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1.
Pain Physician ; 21(5): E555-E564, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30282403

RESUMO

BACKGROUND: Over-expression of spinal protein kinase Cγ(PKCγ) contributes to the induction of persistent bilateral hyperalgesia following inflammatory injury, yet the role of spinal PKCγ in short- and long-lasting pain behavior is poorly understood. OBJECTIVE: This study aimed to characterize the contribution of spinal PKCγ to spontaneous pain and long-lasting bilateral hyperalgesia in formalin-induced inflamed mice using pharmacological inhibition. STUDY DESIGN: Laboratory animal study. SETTING: The study was performed in the Department of Human Anatomy and K.K. Leung Brain Research Centre, Preclinical School of Medicine, the Fourth Military Medical University (Xi'an, China) and the Department of Anesthesiology, Fuzhou General Hospital (Fuzhou, China). METHODS: Male mice were unilaterally intraplantarly injected with formalin to induce inflammatory pain. Spontaneous pain behaviors, including flinches and lickings, were recorded by off-line video during the first hour post-injection and counted. Using von Frey tests, long-lasting bilateral mechanical paw withdrawal thresholds were determined before injection and at indicated time points thereafter. Temporal expression of spinal PKCγ was observed by immunohistochemical staining. For pharmacological inhibition, mice were treated daily with intrathecal Tat carrier or selective PKCγ inhibitor KIG31-1, from 1 hour prior to 10 days after formalin injection. Spontaneous pain behaviors and long-lasting bilateral mechanical hyperalgesia were assessed. Spinal PKCγ expression was also observed by using immunohistochemical staining and western blot. RESULTS: The number of PKCγ-immunoreactive (ir) spinal neurons was significantly higher at 10 days, but not 2 hours, after formalin intraplantar injection, and accompanied by long-lasting bilateral hyperalgesia. Furthermore, long-lasting bilateral hyperalgesia could be reversed by pharmacological inhibition of over-expressed spinal PKCγ; however, pretreating with intrathecal KIG31-1 showed no antinociceptive effects on short-term spontaneous pain behaviors. LIMITATIONS: All results were obtained from the mice and no PKCγ inhibitors were available through clinical practice. Therefore, it remains difficult to draw definitive connections between animal research and human application. CONCLUSION: Our findings suggest that spinal PKCγ plays a predominant role in long-lasting bilateral hyperalgesia, but not in the spontaneous pain behaviors induced by formalin. KEY WORDS: Formalin, spontaneous pain, mechanical hyperalgesia, protein kinase C gamma, KIG31-1, mice.


Assuntos
Dor Crônica/enzimologia , Hiperalgesia/enzimologia , Proteína Quinase C/metabolismo , Medula Espinal/enzimologia , Animais , Comportamento Animal/efeitos dos fármacos , China , Dor Crônica/induzido quimicamente , Formaldeído/toxicidade , Hiperalgesia/induzido quimicamente , Masculino , Camundongos , Medição da Dor/métodos , Ratos Sprague-Dawley , Medula Espinal/efeitos dos fármacos
2.
Mol Pain ; 14: 1744806918783943, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29923456

RESUMO

Protein kinase M ζ is well known for its role in maintaining memory and pain. Previously, we revealed that the activation of protein kinase M ζ in the anterior cingulate cortex plays a role in sustaining neuropathic pain. However, the mechanism by which protein kinase M ζ is expressed in the anterior cingulate cortex by peripheral nerve injury, and whether blocking of protein kinase M ζ using its inhibitor, zeta inhibitory peptide, produces analgesic effects in neuropathic pain maintained chronically after injury, have not previously been resolved. In this study, we show that protein kinase M ζ expression in the anterior cingulate cortex is enhanced by peripheral nerve injury in a transcription-independent manner. We also reveal that the inhibition of protein kinase M ζ through zeta inhibitory peptide treatment is enough to reduce mechanical allodynia responses in mice with one-month-old nerve injuries. However, the zeta inhibitory peptide treatment was only effective for a limited time.


Assuntos
Dor Crônica/enzimologia , Dor Crônica/genética , Giro do Cíngulo/enzimologia , Neuralgia/enzimologia , Neuralgia/genética , Proteína Quinase C/metabolismo , Transcrição Genética , Animais , Dor Crônica/patologia , Giro do Cíngulo/patologia , Lipopeptídeos/farmacologia , Potenciação de Longa Duração , Masculino , Camundongos Endogâmicos C57BL , Neuralgia/patologia , Nervos Periféricos/patologia , Receptores de AMPA , Sinapses/metabolismo , Transcrição Genética/efeitos dos fármacos
3.
Chin J Nat Med ; 16(2): 113-124, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29455726

RESUMO

Due to ineffectiveness and side effects of existing analgesics, chronic pain has become one of the most complex and difficult problems in the clinic. Monoacylglycerol lipase (MAGL) is an essential hydrolase in the endocannabinoid system and has been identified as a potential target for the treatment of pain. In the present study, we designed and synthesized twelve tanshinone IIA analogs and screened their activity against MAGL. Selected compounds were tested for analgesic activity in vivo, with the acetic acid writhing test model. Among the test compounds, compound III-3 (IC50 120 nmol·L-1) showed significant activity against MAGL and ameliorated the clinical progression in the mouse pain model. Additionally, compound III-3, substitution with N-methyl-2-morpholinoacetamide, demonstrated improved solubility relative to tanshinone IIA.


