitos dos fármacos , Nociceptores/fisiologia , Conformação Proteica , Análise de Sequência de RNA , Especificidade da Espécie , Canal de Cátion TRPA1/química
7.
Int J Mol Sci ; 20(12)2019 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-31197115

RESUMO

Over the last decades, a great array of molecular mediators have been identified as potential targets for the treatment of chronic pain. Among these mediators, transient receptor potential (TRP) channel superfamily members have been thoroughly studied. Namely, the nonselective cationic channel, transient receptor potential ankyrin subtype 1 (TRPA1), has been described as a chemical nocisensor involved in noxious cold and mechanical sensation and as rivalling TRPV1, which traditionally has been considered as the most important TRP channel involved in nociceptive transduction. However, few TRPA1-related drugs have succeeded in clinical trials. In the present review, we attempt to discuss the latest data on the topic and future directions for pharmacological intervention.


Assuntos
Analgésicos/farmacologia , Dor Crônica/metabolismo , Neuralgia/metabolismo , Nociceptividade/efeitos dos fármacos , Dor Nociceptiva/metabolismo , Canal de Cátion TRPA1/antagonistas & inibidores , Analgésicos/uso terapêutico , Animais , Dor Crônica/tratamento farmacológico , Humanos , Neuralgia/tratamento farmacológico , Dor Nociceptiva/tratamento farmacológico , Canal de Cátion TRPA1/metabolismo , Canais de Cátion TRPV/antagonistas & inibidores , Canais de Cátion TRPV/metabolismo
8.
Br J Anaesth ; 123(2): e312-e321, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31047645

RESUMO

Nociception, in contrast to pain, is not a subjective feeling, but the physiological encoding and processing of nociceptive stimuli. However, monitoring nociception remains a challenge in attempts to lower the incidence of acute postoperative pain and the move towards a more automated approach to analgesia and anaesthesia. To date, several commercialised devices promise a more accurate reflection of nociception than the traditionally used vital signs, blood pressure and heart rate. This narrative review presents an overview of existing technologies and commercially available devices, and offers a perspective for future research. Although firm conclusions about individual methods may be premature, none currently appears to offer a sufficiently broad applicability. Furthermore, there is currently no firm evidence for any clinically relevant influence of such devices on patient outcome. However, the available monitors have significantly aided the understanding of underlying mechanisms and identification of potential pitfalls.


Assuntos
Monitorização Intraoperatória/métodos , Nociceptividade , Dor Nociceptiva/diagnóstico , Humanos
9.
Med Sci Monit ; 25: 3140-3145, 2019 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-31030206

RESUMO

BACKGROUND Regional anesthesia provides excellent analgesic effects after surgery. However, the effects of regional anesthesia on nociceptive levels during surgery under general anesthesia have not been quantitatively evaluated. To reveal the effects of thoracic paravertebral block (PVB) on nociceptive levels after skin incision during general anesthesia, we performed a retrospective cohort study in patients without serious preoperative conditions or comorbidities undergoing elective video-assisted thoracoscopic surgery (VATS). Nociceptive levels during general anesthesia were calculated using our previously determined Nociceptive Response (NR) equation, which utilizes common hemodynamic parameters. MATERIAL AND METHODS Data on 77 adult patients who underwent VATS from May 2018 to August 2018 were retrospectively obtained from our institutional database. We then performed propensity score matching between patients who received thoracic PVB (PVB group: n=29) and those who did not (Control group: n=48). The averaged values of systolic blood pressure (SBP), heart rate (HR), perfusion index (PI), bispectral index (BIS), and NR from 10 to 5 minutes before skin incision (T0), 5 to 10 minutes (T1), 10 to 15 minutes (T2), 15 to 20 minutes (T3), and 20 to 25 minutes after skin incision (T4), were calculated. RESULTS Twenty-four propensity score-matched patients in each group were analyzed. Mean NR values at T1 and T2 in the PVB group were significantly lower than those in the Control group. SBP, HR, PI, and BIS, however, showed no significant differences between the 2 groups, except for SBP at T2. CONCLUSIONS Thoracic PVB prevented an increase in NR values, which quantitatively represent nociceptive levels under general anesthesia, in patients undergoing VATS.


