The primary aim of this study was to determine the effect of high frequency Transcutaneous Electrical Nerve Stimulation (TENS) on cold sensory function following topical application of menthol. Quantitative sensory testing was used to determine cold sensation and cold pain thresholds before and after topical application of a 40% menthol solution in 9 male and 11 female subjects. In a separate session the effect of TENS (100 HZ, constant pulse, 100µs, 20 minutes) was determined on menthol-induced cold sensation. Menthol produced a distinct cold hyperalgesia which was significantly reduced during the application of high frequency TENS. The analgesic effect of TENS persisted beyond the application period for at least 20 minutes. Menthol also reduced cold detection thresholds but TENS had no effect on this aspect of cold sensation. These data support the use of TENS as a means of treating cold hyperalgesia such as that found in neuropathic pain states.

No description available.

Diss. (sammanfattning) Stockholm : Karol. inst., 2005. / Härtill 6 uppsatser.

Thesis (Ph. D.)--University of Oklahoma. / Includes bibliographical references.

Made available in DSpace on 2014-06-11T19:31:08Z (GMT). No. of bitstreams: 0 Previous issue date: 2009-02-16Bitstream added on 2014-06-13T18:41:45Z : No. of bitstreams: 1 rondon_es_dr_jabo.pdf: 759675 bytes, checksum: 0a47e2de920daaecf1959b4694ea81db (MD5) / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / Em dois ensaios testou-se a eficácia da cetamina e do ifenprodil administrados preventivamente e por via subaracnóidea, no controle da hiperalgesia induzida (p 0,05). As provas farmacológicas utilizaram ratos Wistar em duas etapas: determinação da potência relativa e isobologramas. O estímulo hiperalgésico — injeção intraplantar de prostaglandina E2 - foi avaliado com um analgesímetro digital. Todos fármacos apresentaram ação anti-hiperalgésica com diferentes valores de EC50 crescentes nesta ordem: ifenprodil, cetamina S(+), cetamina racêmica e cetamina R(-). O ifenprodil potencializou a ação da cetamina e seus isômeros e foi potencializado pelo racemato e a forma S(+). Os resultados embasaram os ensaios clínicos. Nestes, oito cães foram utilizados para comparar o efeito anti-hiperalgésico do ifenprodil associado à cetamina racêmica com o uso isolado desta, durante 24 h após lesão cirúrgica incisional no coxim metatársico. Foram avaliados os escores de sedação e de claudicação; contagens da freqüência cardíaca e da respiratória; testes com filamentos de von Frey e medição da superfície de apóio plantar com planímetro nos tempos basal e 60, 90, 120, 180, 240, 480, 720 e 1440 min pós-trauma. A comparação entre grupos e ao longo do tempo revelou que os escores se mantiveram inalterados e as freqüências não variaram significativamente. Os testes de von Frey e com planímetro demonstraram diferenças significativas entre os protocolos. Concluiu-se que, ainda que o estímulo seja cirúrgico, o pré-tratamento com ifenprodil melhora a ação anti-hiperalgésica da cetamina racêmica nas primeiras 24 horas após a lesão. / In two different opportunities, it was tested the efficacy of cetamina and ifenprodil, administered preventively and by spinal route, in the control of induced hyperalgesia (P5 0.05). The pharmacological tests had used Wistar rats in two stages: determination of the relative power and isobolograms. The hyperalgesic stimulus — E2 prostaglandin intraplantar injection — was evaluated by electronic pressure meter. Ali the drugs had presented antihyperalgesic action with different ED50 values increasing in this order: ifenprodil, S(+) ketamine, racemic ketamine and R(-) ketamine. lfenprodil potentiated ketamine and its isomers action, and was potentiated by racemate and S(+) form. fie results had based the clinicai tests. In these, eight dogs had been used to compare the antihyperalgesic effect of ifenprodil associated with ketamine with the isolated use of ketamine during 24 hours after surgicai incision in the metatarsal pad. Sedation and claudication scores, respiratory and cardiac rates, von Frey filaments tests and the determination of plantar support area had been used in baseline and 60, 90, 120, 180, 240, 480, 720 and 1440 min after-trauma. The comparison between groups and throughout the time showed that lhe scores had kept unchanged and the rates had not varied significantly. The tests with von Frey filaments and with planimeter had demonstrated significant differences between the protocols. One concluded that, despite the stimulus is surgical, pretreatment with ifenprodil improves lhe antihyperalgesic action of racemic ketamine in the first 24 hours after the injury.