Assuntos
/administração & dosagem , Analgésicos/administração & dosagem , Analgésicos/síntese química , Dor Crônica/tratamento farmacológico , /química , Analgésicos/química , Animais , Dor Crônica/enzimologia , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos ICR , Monoacilglicerol Lipases/antagonistas & inibidores , Monoacilglicerol Lipases/metabolismo , Relação Estrutura-Atividade
4.
PLoS Biol ; 16(2): e2003452, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29444090

RESUMO

Chronic pain is a debilitating problem, and insights in the neurobiology of chronic pain are needed for the development of novel pain therapies. A genome-wide association study implicated the 5p15.2 region in chronic widespread pain. This region includes the coding region for FAM173B, a functionally uncharacterized protein. We demonstrate here that FAM173B is a mitochondrial lysine methyltransferase that promotes chronic pain. Knockdown and sensory neuron overexpression strategies showed that FAM173B is involved in persistent inflammatory and neuropathic pain via a pathway dependent on its methyltransferase activity. FAM173B methyltransferase activity in sensory neurons hyperpolarized mitochondria and promoted macrophage/microglia activation through a reactive oxygen species-dependent pathway. In summary, we uncover a role for methyltransferase activity of FAM173B in the neurobiology of pain. These results also highlight FAM173B methyltransferase activity as a potential therapeutic target to treat debilitating chronic pain conditions.


Assuntos
Dor Crônica/enzimologia , Histona-Lisina N-Metiltransferase/metabolismo , Animais , Cromossomos Humanos Par 5 , Dor Crônica/genética , Feminino , Técnicas de Silenciamento de Genes , Estudo de Associação Genômica Ampla , Células HEK293 , Histona-Lisina N-Metiltransferase/genética , Humanos , Masculino , Camundongos Endogâmicos C57BL , Microglia/metabolismo , Polimorfismo de Nucleotídeo Único , Espécies Reativas de Oxigênio/metabolismo
5.
J Pharmacol Exp Ther ; 363(2): 176-183, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28855373

RESUMO

Chronic pain, often defined as any pain lasting more than 3 months, is poorly managed because of its multifaceted and complex mechanisms. Calcium/calmodulin-dependent protein kinase II (CaMKII) is a multifunctional serine/threonine kinase that plays a fundamental role in synaptic plasticity, learning, and memory. Recent emerging evidence demonstrates increased expression and activity of CaMKII in the spinal cord and dorsal root ganglia of various chronic pain models. Moreover, our previous studies also find that inhibiting CaMKII could attenuate inflammatory pain and neuropathic pain. In this review, we provide evidence for the involvement of CaMKII in the initiation and development of chronic pain, including neuropathic pain, bone cancer pain, and inflammatory pain. Novel CaMKII inhibitors with potent inhibitory effect and high specificity may be alternative therapeutic strategies for the management of chronic pain in the future.


Assuntos
Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Dor Crônica/enzimologia , Dor Crônica/patologia , Animais , Neoplasias Ósseas/complicações , Dor Crônica/etiologia , Humanos , Neuralgia/enzimologia , Neuralgia/patologia
6.
Mol Pain ; 13: 1744806917733637, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28952414

RESUMO

Background Lumbar disc herniation is a major cause of radicular pain, but the underlying mechanisms remain largely unknown. Spinal activation of src-family kinases are involved in the development of chronic pain from nerve injury, inflammation, and cancer. In the present study, the role of src-family kinases activation in lumbar disc herniation-induced radicular pain was investigated. Results Lumbar disc herniation was induced by implantation of autologous nucleus pulposus, harvest from tail, in lumbar 4/5 spinal nerve roots of rat. Behavior test and electrophysiologic data showed that nucleus pulposus implantation induced persistent mechanical allodynia and thermal hyperalgesia and increased efficiency of synaptic transmission in spinal dorsal horn which underlies central sensitization of pain sensation. Western blotting and immunohistochemistry staining revealed that the expression of phosphorylated src-family kinases was upregulated mainly in spinal microglia of rats with nucleus pulposus. Intrathecal delivery of src-family kinases inhibitor PP2 alleviated pain behaviors, decreased efficiency of spinal synaptic transmission, and reduced phosphorylated src-family kinases expression. Furthermore, we found that the expression of ionized calcium-binding adapter molecule 1 (marker of microglia), tumor necrosis factor-α, interleukin 1 -ß in spinal dorsal horn was increased in rats with nucleus pulposus. Therapeutic effect of PP2 may be related to its capacity in reducing the expression of these factors. Conclusions These findings suggested that central sensitization was involved in radicular pain from lumbar disc herniation; src-family kinases-mediated inflammatory response may be responsible for central sensitization and chronic pain after lumbar disc herniation.