Assuntos
Procedimentos Cirúrgicos Dermatológicos/efeitos adversos , Procedimentos Cirúrgicos Dermatológicos/métodos , Bloqueio Nervoso/métodos , Dor Nociceptiva/prevenção & controle , Dor Pós-Operatória/prevenção & controle , Idoso , Anestesia por Condução/métodos , Anestesia Geral/métodos , Estudos de Coortes , Feminino , Frequência Cardíaca/efeitos dos fármacos , Humanos , Masculino , Monitorização Intraoperatória/métodos , Medição da Dor , Pontuação de Propensão , Estudos Retrospectivos , Cirurgia Torácica Vídeoassistida/efeitos adversos , Cirurgia Torácica Vídeoassistida/métodos
10.
Phytomedicine ; 61: 152836, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31035053

RESUMO

BACKGROUND: Oncological pain is one of the most prevalent and difficult-to-treat symptoms in patients with cancer. p-Cymene (PC) is a monoterpene found in more than 100 different plant species, endowed with various pharmacological properties-particularly antinociceptive. HYPOTHESIS/PURPOSE: PC has antinociceptive effect in a model of oncologic pain due to the activation of the descending inhibitory pathway of pain. STUDY DESIGN: A pre-clinical, longitudinal, blind and randomized study. METHODS: Male Swiss mice were induced with S180 cells in the right hind paw, then treated daily with PC (12.5, 25 and 50 mg/kg, s.c.) and screened for mechanical hyperalgesia, spontaneous nociception, nociception induced by non-noxious palpation, tumor growth, changes in the neuromuscular function and existence of bone degradation in the tumor area. The effect of PC on Ca2+ currents (electrophysiological records), histological and neurochemical changes (immunofluorescence for Fos) were also evaluated. RESULTS: PC reduced (p < 0.05) the mechanical hyperalgesia, the spontaneous (p < 0.001) and non-noxious palpation (p < 0.001) nociceptions, not changing the tumor development, neuromuscular function or histopathological aspects of the paw affected. PC reduced Fos expression in the spinal cord (p < 0.001) and increased this expression in the PAG (p < 0.05) and in the NRM (p < 0.01). PC decreased the density of calcium channel currents (p < 0.05). CONCLUSION: These results suggest the antinociceptive effect of PC on oncologic pain, probably acting in both ascending and descending pain pathways, and modulating the calcium channel currents in order to exert its effects.


Assuntos
Cálcio/metabolismo , Dor do Câncer/tratamento farmacológico , /farmacologia , Analgésicos não Entorpecentes/farmacologia , Animais , Dor do Câncer/metabolismo , Hiperalgesia/tratamento farmacológico , Masculino , Camundongos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Dor Nociceptiva/tratamento farmacológico , Proteínas Proto-Oncogênicas c-fos/metabolismo , Distribuição Aleatória , Sarcoma 180/complicações , Medula Espinal/efeitos dos fármacos , Medula Espinal/metabolismo
11.
Inflammopharmacology ; 27(4): 749-760, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30953227

RESUMO

In continuation with our previous studies on osthole, bergapten, a closely related furanocoumarin was investigated for its ameliorative effect on chemically induced neurogenic and inflammatory hyperalgesia and inflammation in mice. Chemical hyperalgesia and inflammation was induced by administration of formalin (intraplantar), acetic acid (intraperitoneal) and carrageenan (intraplantar) to different groups of animals. Pain responses were quantified and median effective dose (ED50) of bergapten was calculated. Lipopolysaccharide challenge was administered to study inflammatory cytokines which were analyzed in plasma using ELISA. The expression of poly ADP-ribose polymerase (PARP), cyclooxygenase (COX-2) and inducible nitric oxide synthase (iNOS) was quantified by immnofluorescence staining. Bergapten was found to ameliorate both neurogenic and inflammatory hyperalgesia precipitated by formalin, acetic acid induced writhing and carrageenan induced paw inflammation with ED50 dose of 2.96 mg/kg. Bergapten also significantly decreased the levels of TNF-α and IL-6 and the expression of PARP, COX-2 and iNOS in the spine. It is concluded that bergapten is an interesting molecule with significant analgesic and anti-inflammatory activity emanating through the modulation of multiple pain mediating pathways.