Resumo: Em dois ensaios testou-se a eficácia da cetamina e do ifenprodil administrados preventivamente e por via subaracnóidea, no controle da hiperalgesia induzida (p 0,05). As provas farmacológicas utilizaram ratos Wistar em duas etapas: determinação da potência relativa e isobologramas. O estímulo hiperalgésico - injeção intraplantar de prostaglandina E2 - foi avaliado com um analgesímetro digital. Todos fármacos apresentaram ação anti-hiperalgésica com diferentes valores de EC50 crescentes nesta ordem: ifenprodil, cetamina S(+), cetamina racêmica e cetamina R(-). O ifenprodil potencializou a ação da cetamina e seus isômeros e foi potencializado pelo racemato e a forma S(+). Os resultados embasaram os ensaios clínicos. Nestes, oito cães foram utilizados para comparar o efeito anti-hiperalgésico do ifenprodil associado à cetamina racêmica com o uso isolado desta, durante 24 h após lesão cirúrgica incisional no coxim metatársico. Foram avaliados os escores de sedação e de claudicação; contagens da freqüência cardíaca e da respiratória; testes com filamentos de von Frey e medição da superfície de apóio plantar com planímetro nos tempos basal e 60, 90, 120, 180, 240, 480, 720 e 1440 min pós-trauma. A comparação entre grupos e ao longo do tempo revelou que os escores se mantiveram inalterados e as freqüências não variaram significativamente. Os testes de von Frey e com planímetro demonstraram diferenças significativas entre os protocolos. Concluiu-se que, ainda que o estímulo seja cirúrgico, o pré-tratamento com ifenprodil melhora a ação anti-hiperalgésica da cetamina racêmica nas primeiras 24 horas após a lesão. / Abstract: In two different opportunities, it was tested the efficacy of cetamina and ifenprodil, administered preventively and by spinal route, in the control of induced hyperalgesia (P5 0.05). The pharmacological tests had used Wistar rats in two stages: determination of the relative power and isobolograms. The hyperalgesic stimulus - E2 prostaglandin intraplantar injection - was evaluated by electronic pressure meter. Ali the drugs had presented antihyperalgesic action with different ED50 values increasing in this order: ifenprodil, S(+) ketamine, racemic ketamine and R(-) ketamine. lfenprodil potentiated ketamine and its isomers action, and was potentiated by racemate and S(+) form. fie results had based the clinicai tests. In these, eight dogs had been used to compare the antihyperalgesic effect of ifenprodil associated with ketamine with the isolated use of ketamine during 24 hours after surgicai incision in the metatarsal pad. Sedation and claudication scores, respiratory and cardiac rates, von Frey filaments tests and the determination of plantar support area had been used in baseline and 60, 90, 120, 180, 240, 480, 720 and 1440 min after-trauma. The comparison between groups and throughout the time showed that lhe scores had kept unchanged and the rates had not varied significantly. The tests with von Frey filaments and with planimeter had demonstrated significant differences between the protocols. One concluded that, despite the stimulus is surgical, pretreatment with ifenprodil improves lhe antihyperalgesic action of racemic ketamine in the first 24 hours after the injury. / Orientador: Carlos Augusto Araújo Valadão / Coorientador: Carlos Amilcar Parada / Banca: Juan Carlos Duque Moreno / Banca: Silvana Lima Górniak / Banca: Stelio Pacca Loureiro Luna / Banca: Antonio de Queiroz Neto / Doutor