Assuntos
Dor Crônica/complicações , Dor Crônica/enzimologia , Deslocamento do Disco Intervertebral/complicações , Deslocamento do Disco Intervertebral/enzimologia , Vértebras Lombares/patologia , Microglia/enzimologia , Quinases da Família src/metabolismo , Potenciais de Ação/efeitos dos fármacos , Animais , Comportamento Animal , Dor Crônica/fisiopatologia , Ativação Enzimática/efeitos dos fármacos , Hiperalgesia/complicações , Hiperalgesia/patologia , Interleucina-1beta/metabolismo , Deslocamento do Disco Intervertebral/fisiopatologia , Vértebras Lombares/efeitos dos fármacos , Vértebras Lombares/fisiopatologia , Masculino , Microglia/efeitos dos fármacos , Núcleo Pulposo/transplante , Fosforilação/efeitos dos fármacos , Pirimidinas/farmacologia , Ratos Sprague-Dawley , Corno Dorsal da Medula Espinal/efeitos dos fármacos , Corno Dorsal da Medula Espinal/patologia , Corno Dorsal da Medula Espinal/fisiopatologia , Fator de Necrose Tumoral alfa/metabolismo , Regulação para Cima/efeitos dos fármacos
7.
J Neuroinflammation ; 14(1): 168, 2017 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-28835277

RESUMO

BACKGROUND: A subset of osteoarthritis (OA) patients experience joint pain with neuropathic characteristics. Mediators such as neutrophil elastase, a serine proteinase, may be released during acute OA inflammatory flares. We have previously shown that local administration of neutrophil elastase causes joint inflammation and pain via activation of proteinase-activated receptor-2 (PAR2). The aim of this study was to examine the contribution of endogenous neutrophil elastase and PAR2 to the development of joint inflammation, pain, and neuropathy associated with monoiodoacetate (MIA)-induced experimental OA. METHODS: MIA (0.3 mg/10 µl) was injected into the right knee joint of male C57BL/6 mice (20-34 g). Joint inflammation (edema, leukocyte kinetics), neutrophil elastase proteolytic activity, tactile allodynia, and saphenous nerve demyelination were assessed over 14 days post-injection. The effects of inhibiting neutrophil elastase during the early inflammatory phase of MIA (days 0 to 3) were determined using sivelestat (50 mg/kg i.p.) and serpinA1 (10 µg i.p.). Involvement of PAR2 in the development of MIA-induced joint inflammation and pain was studied using the PAR2 antagonist GB83 (5 µg i.p. days 0 to 1) and PAR2 knockout animals. RESULTS: MIA caused an increase in neutrophil elastase proteolytic activity on day 1 (P < 0.0001), but not on day 14. MIA also generated a transient inflammatory response which peaked on day 1 (P < 0.01) then subsided over the 2-week time course. Joint pain appeared on day 1 and persisted to day 14 (P < 0.0001). By day 14, the saphenous nerve showed signs of demyelination. Early treatment with sivelestat and serpinA1 blocked the proteolytic activity of neutrophil elastase on day 1 (P < 0.001), and caused lasting improvements in joint inflammation, pain, and saphenous nerve damage (P < 0.05). MIA-induced synovitis was reversed by early treatment with GB83 and attenuated in PAR2 knockout mice (P < 0.05). PAR2 knockout mice also showed reduced MIA-induced joint pain (P < 0.0001) and less nerve demyelination (P = 0.81 compared to saline control). CONCLUSIONS: Neutrophil elastase and PAR2 contribute significantly to the development of joint inflammation, pain, and peripheral neuropathy associated with experimental OA, suggesting their potential as therapeutic targets.


Assuntos
Dor Crônica/enzimologia , Elastase de Leucócito/antagonistas & inibidores , Neuralgia/enzimologia , Osteoartrite/enzimologia , Profilaxia Pré-Exposição/métodos , Inibidores de Serino Proteinase/administração & dosagem , Animais , Dor Crônica/diagnóstico por imagem , Dor Crônica/prevenção & controle , Glicina/administração & dosagem , Glicina/análogos & derivados , Elastase de Leucócito/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neuralgia/diagnóstico por imagem , Neuralgia/prevenção & controle , Osteoartrite/diagnóstico por imagem , Osteoartrite/tratamento farmacológico , Sulfonamidas/administração & dosagem
8.
Mol Pain ; 13: 1744806917726713, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28849714