Assuntos
5-Metoxipsoraleno/farmacologia , Ciclo-Oxigenase 2/metabolismo , Citocinas/metabolismo , Inflamação/tratamento farmacológico , Óxido Nítrico Sintase Tipo II/metabolismo , Dor Nociceptiva/tratamento farmacológico , Inibidores de Poli(ADP-Ribose) Polimerases/metabolismo , Coluna Vertebral/efeitos dos fármacos , Analgésicos/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Carragenina/farmacologia , Feminino , Hiperalgesia/tratamento farmacológico , Hiperalgesia/metabolismo , Inflamação/metabolismo , Mediadores da Inflamação/metabolismo , Lipopolissacarídeos/farmacologia , Masculino , Camundongos , Dor Nociceptiva/metabolismo , Coluna Vertebral/metabolismo
12.
Eur J Med Chem ; 168: 189-198, 2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30822708

RESUMO

The pivotal role of the stereocenter at the N-substituent of the 6,7-benzomorphan scaffold was investigated combining synthetic and pharmacological approaches. 2R- and 2S-diastereoisomers of the multitarget MOR/DOR antinociceptive ligand LP2 (1) were synthesized and their pharmacological profile was evaluated in in vitro and vivo assays. From our results, 2S-LP2 (5) showed an improved pharmacological profile in comparison to LP2 (1) and 2R-LP2 (4). 2S-LP2 (5) elicited an antinociceptive effect with a 1.5- and 3-times higher potency than LP2 (1) and R-antipode (4), respectively. In vivo effect of 2S-LP2 (5) was consistent with the improved MOR/DOR efficacy profile assessed by radioligand binding assay, to evaluate the opioid receptor affinity, and BRET assay, to evaluate the capability to promote receptor/G-protein and receptor/ß-arrestin 2 interaction. 2S-LP2 (5) was able to activate, with different efficacy, G-protein pathway over ß-arrestin 2, behaving as biased agonist at MOR and mainly at DOR. Considering the therapeutic potential of both multitarget MOR/DOR agonism and functional selectivity over G-protein, the 2S-LP2 (5) biased multitarget MOR/DOR agonist could provide a safer treatment opportunity.


Assuntos
Analgésicos Opioides/farmacologia , Benzomorfanos/farmacologia , Descoberta de Drogas , Receptores Opioides delta/agonistas , Receptores Opioides mu/agonistas , Analgésicos Opioides/síntese química , Analgésicos Opioides/química , Animais , Benzomorfanos/síntese química , Benzomorfanos/química , Relação Dose-Resposta a Droga , Humanos , Camundongos , Estrutura Molecular , Dor Nociceptiva/tratamento farmacológico , Medição da Dor , Relação Estrutura-Atividade
13.
Cell Mol Life Sci ; 76(10): 1889-1899, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30788514

RESUMO

Chronic neuropathic pain is a debilitating condition that remains challenging to treat. Glutamate N-methyl-D-aspartate receptor (NMDAR) antagonists have been used to treat neuropathic pain, but the exact sites of their actions have been unclear until recently. Although conventionally postsynaptic, NMDARs are also expressed presynaptically, particularly at the central terminals of primary sensory neurons, in the spinal dorsal horn. However, presynaptic NMDARs in the spinal cord are normally quiescent and are not actively involved in physiological nociceptive transmission. In this review, we describe the emerging role of presynaptic NMDARs at the spinal cord level in chronic neuropathic pain and the implications of molecular mechanisms for more effective treatment. Recent studies indicate that presynaptic NMDAR activity at the spinal cord level is increased in several neuropathic pain conditions but not in chronic inflammatory pain. Increased presynaptic NMDAR activity can potentiate glutamate release from primary afferent terminals to spinal dorsal horn neurons, which is crucial for the synaptic plasticity associated with neuropathic pain caused by traumatic nerve injury and chemotherapy-induced peripheral neuropathy. Furthermore, α2δ-1, previously considered a calcium channel subunit, can directly interact with NMDARs through its C-terminus to increase presynaptic NMDAR activity by facilitating synaptic trafficking of α2δ-1-NMDAR complexes in neuropathic pain caused by chemotherapeutic agents and peripheral nerve injury. Targeting α2δ-1-bound NMDARs with gabapentinoids or α2δ-1 C-terminus peptides can attenuate nociceptive drive form primary sensory nerves to dorsal horn neurons in neuropathic pain.


