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1.
Anesth Analg ; 129(4): e118-e121, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-29916862

RESUMO

Oxytocin has known antinociceptive effects and is upregulated perinatally. This pilot study investigated the association of plasma oxytocin and postcesarean incisional pain. Plasma samples from 18 patients undergoing elective cesarean delivery were drawn at 1 hour preoperatively and 1 and 24 hours postoperatively and analyzed by using enzyme-linked immunosorbent assay. Pain was assessed at 1 day, 8 weeks, 3 months, and 6 months postoperatively. Incisional pain at 24 hours was inversely correlated with 1- and 24-hour oxytocin levels, with higher plasma oxytocin associated with lower pain (ρ, -0.52 and -0.66; P < .05).


Assuntos
Variação Biológica da População , Cesárea/efeitos adversos , Ocitocina/sangue , Dor Pós-Operatória/sangue , Adulto , Biomarcadores/sangue , Feminino , Humanos , Dor Pós-Operatória/diagnóstico , Dor Pós-Operatória/etiologia , Dor Pós-Operatória/prevenção & controle , Projetos Piloto , Gravidez , Fatores de Tempo , Regulação para Cima
2.
Anesth Analg ; 122(3): 719-729, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26646348

RESUMO

BACKGROUND: Antidepressant S-duloxetine alleviates intractable pain associated with diabetic peripheral neuropathy and fibromyalgia. It also reduces both acute and persistent pain in various animal models. This study addresses whether the enantiomer, R-duloxetine, and the homolog, N-methyl duloxetine, could act as analgesics and whether they block neuronal Na⁺ channels. METHODS: The rat incision plus extension model on the dorsothoracic skin was applied to evoke postoperative mechanoallodynia and hyperalgesia, measured for 5 days postoperatively by local responses to von Frey filaments. R-Duloxetine and N-methyl duloxetine were administered systemically (intraperitoneal) or locally (subcutaneous [SC]) 1 hour before the surgery. The block of Na currents in rat neuronal GH3 cells was determined under the whole-cell configuration. RESULTS: Ipsilateral SC injections (2 mg/0.4 mL) of R-duloxetine and N-methyl duloxetine reduced both postoperative allodynia and hyperalgesia by approximately 89% to 99% in the area under the curve of skin responses next to incision over 5 days. Systemic intraperitoneal injections at a higher dosage (10 mg) had smaller analgesic effects (reduced by approximately 53%-69%), whereas contralateral SC injections (10 mg) were ineffective. Both R-duloxetine and N-methyl duloxetine blocked neuronal Na⁺ currents, with a higher affinity for the inactivated than the resting states. In addition, both drugs elicited significant use-dependent block of Na currents when stimulated at 5 Hz. CONCLUSIONS: R-Duloxetine and N-methyl duloxetine are highly effective against postoperative pain using the skin incision model, and they elicit both tonic and use-dependent block of neuronal Na⁺ channels. Our results suggest that R-duloxetine and N-methyl duloxetine are applicable as novel analgesics.


Assuntos
Analgésicos/farmacologia , Antidepressivos de Segunda Geração/farmacologia , Cloridrato de Duloxetina/análogos & derivados , Cloridrato de Duloxetina/farmacologia , Dor Pós-Operatória/tratamento farmacológico , Animais , Linhagem Celular , Hiperalgesia/tratamento farmacológico , Injeções Intraperitoneais , Injeções Subcutâneas , Masculino , Neurônios/efeitos dos fármacos , Técnicas de Patch-Clamp , Estimulação Física , Hipófise/citologia , Hipófise/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Bloqueadores dos Canais de Sódio/farmacologia
3.
Anal Biochem ; 468: 28-33, 2015 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-25232999

RESUMO

Antibodies are important tools for the study of protein expression but are often used without full validation. In this study, we used Western blots to characterize antibodies targeted to the N or C terminal (NT or CT, respectively) and the second or third intracellular loop (IL2 or IL3, respectively) of the endothelin B receptor (ETB). The IL2-targeted antibody accurately detected endogenous ETB expression in rat brain and cultured rat astrocytes by labeling a 50-kDa band, the expected weight of full-length ETB. However, this antibody failed to detect transfected ETB in HEK293 cultures. In contrast, the NT-targeted antibody accurately detected endogenous ETB in rat astrocyte cultures and transfected ETB in HEK293 cultures by labeling a 37-kDa band but failed to detect endogenous ETB in rat brain. Bands detected by the CT- or IL3-targeted antibody were found to be unrelated to ETB. Our findings show that functional ETB can be detected at 50 or 37kDa on Western blot, with drastic differences in antibody affinity for these bands. The 37-kDa band likely reflects ETB processing, which appears to be dependent on cell type and/or culture condition.