RESUMO

Chronic pain with comorbid emotional disorders is a prevalent neurological disease in patients under various pathological conditions, yet patients show considerable difference in their vulnerability to developing chronic pain. Understanding the neurobiological basis underlying this pain vulnerability is essential to develop targeted therapies of higher efficiency in pain treatment of precision medicine. However, this pain vulnerability has not been addressed in preclinical pain research in animals to date. In this study, we investigated individual variance in both sensory and affective/emotional dimensions of pain behaviors in response to chronic neuropathic pain condition in a mouse model of chronic pain. We found that mice displayed considerably diverse sensitivities in the chronic pain-induced anxiety- and depression-like behaviors of affective pain. Importantly, the mouse group that was more vulnerable to developing anxiety was also more vulnerable to developing depressive behavior under the chronic pain condition. In contrast, there was relatively much less variance in individual responses in the sensory dimension of pain sensitization. Molecular analysis revealed that those mice vulnerable to developing the emotional disorders showed a significant reduction in the protein level of DNA methyltransferase 3a in the emotion-processing central nucleus of the amygdala. In addition, social stress also revealed significant individual variance in anxiety behavior in mice. These findings suggest that individual pain vulnerability may be inherent mostly in the emotional/affective component of chronic pain and remain consistent in different aspects of negative emotion, in which adaptive changes in the function of DNA methyltransferase 3a for DNA methylation in central amygdala may play an important role. This may open a new avenue of basic research into the neurobiological mechanisms underlying pain vulnerability.


Assuntos
Dor Crônica/enzimologia , DNA (Citosina-5-)-Metiltransferases/metabolismo , Tonsila do Cerebelo/patologia , Animais , Ansiedade/complicações , Comportamento Animal , Depressão/complicações , Masculino , Camundongos Endogâmicos C57BL , Tecido Nervoso/lesões , Neuralgia/enzimologia , Estresse Psicológico/complicações
9.
Neuropharmacology ; 125: 284-294, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28669900

RESUMO

Central sensitization represents a key mechanism mediating chronic pain, a major clinical problem lacking effective treatment options. LIM-domain kinases (LIMKs) selectively regulate several substrates, e.g. cofilin and cAMP response element-binding protein (CREB), that profoundly affect neural activities, such as synaptogenesis and gene expression, thus critical in the consolidation of long-term synaptic potentiation and memory in the brain. In this study, we demonstrate that LIMK deficiency significantly impaired the development of multiple forms of chronic pain. Mechanistic studies focusing on spared nerve injury (SNI) model reveal a pivotal role of LIMKs in the up-regulation of spontaneous excitatory synaptic transmission and synaptogenesis after pain induction. Depending on the pain induction methods, LIMKs can be transiently activated with distinct time courses. Accordingly, pharmacological inhibition of LIMKs targeting this critical period remarkably attenuated central sensitization in the spinal cord and alleviated pain behaviors. We propose selectively targeting LIMKs during their activation phase as a potential therapeutic strategy for clinical management of chronic pain, especially for chronic pain with predictable onset and development time courses, such as chronic post-surgical pain (PSP).


Assuntos
Sensibilização do Sistema Nervoso Central/fisiologia , Dor Crônica/prevenção & controle , Quinases Lim/antagonistas & inibidores , Quinases Lim/fisiologia , Medula Espinal/enzimologia , Fatores de Despolimerização de Actina/metabolismo , Animais , Dor Crônica/enzimologia , Dor Crônica/patologia , Modelos Animais de Doenças , Adjuvante de Freund , Temperatura Alta , Hiperalgesia/enzimologia , Hiperalgesia/patologia , Hiperalgesia/prevenção & controle , Quinases Lim/deficiência , Quinases Lim/genética , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neuralgia/enzimologia , Neuralgia/patologia , Neuralgia/prevenção & controle , Distribuição Aleatória , Medula Espinal/efeitos dos fármacos , Medula Espinal/patologia , Sinapses/efeitos dos fármacos , Sinapses/enzimologia , Sinapses/patologia , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/fisiologia , Técnicas de Cultura de Tecidos
10.
Biol Psychiatry ; 82(5): 370-379, 2017 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-28359564

RESUMO

BACKGROUND: Depression is frequently associated with chronic pain or chronic stress. Among cortical areas, the anterior cingulate cortex (ACC, areas 24a and 24b) appears to be important for mood disorders and constitutes a neuroanatomical substrate for investigating the underlying molecular mechanisms. The current work aimed at identifying ACC molecular factors subserving depression. METHODS: Anxiodepressive-like behaviors in C57BL/6J male mice were induced by neuropathic pain, unpredictable chronic mild stress, and optogenetic ACC stimulation and were evaluated using novelty suppressed feeding, splash, and forced swim tests. ACC molecular changes in chronic pain-induced depression were uncovered through whole-genome expression analysis. Further mechanistic insights were provided by chromatin immunoprecipitation, Western blot, and immunostaining. The causal link between molecular changes and depression was studied using knockout, pharmacological antagonism, and local viral-mediated gene knockdown. RESULTS: Under chronic pain-induced depression, gene expression changes in the ACC highlighted the overexpression of a regulator of the mitogen-activated protein kinase pathway, mitogen-activated protein kinase phosphatase-1 (MKP-1). This upregulation is associated with the presence of transcriptionally active chromatin marks (acetylation) at its proximal promoter region as well as increased cyclic adenosine monophosphate response element-mediated transcriptional activity and phosphorylation of cyclic adenosine monophosphate response element binding protein and activating transcription factor. MKP-1 overexpression is also observed with unpredictable chronic mild stress and repeated ACC optogenetic stimulation and is reversed by fluoxetine. A knockout, an antagonist, or a local silencing of MKP-1 attenuates depressive-like behaviors, pointing to an important role of this phosphatase in depression. CONCLUSIONS: These data point to ACC MKP-1 as a key factor in the pathophysiology of depression and a potential target for treatment development.