Assuntos
Neuralgia/fisiopatologia , Dor Nociceptiva/fisiopatologia , Receptores de N-Metil-D-Aspartato/fisiologia , Receptores Pré-Sinápticos/fisiologia , Medula Espinal/fisiopatologia , Animais , Camundongos , Neuralgia/metabolismo , Nociceptividade/fisiologia , Dor Nociceptiva/metabolismo , Nociceptores/metabolismo , Nociceptores/fisiologia , Ratos , Receptores de N-Metil-D-Aspartato/metabolismo , Receptores Pré-Sinápticos/metabolismo
14.
Zhongguo Zhen Jiu ; 39(1): 111-4, 2019 Jan 12.
Artigo em Chinês | MEDLINE | ID: mdl-30672266

RESUMO

The clinical research articles relevant with Fu's subcutaneous needling therapy (FSN) were retrieved from CNKI, WANFANG, CBM and PubMed databases till January 2018 since the establishment of database. According to the general international criteria of disease classification, the diseases involved in the articles were classified and summarized. In terms of the clinical application and research of FSN, the questions were extracted and commented through expert's consultation. As a result, 412 articles were included. The statistical results of disease spectrum indicated that FSN was adopted in 65 kinds of diseases in 11 systems. Of these diseases, the relevant somatic pain disorders in the musculoskeletal system were the most appropriate. Professor FU Zhong-hua explained that the clinical physicians of FSN should select the muscle-related disorders as the clinical research subject and treat them with normalized manipulation of FSN. The research on FSN is still at the preliminary stage. It needs more high-quality clinical and basic researches to provide the evidences for the therapeutic effects of FSN.


Assuntos
Analgesia por Acupuntura , Terapia por Acupuntura , Dor Nociceptiva , Pontos de Acupuntura , Humanos , Dor Nociceptiva/terapia
15.
Neuropharmacology ; 148: 291-304, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30668942

RESUMO

Neuropathic pain is a complex disorder associated with emotional and cognitive deficits that may impair nociceptive manifestations. There is high inter-individual variability in the manifestations of human neuropathic pain, which largely depends on personality traits. We aim to identify the influence of different behavioral traits in the inter-individual vulnerability to neuropathic pain manifestations using behavioral, electrophysiological and genetic approaches. We first selected mice with extreme social and emotional traits and look for correlation with the spontaneous neuronal activity in the central amygdala. Neuropathic pain was induced to these mice to evaluate the influence of behavioral traits on nociceptive manifestations and gene expression profiles in the amygdala. Our results show an association of the spontaneous central amygdala neuronal activity with the sociability behavior. We demonstrate that low sociable, high anxious and low depressive phenotypes develop enhanced nociceptive hypersensitivity after nerve injury. However, greater emotional alterations and cognitive impairment are observed in high sociable, anxious-like and depressive-like mice, indicating that nociceptive, emotional and cognitive manifestations of neuropathic pain do not correlate with each other. Gene analyses identify high Pdyn and Il6 levels in the amygdala as indicative of enhanced nociceptive hypersensitivity and reveal an association between high Gadd45 expression and attenuated emotional and cognitive manifestations of neuropathic pain.