Assuntos
Receptor de Endotelina B/imunologia , Animais , Afinidade de Anticorpos , Especificidade de Anticorpos , Astrócitos/metabolismo , Western Blotting/métodos , Encéfalo/metabolismo , Células Cultivadas , Epitopos/química , Epitopos/imunologia , Células HEK293 , Humanos , Ratos , Receptor de Endotelina B/química , Receptor de Endotelina B/metabolismo , Proteínas Recombinantes/química , Proteínas Recombinantes/imunologia , Proteínas Recombinantes/metabolismo
4.
Anesth Analg ; 120(6): 1375-84, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25902323

RESUMO

BACKGROUND: Postoperative pain is treated incompletely and ineffectively in many circumstances, and chronic postoperative pain causes suffering and diminishes productivity. The objective of this project is to determine whether a recently developed slow-release formulation of bupivacaine was effective in reducing the experimental chronic postoperative pain. METHODS: In male Sprague-Dawley rats (250-300 g body weight), bupivacaine-releasing microspheres (MS-Bupi), containing 60 mg of bupivacaine base, were locally injected (MS-Bupi-L) 2 hours preoperatively into the subcutaneous compartment at the locus for experimental thoracotomy. Hypersensitivity to tactile stimulation was assessed by reductions in the threshold force required to induce a response to von Frey filaments (VFH) applied to the hairy back near the incision/retraction site. Pain behavior was assessed using a Qualitative Hyperalgesia Profile. Control groups included rats receiving the same dose of MS-Bupi but at a distant site on the back (MS-Bupi-D, testing for systemic drug actions) and rats receiving the same mass of microspheres with no drug (MS-Placebo) at the wound site. Rats were tested for 3 days before and 28 days (postoperative days [PODs]) after the procedure. Withdrawal threshold differences, which were the primary outcome measure, among all treatment groups were assessed by the Kruskal-Wallis test, after which pairwise comparisons were made by determining Wilcoxon-Mann-Whitney odds (WMWodds), with Bonferroni correction of the confidence intervals. RESULTS: Microsphere bupivacaine released near the incision reduced the chronic tactile allodynia after thoracotomy. The threshold values during PODs 14 to 28 were different among the 3 treatment groups when examined on PODs 14, 16, 18, 23, 25, and 28 but not on POD21 (P = 0.0603). WMWodds showed that threshold of the MS-Bupi-L group differed from those of the MS-Bupi-D and the MS-Placebo groups for all the tested PODs, whereas the thresholds of the MS-Bupi-D group never differed from those of the MS-Placebo group. Area-under-curve analysis for threshold reductions below baseline, using WMWodds, also showed a reduction during the entire 28 PODs that was greater for the MS-Bupi-L group compared with the MS-Placebo or MS-Bupi-D group. The incidence of intense pain scores by the Qualitative Hyperalgesia Profile analysis was observed in 7 of 8 rats in the MS-Placebo group and in 5 of 8 rats in the MS-Bupi-L group. CONCLUSIONS: Local slow release of bupivacaine subcutaneously from the MS-Bupi formulation suppresses postoperative mechanical hypersensitivity for ≥4 weeks after experimental thoracotomy. Systemic bupivacaine from this treatment has no effect on this hypersensitivity.


Assuntos
Anestésicos Locais/administração & dosagem , Bupivacaína/administração & dosagem , Hiperalgesia/prevenção & controle , Dor Pós-Operatória/prevenção & controle , Toracotomia/efeitos adversos , Animais , Preparações de Ação Retardada , Esquema de Medicação , Hiperalgesia/diagnóstico , Hiperalgesia/etiologia , Masculino , Microesferas , Medição da Dor , Limiar da Dor/efeitos dos fármacos , Dor Pós-Operatória/diagnóstico , Dor Pós-Operatória/etiologia , Cuidados Pré-Operatórios , Ratos Sprague-Dawley , Fatores de Tempo , Tato
5.
Anesth Analg ; 121(2): 532-44, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26049779

RESUMO

BACKGROUND: Duloxetine is an antidepressant effective for major depressive disorder and also the alleviation of pain for patients with diabetic peripheral neuropathy, chronic musculoskeletal pain, and fibromyalgia. How duloxetine works in pain relief remains unknown. In this study, we address whether duloxetine could act as an analgesic via systemic and local applications. METHODS: Efficacies of bupivacaine and duloxetine applied subcutaneously at the incision site against acute postoperative pain were compared after rat skin incision. Contralateral and intraperitoneal injections were used to assess systemic efficacy of duloxetine. Local anesthetic actions were assayed through functional block of the rat sciatic nerve. Inhibition by duloxetine of neuronal Na channels was characterized in rat GH3 cells. RESULTS: Our studies showed that subcutaneous duloxetine (2 mg) reduced hyperalgesia and allodynia for several days after skin incision, whereas subcutaneous bupivacaine (2 mg) did not. Contralaterally injected duloxetine (10 mg) had minimal effects on postoperative pain. Intraperitoneal duloxetine also reduced both allodynia and hyperalgesia, albeit at higher doses (10-20 mg). Duloxetine (2 mg) inhibited motor and nociceptive functions via sciatic nerve block for approximately 24 hours. It also reduced Na currents with 50% inhibitory concentrations of 30.4 ± 1.2 µM and 4.26 ± 0.19 µM (n = 8) for resting and fast-inactivated channels, respectively. Furthermore, duloxetine (10 µM) elicited additional use-dependent block of peak Na currents by approximately 70% when stimulated at 5 Hz. CONCLUSIONS: Our results demonstrate that duloxetine can act as a local anesthetic and an analgesic drug via both local and systemic applications. Because duloxetine inhibits neuronal Na currents with high potency, it may exert its antihyperalgesic effects through inhibition of the spontaneous nerve impulses that result from peripheral injury, encompassing its actions on multiple central nervous system and peripheral targets.