Assuntos
Transtorno Depressivo/enzimologia , Fosfatase 1 de Especificidade Dupla/metabolismo , Giro do Cíngulo/enzimologia , Animais , Antidepressivos de Segunda Geração/farmacologia , Dor Crônica/enzimologia , Transtorno Depressivo/tratamento farmacológico , Modelos Animais de Doenças , Fosfatase 1 de Especificidade Dupla/genética , Epigênese Genética , Fluoxetina/farmacologia , Expressão Gênica/efeitos dos fármacos , Giro do Cíngulo/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Regiões Promotoras Genéticas , Proteínas Proto-Oncogênicas c-fos/metabolismo , Estresse Psicológico/tratamento farmacológico , Estresse Psicológico/enzimologia , Regulação para Cima/efeitos dos fármacos
11.
Behav Brain Res ; 326: 69-76, 2017 05 30.
Artigo em Inglês | MEDLINE | ID: mdl-28259677

RESUMO

The soluble epoxide hydrolase (sEH) is a regulatory enzyme responsible for the metabolism of bioactive lipid epoxides of both omega-6 and omega-3 long chain polyunsaturated fatty acids. These natural epoxides mediate cell signaling in several physiological functions including blocking inflammation, high blood pressure and both inflammatory and neuropathic pain. Inhibition of the sEH maintains the level of endogenous bioactive epoxy-fatty acids (EpFA) and allows them to exert their generally beneficial effects. The Akita (Ins2Akita or Ins2C96Y) mice represent a maturity-onset of diabetes of the young (MODY) model in lean, functionally unimpaired animals, with a sexually dimorphic disease phenotype. This allowed for a test of male and female mice in a battery of functional and nociceptive assays to probe the role of sEH in this system. The results demonstrate that inhibiting the sEH is analgesic in diabetic neuropathy and this occurs in a sexually dimorphic manner. Interestingly, sEH activity is also sexually dimorphic in the Akita model, and moreover correlates with disease status particularly in the hearts of male mice. In addition, in vivo levels of oxidized lipid metabolites also correlate with increased sEH expression and the pathogenesis of disease in this model. Thus, sEH is a target to effectively block diabetic neuropathic pain but also demonstrates a potential role in mitigating the progression of this disease.


Assuntos
Benzoatos/farmacologia , Dor Crônica/enzimologia , Nefropatias Diabéticas/enzimologia , Epóxido Hidrolases/antagonistas & inibidores , Ácidos Graxos/metabolismo , Neuralgia/enzimologia , Compostos de Fenilureia/farmacologia , Animais , Benzoatos/administração & dosagem , Dor Crônica/tratamento farmacológico , Nefropatias Diabéticas/sangue , Nefropatias Diabéticas/tratamento farmacológico , Modelos Animais de Doenças , Epóxido Hidrolases/efeitos dos fármacos , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neuralgia/sangue , Neuralgia/tratamento farmacológico , Compostos de Fenilureia/administração & dosagem , Caracteres Sexuais
12.
Curr Pharm Des ; 23(12): 1860-1868, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28190392

RESUMO

Chronic pain is among the most disabling and costly disorders, with prevalence ranging from 10% to 55%. However, current therapeutic strategies for chronic pain are unsatisfactory due to our poor understanding of its mechanisms. Thus, novel therapeutic targets need to be found in order to improve these patients' quality of life. PI3K and its downstream Akt are widely expressed in the spinal cord, particularly in the laminae I-IV of the dorsal horn, where nociceptive C and Aδ fibers of primary afferents principally terminate. Recent studies have demonstrated their critical roles in the development and maintenance of chronic pain. In this review, we summarized the roles and mechanisms of PI3K/Akt pathway in the progression of chronic pain through sciatic nerve injury, diabetic neuropathy, spinal cord injury, bone cancer, opioid tolerance, or opioid-induced hyperalgesia.