Assuntos
Cognição/fisiologia , Emoções/fisiologia , Individualidade , Neuralgia/fisiopatologia , Neuralgia/psicologia , Dor Nociceptiva/psicologia , Animais , Comportamento Animal , Proteínas de Ciclo Celular/biossíntese , Núcleo Central da Amígdala/metabolismo , Núcleo Central da Amígdala/fisiologia , Encefalinas/metabolismo , Expressão Gênica , Interleucina-6/metabolismo , Masculino , Camundongos , Neuralgia/complicações , Dor Nociceptiva/complicações , Precursores de Proteínas/metabolismo , Comportamento Social
16.
Drug Res (Stuttg) ; 69(7): 401-405, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30616248

RESUMO

AIM: The purpose of this study was to evaluate the antinociceptive interaction between bupivacaine and Artemisia aucheri. L encapsulated nanoparticles. METHODS AND MATERIALS: The effect of bupivacaine and Artemisia aucheri.L alone, and their encapsulated co-administration was assessed using the 3% formalin test in rat. Increasing doses of bupivacaine (31.6, 100, 178, and 316 mg/kg) or Artemisia aucheri.L (5.6, 10, 17.8, and 31.6 mg/kg) were given i.p. 10 min before 3% formalin administration. RESULTS: The possible mechanism(s) of action were analyzed for the encapsulated co-administration, naloxone (1 mg/kg) and N (G)-nitro-L-arginine methyl ester (L-NAME) (3 mg/kg) were used. Interaction index and isobolographic analysis and the demonstrated a synergistic effect. The experimental ED30 was lower as compared with theoretical ED30. Naloxone was shown to reduce the antinociceptive effect of the encapsulated co-administration. DISCUSSION: These data suggest that the bupivacaine and Artemisia aucheri.L encapsulated nanoparticles gave a synergistic effect.


Assuntos
Artemisia/química , Bupivacaína/administração & dosagem , Portadores de Fármacos/química , Dor Nociceptiva/tratamento farmacológico , Extratos Vegetais/administração & dosagem , Animais , Bupivacaína/farmacocinética , Modelos Animais de Doenças , Composição de Medicamentos , Sinergismo Farmacológico , Humanos , Injeções , Masculino , Nanopartículas Metálicas/química , Dor Nociceptiva/diagnóstico , Dor Nociceptiva/etiologia , Medição da Dor , Extratos Vegetais/farmacocinética , Ratos
17.
Eur J Pain ; 23(3): 539-554, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30318662

RESUMO

BACKGROUND: Translating efficacy of analgesic drugs from animal models to humans remains challenging. Reasons are multifaceted, but lack of sufficiently rigorous preclinical study design criteria and phenotypically relevant models may be partly responsible. To begin to address this fundamental issue, we assessed the analgesic efficacy of morphine in three inbred rat strains (selected based on stress reactivity and affective/pain phenotypes), and outbred Sprague Dawley (SD) rats supplied from two vendors. METHODS: Sensitivity to morphine (0.3-6.0 mg/kg, s.c.) was evaluated in the hot plate test of acute thermal nociception, the Complete Freund's Adjuvant (CFA) model of inflammatory-induced mechanical hyperalgesia, and in a locomotor motility assay in male rats from the following strains; Lewis (LEW), Fischer (F344), Wistar Kyoto (WKY), and SD's from Envigo and Charles River. RESULTS: F344 and SD rats were similarly sensitive to morphine in hot plate and CFA-induced inflammatory hyperalgesia (Minimum Effective Dose (MED) = 3.0 mg/kg). WKY rats developed a less robust mechanical hypersensitivity after CFA injection, and were less sensitive to morphine in both pain tests (MED = 6.0 mg/kg). LEW rats were completely insensitive to morphine in the hot plate test, in contrast to the reversal of CFA-induced hyperalgesia (MED = 3.0 mg/kg). All strains exhibited a dose-dependent reduction in locomotor activity at 3.0-6.0 mg/kg. CONCLUSION: Sensory phenotyping in response to acute thermal and inflammatory-induced pain, and sensitivity to morphine in various inbred and outbred rat strains indicates that different pathophysiological mechanisms are engaged after injury. This could have profound implications for translating preclinical drug discovery efforts into pain patients. SIGNIFICANCE: The choice of rat strain used in preclinical pain research can profoundly affect the outcome of experiments in relation to (a) nociceptive threshold responses, and (b) efficacy to analgesic treatment, in assays of acute and tonic inflammatory nociceptive pain.