Assuntos
Analgésicos/farmacologia , Procedimentos Cirúrgicos Dermatológicos , Hiperalgesia/prevenção & controle , Dor Pós-Operatória/prevenção & controle , Tiofenos/farmacologia , Administração Cutânea , Analgésicos/administração & dosagem , Anestésicos Locais/farmacologia , Animais , Bupivacaína/farmacologia , Células Cultivadas , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Cloridrato de Duloxetina , Hiperalgesia/diagnóstico , Hiperalgesia/metabolismo , Hiperalgesia/fisiopatologia , Injeções Intraperitoneais , Masculino , Medição da Dor , Dor Pós-Operatória/diagnóstico , Dor Pós-Operatória/metabolismo , Dor Pós-Operatória/fisiopatologia , Hipófise/efeitos dos fármacos , Hipófise/metabolismo , Ratos Sprague-Dawley , Nervo Isquiático/efeitos dos fármacos , Nervo Isquiático/metabolismo , Nervo Isquiático/fisiopatologia , Bloqueadores dos Canais de Sódio/farmacologia , Canais de Sódio/efeitos dos fármacos , Canais de Sódio/metabolismo , Tiofenos/administração & dosagem , Fatores de Tempo
6.
Anesth Analg ; 121(4): 1065-1077, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26218866

RESUMO

BACKGROUND: Contralateral hyperalgesia, occurring after unilateral injury, is usually explained by central sensitization in spinal cord and brain. We previously reported that injection of endothelin-1 (ET-1) into one rat hindpaw induces prolonged mechanical and chemical sensitization of the contralateral hindpaw. Here, we examined the role of contralateral efferent activity in this process. METHODS: ET-1 (2 nmol, 10 µL) was injected subcutaneously into the plantar surface of right (ipsilateral) hindpaw (ILP), and the thermal response latency and mechanical threshold for nocifensive withdrawal were determined by the use of, respectively, plantar radiant heating and von Frey filaments, for both ILP and contralateral hindpaws (CLP). Either paw was anesthetized for 60 minutes by direct injection of bupivacaine (0.25%, 40 µL), 30 minutes before ET-1. Alternatively, the contralateral sciatic nerve was blocked for 6 to 12 hours by percutaneous injection of bupivacaine-releasing microspheres 30 minutes before injection of ET-1. Systemic actions of these bupivacaine formulations were simulated by subcutaneous injection at the nuchal midline. RESULTS: After the injection of ET-1, the mechanical threshold of both ILP and CLP decreased by 2 hours, appeared to be lowest around 24 hours, and recovered through 48 hours to preinjection baseline at 72 hours. These hypersensitive responses were suppressed by bupivacaine injected into the ipsilateral paw before ET-1. Injection of the CLP by bupivacaine also suppressed the hypersensitivity of the CLP at all test times, and that of the ILP, except at 2 hours when it increased the sensitivity. This same pattern of change occurred when the contralateral sciatic nerve was blocked by bupivacaine-releasing microspheres. The systemic actions of these bupivacaine formulations were much smaller and only reached significance at 24 hours post-ET-1. Thermal hypersensitivity after ET-1 injection also occurred in both ILP and CLP and showed the same pattern in response to the 2 contralateral anesthetic procedures. CONCLUSIONS: These results show that efferent transmission through the contralateral innervation into the paw is necessary for contralateral sensitization by ET-1, suggesting that the release of substances by distal nerve endings is involved. The release of substances in the periphery is essential for contralateral sensitization by ET-1 and may also contribute to secondary hyperalgesia, occurring at loci distant from the primary injury, that occurs after surgery or nerve damage.


Assuntos
Endotelina-1/toxicidade , Membro Posterior/efeitos dos fármacos , Temperatura Alta , Hiperalgesia/induzido quimicamente , Neurônios Eferentes/efeitos dos fármacos , Tato , Animais , Endotelina-1/administração & dosagem , Membro Posterior/inervação , Membro Posterior/fisiopatologia , Temperatura Alta/efeitos adversos , Hiperalgesia/fisiopatologia , Injeções Subcutâneas , Masculino , Medição da Dor/efeitos dos fármacos , Medição da Dor/métodos , Ratos , Ratos Sprague-Dawley
8.
Anesth Analg ; 117(3): 717-730, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23921651

RESUMO

BACKGROUND: Acute postoperative pain causes physiological deficits and slows recovery. Reduction of such pain by local anesthetics that are delivered for several days postoperatively is a desirable clinical objective, which is approached by a new formulation and applied in animal studies reported here. METHODS: We subcutaneously injected a new formulation of poly-lactic-co-glycolic acid polymer microspheres, which provides steady drug release for 96+ hours into rats at the dorsal region 2 hours before surgery. A single 1.2-cm-long skin incision was followed by blunt dissection of skin away from the underlying fascia, and closed by 2 sutures, followed by 14 days of testing. Microspheres containing 5, 10, 20, and 40 mg bupivacaine were injected locally 2 hours before surgery; bupivacaine-free microspheres were the vehicle control, and bupivacaine HCl solution (0.5%), the positive control. Mechanical sensitivity was determined by the frequency of local muscle contractions to repeated pokes with nylon monofilaments (von Frey hairs) exerting 4 and 15 g forces, testing, respectively, allodynia and hyperalgesia, and by pinprick. RESULTS: Injection of bupivacaine microspheres (40 mg drug) into intact skin reduced responses to 15 g von Frey hairs for 6 hours and to pinprick for 36 hours. Respective reductions from bupivacaine HCl lasted for 3 and 2 hours. Skin incision and dissection alone caused mechanical allodynia and hyperalgesia for 14 days. Microspheres containing 20 or 40 mg bupivacaine suppressed postoperative hypersensitivity for up to 3 days, reduced integrated allodynia (area under curve of response versus time) over postoperative days 1 to 5 by 51% ± 20% (mean ± SE) and 78% ± 12%, and reduced integrated hyperalgesia by 55% ± 13% and 64% ± 11%, for the respective doses. Five and ten milligrams bupivacaine in microspheres and the 0.5% bupivacaine solution were ineffective in reducing postoperative hypersensitivity, as were 40 mg bupivacaine microspheres injected contralateral to the incision. CONCLUSIONS: Significant suppression of postoperative pain by the slow-release bupivacaine preparation outlasts its anesthetic action on intact skin. These findings demonstrate preventive analgesia and indicate the importance of acute processes in the development of chronic postoperative pain.