Assuntos
Dor Crônica/tratamento farmacológico , Dor Crônica/enzimologia , Proteína Oncogênica v-akt/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Animais , Humanos
13.
J Pain ; 18(5): 490-498, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28065813

RESUMO

Pain in sickle cell disease (SCD) is associated with increased morbidity, mortality, and high health care costs. Although episodic acute pain is the hallmark of this disorder, there is an increasing awareness that chronic pain is part of the pain experience of many older adolescents and adults. A common set of criteria for classifying chronic pain associated with SCD would enhance SCD pain research efforts in epidemiology, pain mechanisms, and clinical trials of pain management interventions, and ultimately improve clinical assessment and management. As part of the collaborative effort between the Analgesic, Anesthetic, and Addiction Clinical Trial Translations Innovations Opportunities and Networks public-private partnership with the U.S. Food and Drug Administration and the American Pain Society, the Analgesic, Anesthetic, and Addiction Clinical Trial Translations Innovations Opportunities and Networks-American Pain Society Pain Taxonomy initiative developed the outline of an optimal diagnostic system for chronic pain conditions. Subsequently, a working group of experts in SCD pain was convened to generate core diagnostic criteria for chronic pain associated with SCD. The working group synthesized available literature to provide evidence for the dimensions of this disease-specific pain taxonomy. A single pain condition labeled chronic SCD pain was derived with 3 modifiers reflecting different clinical features. Future systematic research is needed to evaluate the feasibility, validity, and reliability of these criteria. PERSPECTIVE: An evidence-based classification system for chronic SCD pain was constructed for the Analgesic, Anesthetic, and Addiction Clinical Trial Translations Innovations Opportunities and Networks-American Pain Society Pain Taxonomy initiative. Applying this taxonomy may improve assessment and management of SCD pain and accelerate research on epidemiology, mechanisms, and treatments for chronic SCD pain.


Assuntos
Anemia Falciforme/complicações , Dor Crônica/diagnóstico , Dor Crônica/etiologia , Medição da Dor/métodos , Medição da Dor/normas , Sociedades Médicas/normas , Anemia Falciforme/epidemiologia , Dor Crônica/enzimologia , Medicina Baseada em Evidências , Humanos , Parcerias Público-Privadas , Estados Unidos , United States Food and Drug Administration/normas
14.
Exp Suppl ; 107: 257-285, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27812984

RESUMO

Chronic pain is a major clinical problem that is poorly treated with available therapeutics. Adenosine monophosphate-activated protein kinase (AMPK) has recently emerged as a novel target for the treatment of pain with the exciting potential for disease modification. AMPK activators inhibit signaling pathways that are known to promote changes in the function and phenotype of peripheral nociceptive neurons and promote chronic pain. AMPK activators also reduce the excitability of these cells suggesting that AMPK activators may be efficacious for the treatment of chronic pain disorders, like neuropathic pain, where changes in the excitability of nociceptors is thought to be an underlying cause. In agreement with this, AMPK activators have now been shown to alleviate pain in a broad variety of preclinical pain models indicating that this mechanism might be engaged for the treatment of many types of pain in the clinic. A key feature of the effect of AMPK activators in these models is that they can lead to a long-lasting reversal of pain hypersensitivity even long after treatment cessation, indicative of disease modification. Here, we review the evidence supporting AMPK as a novel pain target pointing out opportunities for further discovery that are likely to have an impact on drug discovery efforts centered around potent and specific allosteric activators of AMPK for chronic pain treatment.


Assuntos
Proteínas Quinases Ativadas por AMP/genética , Analgésicos/uso terapêutico , Dor Crônica/tratamento farmacológico , Neuropatias Diabéticas/tratamento farmacológico , Neoplasias/tratamento farmacológico , Neuralgia/tratamento farmacológico , Proteínas Quinases Ativadas por AMP/metabolismo , Dor Crônica/enzimologia , Dor Crônica/genética , Dor Crônica/patologia , Neuropatias Diabéticas/enzimologia , Neuropatias Diabéticas/genética , Neuropatias Diabéticas/patologia , Ativação Enzimática/efeitos dos fármacos , Regulação da Expressão Gênica , Humanos , Inflamação , Canais Iônicos/genética , Canais Iônicos/metabolismo , Terapia de Alvo Molecular , Morfina/uso terapêutico , Neoplasias/enzimologia , Neoplasias/genética , Neoplasias/patologia , Neuralgia/enzimologia , Neuralgia/genética , Neuralgia/patologia , Nociceptores/efeitos dos fármacos , Nociceptores/enzimologia , Nociceptores/patologia , Subunidades Proteicas/genética , Subunidades Proteicas/metabolismo , Transdução de Sinais
15.
Nat Genet ; 48(12): 1564-1569, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27749843

RESUMO

Elevated basal serum tryptase levels are present in 4-6% of the general population, but the cause and relevance of such increases are unknown. Previously, we described subjects with dominantly inherited elevated basal serum tryptase levels associated with multisystem complaints including cutaneous flushing and pruritus, dysautonomia, functional gastrointestinal symptoms, chronic pain, and connective tissue abnormalities, including joint hypermobility. Here we report the identification of germline duplications and triplications in the TPSAB1 gene encoding α-tryptase that segregate with inherited increases in basal serum tryptase levels in 35 families presenting with associated multisystem complaints. Individuals harboring alleles encoding three copies of α-tryptase had higher basal serum levels of tryptase and were more symptomatic than those with alleles encoding two copies, suggesting a gene-dose effect. Further, we found in two additional cohorts (172 individuals) that elevated basal serum tryptase levels were exclusively associated with duplication of α-tryptase-encoding sequence in TPSAB1, and affected individuals reported symptom complexes seen in our initial familial cohort. Thus, our findings link duplications in TPSAB1 with irritable bowel syndrome, cutaneous complaints, connective tissue abnormalities, and dysautonomia.