Assuntos
Analgésicos/uso terapêutico , Morfina/uso terapêutico , Dor Nociceptiva/tratamento farmacológico , Animais , Modelos Animais de Doenças , Descoberta de Drogas , Adjuvante de Freund/efeitos adversos , Hiperalgesia/tratamento farmacológico , Masculino , Dor Nociceptiva/etiologia , Medição da Dor , Ratos , Ratos Endogâmicos F344 , Ratos Endogâmicos Lew , Ratos Endogâmicos WKY , Ratos Sprague-Dawley
18.
Eur J Pain ; 23(4): 765-783, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30427564

RESUMO

BACKGROUND: Nociceptive pain remains a prevalent clinical problem and often poorly responsive to the currently available analgesics. Previous studies have shown that astroglial glutamate transporter-1 (GLT-1) in the hippocampus and anterior cingulate cortex (ACC) is critically involved in pain processing and modulation. However, the role of astroglial GLT-1 in nociceptive pain involving the hippocampus and ACC remains unknown. We investigated the role of 3-[[(2-Methylphenyl) methyl]thio]-6-(2-pyridinyl)-pyridazine (LDN-212320), a GLT-1 activator, in nociceptive pain model and hippocampal-dependent behavioural tasks in mice. METHODS: We evaluated the effects of LDN-212320 in formalin-induced nociceptive pain model. In addition, formalin-induced impaired hippocampal-dependent behaviours were measured using Y-maze and object recognition test. Furthermore, GLT-1 expression and extracellular signal-regulated kinase phosphorylation (pERK1/2) were measured in the hippocampus and ACC using Western blot analysis and immunohistochemistry. RESULTS: The LDN-212320 (10 or 20 mg/kg, i.p) significantly attenuated formalin-evoked nociceptive behaviour. The antinociceptive effects of LDN-212320 were reversed by systemic administration of DHK (10 mg/kg, i.p), a GLT-1 antagonist. Moreover, LDN-212320 (10 or 20 mg/kg, i.p) significantly reversed formalin-induced impaired hippocampal-dependent behaviour. In addition, LDN-212320 (10 or 20 mg/kg, i.p) increased GLT-1 expressions in the hippocampus and ACC. On the other hand, LDN-212320 (20 mg/kg, i.p) significantly reduced formalin induced-ERK phosphorylation, a marker of nociception, in the hippocampus and ACC. CONCLUSION: These results suggest that the GLT-1 activator LDN-212320 prevents nociceptive pain by upregulating astroglial GLT-1 expression in the hippocampus and ACC. Therefore, GLT-1 activator could be a novel drug candidate for nociceptive pain. SIGNIFICANCE: The present study provides new insights and evaluates the role of GLT-1 activator in the modulation of nociceptive pain involving hippocampus and ACC. Here, we provide evidence that GLT-1 activator could be a potential therapeutic utility for the treatment of nociceptive pain.


Assuntos
Comportamento Animal/efeitos dos fármacos , Transportador 2 de Aminoácido Excitatório/efeitos dos fármacos , Nociceptividade/efeitos dos fármacos , Piridazinas/farmacologia , Piridinas/farmacologia , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Transportador 2 de Aminoácido Excitatório/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/efeitos dos fármacos , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Formaldeído/toxicidade , Giro do Cíngulo/efeitos dos fármacos , Giro do Cíngulo/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Masculino , Camundongos , Dor Nociceptiva/induzido quimicamente , Dor Nociceptiva/metabolismo , Dor Nociceptiva/fisiopatologia , Dor/metabolismo , Medição da Dor , Fosforilação
19.
Neurol Res ; 41(1): 52-59, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30325723