Assuntos
Anestésicos Locais/administração & dosagem , Bupivacaína/administração & dosagem , Microesferas , Dor Pós-Operatória/tratamento farmacológico , Pele/efeitos dos fármacos , Anestesia Local , Animais , Comportamento Animal/efeitos dos fármacos , Interpretação Estatística de Dados , Relação Dose-Resposta a Droga , Sistemas de Liberação de Medicamentos , Cabelo , Hiperalgesia/prevenção & controle , Masculino , Medição da Dor , Estimulação Física , Ratos , Ratos Sprague-Dawley , Análise Espectral Raman
9.
Pharmacol Res ; 64(3): 258-67, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21515378

RESUMO

Endothelin-1 (ET-1) is a pain mediator, elevated in skin after injury, which potentiates noxious thermal and mechanical stimuli (hyperalgesia) through the activation of ET(A) (and, perhaps, ET(B)) receptors on pain fibers. Part of the mechanism underlying this effect has recently been shown to involve potentiation of neuronal TRPV1 by PKCɛ. However, the early steps of this pathway, which are recapitulated in HEK 293 cells co-expressing TRPV1 and ET(A) receptors, remain unexplored. To clarify these steps, we investigated the pharmacological profile and signaling properties of native endothelin receptors in immortalized cell lines including HEK 293 and ND7 model sensory neurons. Previously we showed that in ND7/104, a dorsal root ganglia-derived cell line, ET-1 elicits a rise in intracellular calcium ([Ca(2+)](in)) which is blocked by BQ-123, an ET(A) receptor antagonist, but not by BQ-788, an ET(B) receptor antagonist, suggesting that ET(A) receptors mediate this effect. Here we extend these findings to HEK 293T cells. Examination of the expression of ET(A) and ET(B) receptors by RT-PCR and [(125)I]-ET-1 binding experiments confirms the slight predominance of ET(A) receptor binding sites and messenger RNA in both ND7/104 and HEK 293T cells. In addition, selective agonists of the ET(B) receptor (sarafotoxin 6c, BQ-3020 or IRL-1620) do not induce a transient increase in [Ca(2+)](in). Furthermore, reduction of ET(B) mRNA levels by siRNA does not abrogate calcium mobilization by ET-1 in HEK 293T cells, corroborating the lack of an ET(B) receptor role in this response. However, in HEK 293 cells with low endogenous ET(A) mRNA levels, ET-1 does not induce a transient increase in [Ca(2+)](in). Observation of the [Ca(2+)](in) elevation in ND7/104 and HEK 293T cells in the absence of extracellular calcium suggests that ET-1 elicits a release of calcium from intracellular stores, and pretreatment of the cells with pertussis toxin or a selective inhibitor of phospholipase C (PLC) point to a mechanism involving Gαq/11 coupling. These results are consistent with the hypothesis that a certain threshold of ET(A) receptor expression is necessary to drive a transient [Ca(2+)](in) increase in these cells and that this process involves release of calcium from intracellular stores following Gαq/11 activation.


Assuntos
Cálcio/metabolismo , Citoplasma/metabolismo , Endotelina-1/metabolismo , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/metabolismo , Receptor de Endotelina A/metabolismo , Fosfolipases Tipo C/metabolismo , Animais , Linhagem Celular , Regulação da Expressão Gênica , Células HEK293 , Humanos , Rim/citologia , Camundongos , Ratos , Receptor de Endotelina A/genética , Receptor de Endotelina B/genética , Receptor de Endotelina B/metabolismo , Células Receptoras Sensoriais/metabolismo
10.
Nat Med ; 9(8): 1055-61, 2003 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-12847519

RESUMO

Endothelin-1 (ET-1) is a newly described pain mediator that is involved in the pathogenesis of pain states ranging from trauma to cancer. ET-1 is synthesized by keratinocytes in normal skin and is locally released after cutaneous injury. While it is able to trigger pain through its actions on endothelin-A (ET(A)) receptors of local nociceptors, it can coincidentally produce analgesia through endothelin-B (ET(B)) receptors. Here we map a new endogenous analgesic circuit, in which ET(B) receptor activation induces the release of beta-endorphin from keratinocytes and the activation of G-protein-coupled inwardly rectifying potassium channels (GIRKs, also named Kir-3) linked to opioid receptors on nociceptors. These results indicate the existence of an intrinsic feedback mechanism to control peripheral pain in skin, and establish keratinocytes as an ET(B) receptor-operated opioid pool.