Assuntos
Dor Crônica/genética , Doenças do Tecido Conjuntivo/genética , Variações do Número de Cópias de DNA/genética , Disautonomia Familiar/genética , Gastroenteropatias/genética , Prurido/genética , Dermatopatias/genética , Triptases/sangue , Triptases/genética , Adolescente , Adulto , Idoso , Criança , Dor Crônica/sangue , Dor Crônica/enzimologia , Doenças do Tecido Conjuntivo/sangue , Doenças do Tecido Conjuntivo/enzimologia , Disautonomia Familiar/sangue , Disautonomia Familiar/enzimologia , Feminino , Gastroenteropatias/sangue , Gastroenteropatias/enzimologia , Humanos , Masculino , Pessoa de Meia-Idade , Prurido/sangue , Prurido/enzimologia , Dermatopatias/sangue , Dermatopatias/enzimologia , Adulto Jovem
16.
J Dent Res ; 95(10): 1124-31, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27307048

RESUMO

Microglia are the resident immune cells in the spinal cord and brain. Mounting evidence suggests that activation of microglia plays an important role in the pathogenesis of chronic pain, including chronic orofacial pain. In particular, microglia contribute to the transition from acute pain to chronic pain, as inhibition of microglial signaling reduces pathologic pain after inflammation, nerve injury, and cancer but not baseline pain. As compared with inflammation, nerve injury induces much more robust morphologic activation of microglia, termed microgliosis, as shown by increased expression of microglial markers, such as CD11b and IBA1. However, microglial signaling inhibitors effectively reduce inflammatory pain and neuropathic pain, arguing against the importance of morphologic activation of microglia in chronic pain sensitization. Importantly, microglia enhance pain states via secretion of proinflammatory and pronociceptive mediators, such as tumor necrosis factor α, interleukins 1ß and 18, and brain-derived growth factor. Mechanistically, these mediators have been shown to enhance excitatory synaptic transmission and suppress inhibitory synaptic transmission in the pain circuits. While early studies suggested a predominant role of microglia in the induction of chronic pain, further studies have supported a role of microglia in the maintenance of chronic pain. Intriguingly, recent studies show male-dominant microglial signaling in some neuropathic pain and inflammatory pain states, although both sexes show identical morphologic activation of microglia after nerve injury. In this critical review, we provide evidence to show that caspase 6-a secreted protease that is expressed in primary afferent axonal terminals surrounding microglia-is a robust activator of microglia and induces profound release of tumor necrosis factor α from microglia via activation of p38 MAP kinase. The authors also show that microglial caspase 6/p38 signaling is male dominant in some inflammatory and neuropathic pain conditions. Finally, the authors discuss the relevance of microglial signaling in chronic trigeminal and orofacial pain.


Assuntos
Caspase 6/metabolismo , Dor Crônica/enzimologia , Dor Facial/enzimologia , Microglia/fisiologia , Transdução de Sinais/fisiologia , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Dor Crônica/imunologia , Dor Facial/imunologia , Feminino , Humanos , Masculino , Microglia/enzimologia , Microglia/imunologia , Fatores Sexuais , Transdução de Sinais/imunologia
17.
Brain Res Bull ; 125: 44-52, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27090944

RESUMO

Chronic pain is a complex clinical condition that reduces the quality of life for billions of people. In recent years, the role of epigenetic modulation in the control of long-term neuronal plasticity has attracted the attention of pain researchers. The epigenetic mechanisms include covalent modifications of DNA and/or histone proteins. Mounting evidence suggests that the activity of histone deacetylases (HDACs) and levels of histone acetylation are dynamic and that these enzymes modulate pain-related synaptic plasticity. Therefore, HDACs play essential roles in chronic pain development and maintenance. In this mini review, we will discuss the role of HDACs in the pathogenesis of chronic pain and will consider the therapeutic value of HDAC inhibitors in treating chronic pain.


Assuntos
Dor Crônica/tratamento farmacológico , Inibidores de Histona Desacetilases/uso terapêutico , Animais , Dor Crônica/enzimologia , Histona Desacetilases/metabolismo , Humanos
18.
Postgrad Med ; 128(1): 18-22, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26635137