RESUMO

Background/Aims: Paclitaxel is largely used as a chemotherapeutic agent for the treatment of several types of cancers. However, one of the significant limiting complications of paclitaxel is painful peripheral neuropathy during its therapy. The purposes of this study were to examine (1) the effects of blocking mammalian target of rapamycin (mTOR) on mechanical and thermal hypersensitivity evoked by paclitaxel; and (2) the underlying mechanisms responsible for the role of mTOR in regulating paclitaxel-induced neuropathic pain. Methods: Behavioral test was performed to determine mechanical and thermal sensitivity in rats. ELISA was used to examine the levels of proinflammatory cytokines (PICs including IL-1ß, IL-6, and TNF-α) and substance P and calcitonin gene-related peptide (CGRP) in the dorsal root ganglion (DGR); and Western blot analysis was used to examine expression of mTOR signal pathway. Results: Paclitaxel increased mechanical and thermal sensitivity as compared with vehicle control animals (P < 0.05 vs. controls). Paclitaxel also amplified the expression of p-mTOR, mTOR-mediated phosphorylation of p70 ribosomal S6 protein kinase 1 (p-S6K1), 4E-binding protein 1 (p-4E-BP1) in the DRG. Blocking mTOR using rapamycin attenuated peripheral painful neuropathy observed in paclitaxel rats (P < 0.05 vs. without rapamycin). This inhibitory effect was accompanied with decreases of IL-1ß, IL-6, and TNF-α as well as substance P and CGRP. In addition, inhibition of phosphatidylinositide 3-kinase (p-PI3K) attenuated expression of p-mTOR and PICs/substance P/CGRP in paclitaxel rats and this further attenuated mechanical and thermal hypersensitivity. Conclusions: The data revealed specific signaling pathways leading to paclitaxel-induced peripheral neuropathic pain, including the activation of PI3K-mTOR, PIC signal, and substance P and CGRP. Inhibition of these pathways alleviates neuropathic pain. Targeting one or more of these molecular mediators may present new opportunities for treatment and management of neuropathic pain observed during chemotherapeutic application of paclitaxel.


Assuntos
Anti-Inflamatórios/farmacologia , Antineoplásicos Fitogênicos/efeitos adversos , Citocinas/metabolismo , Dor Nociceptiva/tratamento farmacológico , Paclitaxel/efeitos adversos , Sirolimo/farmacologia , Animais , Hiperalgesia/tratamento farmacológico , Hiperalgesia/etiologia , Hiperalgesia/metabolismo , Inflamação/tratamento farmacológico , Inflamação/etiologia , Inflamação/metabolismo , Masculino , Dor Nociceptiva/etiologia , Dor Nociceptiva/metabolismo , Ratos Sprague-Dawley , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/metabolismo
20.
J Colloid Interface Sci ; 536: 196-207, 2019 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-30368091

RESUMO

The paper focuses on the synthesis and characterization of new drug delivery systems for local therapy. They were prepared by in situ hydrogelation of chitosan biopolymer with nitrosalicylaldehyde in the presence of a model drug, varying the crosslinking density. The structural, supramolecular and morphological characteristics of the systems were studied by FTIR spectroscopy, X-ray diffraction and, POM and SEM microscopy. In vitro release of the drug has been explored in simulated physiological conditions and in vivo release was investigated by the somatic pain model on rats. Information on the biodegradation of the systems was gain by simulating experiments of enzymatic degradation. The systems were biodegradable and showed a prolonged drug release, assuring an in vivo efficient therapeutic effect over 5 days, with no systemic toxicity. All these findings demonstrated that the new hydrogels based on nitrosalicyl-imine-chitosan provides a practical approach for sustained drug delivery for local chemotherapy.


Assuntos
Quitosana/química , Diclofenaco/uso terapêutico , Sistemas de Liberação de Medicamentos , Hidrogéis/química , Iminas/química , Nitrocompostos/química , Dor Nociceptiva/tratamento farmacológico , Ácido Salicílico/química , Animais , Diclofenaco/administração & dosagem , Modelos Animais de Doenças , Masculino , Tamanho da Partícula , Ratos , Ratos Wistar , Propriedades de Superfície
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