Assuntos
Analgesia , Dor/metabolismo , Canais de Potássio Corretores do Fluxo de Internalização , Receptores de Endotelina/metabolismo , Transdução de Sinais , Pele/lesões , Animais , Células Cultivadas , Endotelina-1/metabolismo , Canais de Potássio Corretores do Fluxo de Internalização Acoplados a Proteínas G , Humanos , Queratinócitos/citologia , Queratinócitos/metabolismo , Masculino , Medição da Dor , Canais de Potássio/metabolismo , Ratos , Ratos Sprague-Dawley , Receptor de Endotelina B , Receptores Opioides delta/metabolismo , Receptores Opioides kappa/metabolismo , Receptores Opioides mu/metabolismo , Pele/citologia , beta-Endorfina/metabolismo
11.
Can J Physiol Pharmacol ; 88(6): 668-75, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20628433

RESUMO

A profound tachyphylaxis of the acute nocifensive flinching (pain) response to subcutaneous injection of endothelin-1 (ET-1) into the hind paw footpad is shown by the reduced response to a second injection. Flinching from the second injection was 20% +/- 5%, 57% +/- 18%, 79% +/- 35%, and 100% +/- 17% of that from the first injection (both 200 micromol/L, 2 nmol) at respective intervals of 24, 30, 48, and 72 h. Inhibition of afferent impulses by local anesthesia of the sciatic nerve, reducing initial flinching to 6%-13% of control, did not affect the tachyphylaxis for the second injection at 24 h. There was no cross-desensitization between formalin and ET-1 injected sequentially into the same paw. Suppression of descending inhibitory effects from endogenous opiates by naloxone (5-8 mg/kg, i.p.), given 30 min before the second ET-1 injection, did not prevent tachyphylaxis. Diffuse effects caused by an initial subcutaneous ET-1 injection into the tail or forepaw resulted in sensitization of the response to ET-1 in the hind paw, rather than tachyphylaxis. In contrast, selective inhibition of local ETA receptors during the initial administration of ET-1, by the antagonist BQ-123 (3.2 mmol/L), reduced tachyphylaxis of nocifensive flinching. Therefore, prolonged pain tachyphylaxis is not due to reduced responsiveness of the CNS, but rather depends on the functional sensitivity or availability of peripheral ET(A) receptors.


Assuntos
Sistema Nervoso Central/fisiologia , Endotelina-1/farmacologia , Dor/induzido quimicamente , Taquifilaxia/fisiologia , Anestésicos/farmacologia , Animais , Antagonistas do Receptor de Endotelina A , Endotelina-1/administração & dosagem , Pé/inervação , Formaldeído/administração & dosagem , Formaldeído/farmacologia , Membro Posterior/efeitos dos fármacos , Membro Posterior/inervação , Hiperalgesia/induzido quimicamente , Masculino , Naloxona/farmacologia , Medição da Dor , Peptídeos Cíclicos/farmacologia , Ratos , Ratos Sprague-Dawley , Nervo Isquiático/efeitos dos fármacos , Fatores de Tempo , Tato
12.
Brain Res Rev ; 60(1): 135-48, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19150373

RESUMO

Mitogen-activated protein kinases (MAPKs) are important for intracellular signal transduction and play critical roles in regulating neural plasticity and inflammatory responses. The MAPK family consists of three major members: extracellular signal-regulated kinases (ERK), p38, and c-Jun N-terminal kinase (JNK), which represent three separate signaling pathways. Accumulating evidence shows that all three MAPK pathways contribute to pain sensitization after tissue and nerve injury via distinct molecular and cellular mechanisms. Activation (phosphorylation) of MAPKs under different persistent pain conditions results in the induction and maintenance of pain hypersensitivity via non-transcriptional and transcriptional regulation. In particular, ERK activation in spinal cord dorsal horn neurons by nociceptive activity, via multiple neurotransmitter receptors, and using different second messenger pathways plays a critical role in central sensitization by regulating the activity of glutamate receptors and potassium channels and inducing gene transcription. ERK activation in amygdala neurons is also required for inflammatory pain sensitization. After nerve injury, ERK, p38, and JNK are differentially activated in spinal glial cells (microglia vs astrocytes), leading to the synthesis of proinflammatory/pronociceptive mediators, thereby enhancing and prolonging pain. Inhibition of all three MAPK pathways has been shown to attenuate inflammatory and neuropathic pain in different animal models. Development of specific inhibitors for MAPK pathways to target neurons and glial cells may lead to new therapies for pain management. Although it is well documented that MAPK pathways can increase pain sensitivity via peripheral mechanisms, this review will focus on central mechanisms of MAPKs, especially ERK.