Orientador: Maria Cláudia Gonçalves de Oliveira Fusaro / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Aplicadas / Made available in DSpace on 2018-08-25T13:05:07Z (GMT). No. of bitstreams: 1 Melo_Brunade_M.pdf: 1160481 bytes, checksum: cafc4360aa16080c8eb0784f74e162b8 (MD5) Previous issue date: 2014 / Resumo: Estudos demonstram que a dor muscular induzida por contração isométrica sustentada (CIS) possui importante impacto socioeconômico, no entanto, apesar de sua relevância clínica, os mecanismos inflamatórios envolvidos no desenvolvimento desse tipo de dor ainda são pouco compreendidos. O objetivo deste estudo foi analisar os mecanismos inflamatórios envolvidos no desenvolvimento desse tipo de hiperalgesia muscular. Para isso foi utilizado o modelo de hiperalgesia muscular induzido por contração isométrica sustentada, recentemente desenvolvido por nosso grupo de pesquisa, que consiste na indução de contração muscular isométrica no músculo gastrocnêmio de ratos machos Wistar, pesando entre 200 e 250g, que receberam uma corrente elétrica através do equipamento da marca Grass, modelo SX88R, corrente monofásica, pulso repetido, frequência de 50Hz, duração de pulso de 19ms através de eletrodos tipo agulha, pelo período de 1 hora. Para traçar o perfil inflamatório deste modelo foram administrados via intramuscular, 5 minutos, antes da contração isométrica as seguintes drogas: DALB K (3;30'mu'g) e Bradizida (1,5;15 'mu'g)(antagonistas dos receptores de bradicinina B1 e B2, respectivamente), Atenolol (0,6; 6'mu'g) e ICI 118551(0,15;1,5'mu'g) (antagonistas dos receptores adrenérgicos 'beta'1 e 'beta', respectivamente), Indometacina, uma hora antes (10;100'mu'g) (inibidor não seletivo das cicloxigenases) e A317491 (0,6; 6; 60 'mug) (antagonista seletivo dos receptores P2X3 e P2X2/3); e administrado intraperitoneal, 20 minutos antes, a Fucoidina (25mg/Kg) (inibidora da ação das selectinas). Os resultados demonstraram que todos esses antagonistas e inibidores reduziram significativamente a hiperalgesia muscular induzida pela contração isométrica sustentada, confirmando o envolvimento da bradicinina, aminas simpatomiméticas, prostaglandinas, neutrófilos e do ATP endógeno via receptores P2X3 e P2X2/3 na hiperalgesia muscular induzida pela contração isométrica sustentada. Esses resultados delineiam pela primeira vez o perfil inflamatório da hiperalgesia muscular induzida por contração isométrica sustentada e sugerem importantes alvos terapêuticos para estudo e tratamento da dor muscular, além de abrir novas perspectivas de estudo de outros mecanismos importantes no desenvolvimento da mesma / Abstract: Studies show that muscle pain induced by sustained isometric contraction (CIS) have an important socioeconomic impact, however, despite their clinical relevance, the inflammatory mechanisms involved in the development of this type of pain are still poorly understood. The aim of this study was to analyze the inflammatory mechanisms involved in the development of this type of muscle hyperalgesia. For this model of muscle hyperalgesia induced by sustained isometric contraction, recently developed by our research group, which consists of the induction of isometric muscle contraction in the gastrocnemius muscle of male Wistar rats were used, weighing between 200 and 250g, receiving an electric current through the equipment brand Grass , model SX88R , single phase , repeated pulse frequency of 50 Hz , pulse duration of 19ms via needle-like electrodes for a period of 1 hour. To trace the inflammatory profile of this model, the following drugs were administered intramuscularly 5 minutes before the isometric contraction: DALB K (3; 30'mu'g) and Bradizyde (1.5, 15 mg) (antagonists of bradykinin B1 and B2 receptors, respectively), Atenolol (0.6 ; 6'mu'g) and ICI 118551 (0.15, 1.5 mg) ('beta1 and 'beta'2 adrenergic receptor antagonists, respectively), indomethacin (10 ; 100'mu'g ) ( inhibitory action of cyclooxygenase ) and A317491 ( 0.6 , 6, 60 mg) (selective antagonist of P2X3 and P2X2 / 3 receptors) , and administered intraperitoneally 20 minutes before the fucoidin ( 25mg/Kg ) ( inhibitory action of selectins) . The results showed that all of these antagonists and inhibitors significantly reduced muscular hyperalgesia induced by sustained isometric contraction, confirming the involvement of bradykinin, sympathomimetic amines, prostaglandins, neutrophils and endogenous ATP via P2X3 and P2X2/3 receptors in muscle hyperalgesia induced by isometric contraction sustained. These results delineate first the inflammatory profile of muscle hyperalgesia induced by sustained isometric contraction and suggest important targets for study and treatment of muscle pain, and open new perspectives for the study of other important mechanisms in the development of the same / Mestrado / Biodinâmica do Movimento Humano e Esporte / Mestra em Ciências da Nutrição e do Esporte e Metabolismo