RESUMO

OBJECTIVE: To identify possible underlying causes of poor oral opioid effectiveness. METHODS: Ninety-five (95) adults who were referred for evaluation and medical management of their intractable pain were screened to determine if oral opioids provided enough pain relief to physically and mentally function and carry out activities of daily living. A clinical evaluation included history, physical examination, cytochrome P450 enzyme testing and a hydromorphone injection to help confirm lack of oral opioid effectiveness. RESULTS: Twenty (20; 21.1%) of the 95 patients reported that three or more oral opioids had not provided enough pain relief to allow them to mentally and physically function and carry out activities of daily living. Patients all reported some typical symptoms of malabsorption including nausea and steatorrhea, and 14 (70.0%) reported that they had observed undigested medication in their stools. Fifteen (15; 75.0%) had experienced pain relief with an injectable opioid. Two major causes for lack of oral opioid effectiveness were apparent: (1) gastrointestinal disorder (11; 55.0%) and (2) cytochrome P450 enzymatic defects (9; 45.0%). In addition to these basic causes, a number of other possible contributing factors were identified which included abdominal, pelvic and spine surgeries, traumatic brain and neck injury, and autoimmune disorders. CONCLUSIONS: There is a group of intractable pain patients who do not effectively metabolize oral opioids. Although gastrointestinal disease and cytochrome P450 enzymatic defects appeared to be dominant causes of oral opioid ineffectiveness, there were other possible contributing factors such as abdominal, pelvic and spine surgeries, head and neck trauma, and autoimmune disease. Pain patients who report poor oral opioid effectiveness should be evaluated for the presence of underlying pathologic conditions which may interfere with oral opioid metabolism and, if found, be considered for nonoral opioid treatment.


Assuntos
Analgésicos Opioides/administração & dosagem , Dor Crônica/tratamento farmacológico , Sistema Enzimático do Citocromo P-450/metabolismo , Gastroenteropatias/complicações , Administração Oral , Adulto , Idoso , Analgésicos Opioides/metabolismo , Analgésicos Opioides/uso terapêutico , Biomarcadores/metabolismo , Dor Crônica/complicações , Dor Crônica/diagnóstico , Dor Crônica/enzimologia , Feminino , Gastroenteropatias/diagnóstico , Humanos , Injeções Subcutâneas , Síndromes de Malabsorção/complicações , Síndromes de Malabsorção/diagnóstico , Masculino , Pessoa de Meia-Idade , Medição da Dor , Resultado do Tratamento
19.
Pain ; 156 Suppl 1: S2-10, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25789432

RESUMO

Existing analgesics are not efficacious in treating all patients with chronic pain and have harmful side effects when used long term. A deeper understanding of pain signaling and sensitization could lead to the development of more efficacious analgesics. Nociceptor sensitization occurs under conditions of inflammation and nerve injury where diverse chemicals are released and signal through receptors to reduce the activation threshold of ion channels, leading to an overall increase in neuronal excitability. Drugs that inhibit specific receptors have so far been unsuccessful in alleviating pain, possibly because they do not simultaneously target the diverse receptors that contribute to nociceptor sensitization. Hence, the focus has shifted toward targeting downstream convergence points of nociceptive signaling. Lipid mediators, including phosphatidylinositol 4,5-bisphosphate (PIP2), are attractive targets, as these molecules are required for signaling downstream of G-protein-coupled receptors and receptor tyrosine kinases. Furthermore, PIP2 regulates the activity of various ion channels. Thus, PIP2 sits at a critical convergence point for multiple receptors, ion channels, and signaling pathways that promote and maintain chronic pain. Decreasing the amount of PIP2 in neurons was recently shown to attenuate pronociceptive signaling and could provide a novel approach for treating pain. Here, we review the lipid kinases that are known to regulate pain signaling and sensitization and speculate on which additional lipid kinases might regulate signaling in nociceptive neurons.


Assuntos
Dor Crônica/enzimologia , Dor Crônica/terapia , Metabolismo dos Lipídeos/efeitos dos fármacos , Nociceptividade/efeitos dos fármacos , Fosfotransferases/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Humanos
20.
Biomed Res Int ; 2015: 394257, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25685786

RESUMO

Chronic pain represents a major public health problem worldwide. Current pharmacological treatments for chronic pain syndromes, including neuropathic pain, are only partially effective, with significant pain relief achieved in 40-60% of patients. Recent studies suggest that the mammalian target of rapamycin (mTOR) kinase and downstream effectors may be implicated in the development of chronic inflammatory, neuropathic, and cancer pain. The expression and activity of mTOR have been detected in peripheral and central regions involved in pain transmission. mTOR immunoreactivity was found in primary sensory axons, in dorsal root ganglia (DRG), and in dorsal horn neurons. This kinase is a master regulator of protein synthesis, and it is critically involved in the regulation of several neuronal functions, including the synaptic plasticity that is a major mechanism leading to the development of chronic pain. Enhanced activation of this pathway is present in different experimental models of chronic pain. Consistently, pharmacological inhibition of the kinase activity turned out to have significant antinociceptive effects in several experimental models of inflammatory and neuropathic pain. We will review the main evidence from animal and human studies supporting the hypothesis that mTOR may be a novel pharmacological target for the management of chronic pain.


Assuntos
Dor Crônica , Gânglios Espinais/enzimologia , Neuralgia , Manejo da Dor , Células Receptoras Sensoriais/enzimologia , Serina-Treonina Quinases TOR/metabolismo , Animais , Dor Crônica/tratamento farmacológico , Dor Crônica/enzimologia , Humanos , Neuralgia/tratamento farmacológico , Neuralgia/enzimologia , Serina-Treonina Quinases TOR/antagonistas & inibidores
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