Assuntos
Sistema Nervoso Central/enzimologia , Sistema de Sinalização das MAP Quinases/fisiologia , Nociceptores/enzimologia , Dor/enzimologia , Células Receptoras Sensoriais/enzimologia , Animais , Sistema Nervoso Central/fisiopatologia , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Humanos , Mediadores da Inflamação/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Dor/fisiopatologia , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
13.
Reg Anesth Pain Med ; 43(6): 605-612, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29557886

RESUMO

BACKGROUND AND OBJECTIVES: Local anesthetics (LAs) are often infiltrated subcutaneously for localized perioperative numbing. In addition to blocking nerve conduction, LAs act on pathways used by a variety of pain-inducing and inflammatory mediators. We describe the effects in isolated model sensory neurons of LAs on responses to the algogenic and sensitizing peptide, bradykinin (BK). METHODS: ND/7 sensory neurons were stimulated by different concentrations of BK in the presence or absence of LAs, with transient increases in intracellular calcium (Δ[Ca]in) detected fluorometrically in fields of cells. Equilibrium saturable binding of radiolabeled BK also was conducted on the same type of cells, with and without LA. RESULTS: Responses to low BK (5 nM) were inhibited by lidocaine at 1 mM (approximately 35% inhibition) and 10 mM (approximately 70% inhibition), whereas responses to high BK (100 nM) were unaffected by 1 mM yet inhibited (approximately 75%) by 10 mM lidocaine. Bupivacaine (1 and 2 mM) did not reduce peak Δ[Ca]in (using 5 nM BK). Lidocaine's quaternary derivative, QX-314 (10 mM), also was ineffective on peak Ca (5 nM BK). Saturation binding of BK showed that lidocaine lowered the binding capacity (Bmax) without changing the KD, consistent with noncompetitive inhibition. CONCLUSIONS: At subclinical concentrations, lidocaine suppresses BK's activation of model sensory neurons. This effect adds to the known analgesic mechanisms of LAs and likely contributes to the reduction of postincisional pain.


Assuntos
Anestésicos Locais/metabolismo , Antagonistas dos Receptores da Bradicinina/metabolismo , Lidocaína/metabolismo , Receptores da Bradicinina/metabolismo , Células Receptoras Sensoriais/metabolismo , Anestésicos Locais/farmacologia , Animais , Bradicinina/metabolismo , Bradicinina/farmacologia , Antagonistas dos Receptores da Bradicinina/farmacologia , Linhagem Celular , Relação Dose-Resposta a Droga , Lidocaína/farmacologia , Camundongos , Ligação Proteica/efeitos dos fármacos , Ligação Proteica/fisiologia , Ratos , Células Receptoras Sensoriais/efeitos dos fármacos
14.
J Neurosci ; 26(13): 3551-60, 2006 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-16571763

RESUMO

Optimal management of neuropathic pain is a major clinical challenge. We investigated the involvement of c-Jun N-terminal kinase (JNK) in neuropathic pain produced by spinal nerve ligation (SNL) (L5). SNL induced a slow (>3 d) and persistent (>21 d) activation of JNK, in particular JNK1, in GFAP-expressing astrocytes in the spinal cord. In contrast, p38 mitogen-activated protein kinase activation was found in spinal microglia after SNL, which had fallen to near basal level by 21 d. Intrathecal infusion of a JNK peptide inhibitor, D-JNKI-1, did not affect normal pain responses but potently prevented and reversed SNL-induced mechanical allodynia, a major symptom of neuropathic pain. Intrathecal D-JNKI-1 also suppressed SNL-induced phosphorylation of the JNK substrate, c-Jun, in spinal astrocytes. However, SNL-induced upregulation of GFAP was not attenuated by spinal D-JNKI-1 infusion. Furthermore, SNL induced a rapid (<12 h) but transient activation of JNK in the L5 (injured) but not L4 (intact) DRG. JNK activation in the DRG was mainly found in small-sized C-fiber neurons. Infusion of D-JNKI-1 into the L5 DRG prevented but did not reverse SNL-induced mechanical allodynia. Finally, intrathecal administration of an astroglial toxin, l-alpha-aminoadipate, reversed mechanical allodynia. Our data suggest that JNK activation in the DRG and spinal cord play distinct roles in regulating the development and maintenance of neuropathic pain, respectively, and that spinal astrocytes contribute importantly to the persistence of mechanical allodynia. Targeting the JNK pathway in spinal astroglia may present a new and efficient way to treat neuropathic pain symptoms.


Assuntos
Astrócitos/enzimologia , Gânglios Espinais/enzimologia , Hiperalgesia/enzimologia , MAP Quinase Quinase 4/metabolismo , Neuralgia/enzimologia , Neurônios Aferentes/enzimologia , Peptídeos/administração & dosagem , Animais , Astrócitos/efeitos dos fármacos , Ativação Enzimática/efeitos dos fármacos , Gânglios Espinais/efeitos dos fármacos , Hiperalgesia/complicações , Hiperalgesia/prevenção & controle , MAP Quinase Quinase 4/antagonistas & inibidores , Masculino , Neuralgia/complicações , Neuralgia/prevenção & controle , Neurônios Aferentes/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Nervos Espinhais/efeitos dos fármacos , Nervos Espinhais/lesões
15.
J Negat Results Biomed ; 6: 8, 2007 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-17623103

RESUMO

BACKGROUND: Sandhoff disease is an inherited lysosomal storage disease caused by a mutation in the gene for the beta-subunit (Hexb gene) of beta-hexosaminidase A (alphabeta) and B (beta beta). The beta-subunit together with the GM2 activator protein catabolize ganglioside GM2. This enzyme deficiency results in GM2 accumulation primarily in the central nervous system. To investigate how abnormal GM2 catabolism affects the peripheral nervous system in a mouse model of Sandhoff disease (Hexb-/-), we examined the electrophysiology of dissected sciatic nerves, structure of central and peripheral myelin, and lipid composition of the peripheral nervous system. RESULTS: We detected no significant difference in signal impulse conduction velocity or any consistent change in the frequency-dependent conduction slowing and failure between freshly dissected sciatic nerves from the Hexb+/- and Hexb-/- mice. The low-angle x-ray diffraction patterns from freshly dissected sciatic and optic nerves of Hexb+/- and Hexb-/- mice showed normal myelin periods; however, Hexb-/- mice displayed a approximately 10% decrease in the relative amount of compact optic nerve myelin, which is consistent with the previously established reduction in myelin-enriched lipids (cerebrosides and sulfatides) in brains of Hexb-/- mice. Finally, analysis of lipid composition revealed that GM2 content was present in the sciatic nerve of the Hexb-/- mice (undetectable in Hexb+/-). CONCLUSION: Our findings demonstrate the absence of significant functional, structural, or compositional abnormalities in the peripheral nervous system of the murine model for Sandhoff disease, but do show the potential value of integrating multiple techniques to evaluate myelin structure and function in nervous system disorders.


Assuntos
Modelos Animais de Doenças , Lipídeos/análise , Bainha de Mielina/química , Condução Nervosa , Sistema Nervoso Periférico/fisiopatologia , Doença de Sandhoff/fisiopatologia , Animais , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Estrutura Molecular , Difração de Raios X
16.
J Pain ; 18(5): 535-545, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28063958

RESUMO

Thoracotomy results in a high frequency of chronic postoperative pain. Resolvins are endogenous molecules, synthesized and released by activated immune cells, effective against inflammatory and neuropathic pain. Different resolvins have differential actions on selective neuronal and glial receptors and enzymes. This article examines the ability of intrathecal resolvin D1 and resolvin D2 to reduce chronic post-thoracotomy pain in rats. Thoracotomy, involving intercostal incision and rib retraction, resulted in a decrease in the mechanical force threshold to induce nocifensive behavior, an enlargement of the pain-sensitive area, and an increase in the fraction of rats showing nocifensive behavior, all for at least 5 weeks. The qualitative nature of the behavioral responses to tactile stimulation changed dramatically after thoracotomy, including the appearance of vigorous behaviors, such as turning, shuddering, and squealing, all absent in naive rats. Intrathecal delivery of resolvin D1 (30 ng/30 µL), at surgery or 4 days later, halved the spread of the mechanosensitive area, lowered by 60% the percent of rats with tactile hypersensitivity, and reduced the drop in threshold for a nocifensive response, along with a reduction in the occurrence of vigorous nocifensive responses. Resolvin D2's actions on threshold changes were statistically the same. These findings suggest that intrathecal resolvins, delivered preoperatively or several days later, can prevent chronic postoperative hyperalgesia. PERSPECTIVE: In studies of rats, the injection of the proresolving compounds of the resolvin-D series into spinal fluid, before or just after thoracotomy surgery, prevents the occurrence of acute and chronic pain. If these chemicals, which have shown no side-effects, were used in humans it might greatly reduce chronic postoperative pain.


Assuntos
Analgésicos/administração & dosagem , Dor Crônica/prevenção & controle , Ácidos Docosa-Hexaenoicos/administração & dosagem , Dor Pós-Operatória/prevenção & controle , Animais , Dor Crônica/etiologia , Modelos Animais de Doenças , Sistemas de Liberação de Medicamentos , Injeções Espinhais/métodos , Masculino , Medição da Dor , Limiar da Dor/efeitos dos fármacos , Dor Pós-Operatória/etiologia , Ratos , Ratos Sprague-Dawley , Toracotomia/efeitos adversos , Fatores de Tempo
17.
Pain ; 158(7): 1332-1341, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28622274

RESUMO

Thoracotomy results in chronic postoperative pain (CPTP) in half of the cases. Earlier findings in rat models of persistent post-surgical pain suggest that spinal pathways are critical for pain onset but not its maintenance. Descending systems from the brain stem modulate nociceptive transmission in the spinal cord and contribute to persistent pain, but their role in chronic postoperative pain has not been studied. Here, we ablated pronociceptive neurokinin-1 receptor (NK-1R)-expressing neurons in the rat rostral ventromedial medulla (RVM) to identify their role in CPTP. Cells were ablated by microinjection of the neurotoxin Sar, Met(O2)-Substance P (SSP-SAP), either 2 to 3 weeks before ("Prevention" condition) or 10 days after ("Reversal" condition) thoracotomy with rib retraction. Inactive Blank-SAP was the control. Tactile hypersensitivity was defined by lowered force thresholds for nocifensive responses to von Frey filaments applied over the dorsal trunk, and pain-like behavior assessed by the Qualitative Hyperalgesia Profile; both were followed for 5 weeks after surgery. SSP-SAP injection before surgery resulted in ∼95% loss of NK-1R neurons in RVM and prevented postoperative mechano-hypersensitivity. Blank-SAP was ineffective. SSP-SAP given at postoperative day 10 was equally effective in ablating NK-1R neurons but fully reversed mechano-hypersensitivity in only 3 of 9 hypersensitive rats. Fewer rats showed intense pain-like behavior, by Qualitative Hyperalgesia Profile analysis, in the Prevention than in the Control conditions, and the more intense pain behaviors declined along with SSP-SAP-induced Reversal of hypersensitivity. Neurokinin-1 receptor-expressing neurons in RVM appear essential for the development but contribute only partially to the maintenance of CPTP.


Assuntos
Dor Crônica/metabolismo , Hiperalgesia/metabolismo , Bulbo/metabolismo , Neurônios/metabolismo , Dor Pós-Operatória/metabolismo , Receptores da Neurocinina-1/metabolismo , Toracotomia/efeitos adversos , Animais , Dor Crônica/etiologia , Masculino , Limiar da Dor/fisiologia , Dor Pós-Operatória/etiologia , Ratos , Ratos Sprague-Dawley
19.
J Pain ; 7(5 Suppl 3): S1-29, 2006 May.
Artigo em Inglês | MEDLINE | ID: mdl-16632328

RESUMO

UNLABELLED: Clinical and experimental data indicate that changes in the expression of voltage-gated sodium channels play a key role in the pathogenesis of neuropathic pain and that drugs that block these channels are potentially therapeutic. Clinical and experimental data also suggest that changes in voltage-gated sodium channels may play a role in inflammatory pain, and here too sodium-channel blockers may have therapeutic potential. The sodium-channel blockers of interest include local anesthetics, used at doses far below those that block nerve impulse propagation, and tricyclic antidepressants, whose analgesic effects may at least partly be due to blockade of sodium channels. Recent data show that local anesthetics may have pain-relieving actions via targets other than sodium channels, including neuronal G protein-coupled receptors and binding sites on immune cells. Some of these actions occur with nanomolar drug concentrations, and some are detected only with relatively long-term drug exposure. There are 9 isoforms of the voltage-gated sodium channel alpha-subunit, and several of the isoforms that are implicated in neuropathic and inflammatory pain states are expressed by somatosensory primary afferent neurons but not by skeletal or cardiovascular muscle. This restricted expression raises the possibility that isoform-specific drugs might be analgesic and lacking the cardiotoxicity and neurotoxicity that limit the use of current sodium-channel blockers. PERSPECTIVE: Changes in the expression of neuronal voltage-gated sodium channels may play a key role in the pathogenesis of both chronic neuropathic and chronic inflammatory pain conditions. Drugs that block these channels may have therapeutic efficacy with doses that are far below those that impair nerve impulse propagation or cardiovascular function.


Assuntos
Inflamação/complicações , Doenças do Sistema Nervoso/complicações , Dor/etiologia , Bloqueadores dos Canais de Sódio/farmacologia , Canais de Sódio/fisiologia , Anestésicos Locais/farmacologia , Sinalização do Cálcio/fisiologia , Doença Crônica , Humanos , Inflamação/fisiopatologia , Lidocaína/farmacologia , Doenças do Sistema Nervoso/fisiopatologia , Dor/fisiopatologia
20.
Exp Biol Med (Maywood) ; 231(6): 1165-70, 2006 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-16741070

RESUMO

Subcutaneous endothelin-1 (ET-1; 200 microM, 2 nmoles/paw) injected into the rat hind paw, has been shown to cause robust hind paw flinching (HPF) and paw licking, and to induce impulses selectively in primary nociceptors. Here we report that a much lower [ET-1] sensitizes the paw to a nocifensive withdrawal response to tactile stimulation (by von Frey hairs, VFH), a sensitization that involves local TRPV1 receptors. Injection of 10 microM ET-1 (0.1 nmole/paw) causes only marginal HPF but rapidly (20 mins after injection) lowers the force threshold for paw withdrawal (PWT) to VFH, to approximately 30% of pre-injection baseline. Such tactile allodynia persists for 3 hrs. In rats pre-injected with the TRPV1-antagonists capsazepine (CPZ; 1.33 mM) or 5'-iodoresiniferatoxin (I-RTX; 0.13 microM), 15 min before ET-1, a fast initial drop in PWT, as with ET-1 alone, occurs (to 40% or to 19% of baseline, respectively), but this earliest reduction then regresses back to the pre-injection PWT value more rapidly than with ET-1 alone. The recovery of allodynia from the maximum value is about two times faster for ET-1+CPZ and about 4 times faster for ET-1+ I-RTX, compared with that from ET-1 +vehicle (t(1/2) = 130, 60, and 250 mins, respectively). In contrast, spontaneous pain indicated by overt HPF from ET-1 is not attenuated by TRPV1 antagonists. Tactile allodynia is similarly abbreviated by antagonists of both ET(A) (BQ-123, 32 nmoles/paw) and ET(B) (BQ-788, 30 nmoles/paw) receptors, whereas HPF is abolished by this ET(A) antagonist but enhanced by the ET(B) antagonist. We conclude that low ET-1 causes tactile allodynia, which is characterized by a different time-course and pharmacology than ET-1-induced nociception, and that local TRPV1 receptors are involved in the maintenance of this ET-1-induced allodynia but not in the overt algesic action of ET-1.


Assuntos
Endotelina-1/farmacologia , Dor/induzido quimicamente , Canais de Cátion TRPV/metabolismo , Tato/efeitos dos fármacos , Animais , Comportamento Animal/efeitos dos fármacos , Capsaicina/análogos & derivados , Capsaicina/farmacologia , Diterpenos/farmacologia , Relação Dose-Resposta a Droga , Endotelina-1/administração & dosagem , Injeções Subcutâneas , Masculino , Nociceptores/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Tempo de Reação , Receptor de Endotelina A/efeitos dos fármacos , Receptor de Endotelina A/metabolismo , Canais de Cátion TRPV/antagonistas & inibidores
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