BACKGROUND: Containing a brain for signal processing and decision making, and a peripheral component for sensation and response, the nervous system provides higher organisms a powerful method of interacting with their environment. The specific neurons involved in pain sensation are known as nociceptors and are the source of normal nociceptive pain signaling to prompt appropriate responses. Though acute hypersensitization can be advantageous by encouraging an organism to allow an injured area to heal, chronic pain conditions can be pathological and can markedly reduce quality of life. While a variety of genes have been associated with congenital pain conditions, two rare cases examined in this study have not had their mutated genes identified. Potassium voltage-gated channel subfamily H member 8, or KCNH8, is involved in regulating action potential production and propagation, and has not been linked with pain processing of any kind to date. Here, a male patient evaluated at Boston Children’s Hospital contains a novel single-base KCNH8 mutation and possesses an extremely low sensitivity to cold temperatures and mechanical pain, but a higher sensitivity to warmer temperatures. A separate protein, intersectin-2, or ITSN2, normally functions in clathrin-mediated endocytosis and exocytosis. A second patient at Boston Children’s Hospital expresses a previously-unseen point mutation in ITSN2 and experiences erythromelalgia, characterized by episodes of intense pain and red, swollen limbs during ambient warm temperatures. Through the use of Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9 genome editing, this study will produce these specific genetic mutations in mouse lines to explore their effects on mammalian behavior. OBJECTIVES: This project employs two transgenic mouse models to study the behavioral phenotypes associated with rare potentially damaging mutations in KCNH8 and ITSN2 exhibited in the human patients. Through these experiments, a greater understanding of neural pain signaling and sensitivity changes can occur. METHODS: The differences in temperature preference of KCNH8 and ITSN2 mutant mice compared to wild type mice lacking these mutations was studied using thermal plates under cold and warm conditions. Direct application of acetone and von Frey filaments to mouse paws was used to study cold and mechanical sensitivity. Further testing of stamina, anxiety, coordination, and strength were also evaluated. RESULTS: A marked decrease in sensitivity to von Frey stimulation (p<0.01) and acetone administration (p<0.05) was observed in KCNH8 mutant mice. Thermal preference testing demonstrated a decreased preference for warmer temperatures as compared to wild type mice. In addition, anxiety levels were also observed to be slightly higher in these mutant KCNH8 mice (p<0.05). The mutant ITSN2 mice spent less time at cooler temperatures, though surprisingly they significantly preferred warmer conditions as compared to their wild type littermates. A full and partial reversal of these temperature preferences was demonstrated in cold and heat thermal conditions respectively after intraperitoneal gabapentin injection, which normalized the mice toward wild type behavior. CONCLUSIONS: Data from the KCNH8 mutant mouse model indicates an aversion to warmer temperatures and a decreased ability to detect cold or mechanical pressure, much like the human patient. The mutant ITSN2 mice were less likely to spend time at cooler temperatures, indicating heightened sensory sensitivity, but their preference for warmer temperatures suggests a possible desensitization of the affected nociceptors. These results often mirror the patient’s phenotype, but the preference for ambient warmer environments appears opposite to the patient. As the ITSN2 mice feel discomfort at cooler temperatures, a proposed desensitization at warmer temperatures would result in a more comfortable environment and could explain the observed preference. The trends toward normal neural firing rates achieved through gabapentin injection suggest that the aberrant responses in mutant ITSN2 mice is due to altered sensitization, but additional examination under these conditions with a larger group of mice is necessary to further unravel these signaling pathways. However, these extremely encouraging data introduce two new molecular targets for acute pain control.

Background: Nociceptive and neuropathic pain occurs as part of the disease process after traumatic brain injury (TBI) in humans. Central and peripheral inflammation, a major secondary injury process initiated by the traumatic brain injury event, has been implicated in the potentiation of peripheral nociceptive pain. We hypothesized that the inflammatory response to diffuse traumatic brain injury potentiates persistent pain through prolonged immune dysregulation. Results: To test this, adult, male C57BL/6 mice were subjected to midline fluid percussion brain injury or to sham procedure. One cohort of mice was analyzed for inflammation-related cytokine levels in cortical biopsies and serum along an acute time course. In a second cohort, peripheral inflammation was induced seven days after surgery/injury with an intraplantar injection of carrageenan. This was followed by measurement of mechanical hyperalgesia, glial fibrillary acidic protein and Iba1 immunohistochemical analysis of neuroinflammation in the brain, and flow cytometric analysis of T-cell differentiation in mucosal lymph. Traumatic brain injury increased interleukin-6 and chemokine ligand 1 levels in the cortex and serum that peaked within 1-9 h and then resolved. Intraplantar carrageenan produced mechanical hyperalgesia that was potentiated by traumatic brain injury. Further, mucosal T cells from brain-injured mice showed a distinct deficiency in the ability to differentiate into inflammation-suppressing regulatory T cells (Tregs). Conclusions: We conclude that traumatic brain injury increased the inflammatory pain associated with cutaneous inflammation by contributing to systemic immune dysregulation. Regulatory T cells are immune suppressors and failure of T cells to differentiate into regulatory T cells leads to unregulated cytokine production which may contribute to the potentiation of peripheral pain through the excitation of peripheral sensory neurons. In addition, regulatory T cells are identified as a potential target for therapeutic rebalancing of peripheral immune homeostasis to improve functional outcome and decrease the incidence of peripheral inflammatory pain following traumatic brain injury.

Rheumatoid arthritis (RA) is caused by aberrant attack of the joints by native inflammatory system. This can lead to joint destruction and pain that can be debilitating. Increased angiogenesis and innervation by nociceptive afferent fibers are characteristic features of RA joints, which in addition to the elevated levels of a wide variety of inflammatory mediators, are thought to play an important role in the pathogenesis of chronic inflammatory pain associated with RA. Interestingly, a recent report indicates that C–type natriuretic peptide (CNP) is increased in the blood serum of RA patients. Natriuretic peptides (NPs) control natriuresis and normalize changes in blood pressure. Many biological effects of NPs are mediated by guanylate cyclase (GC)–coupled NP receptors, NPR–A and NPR–B, whereas the third NP receptor, NPR–C, lacks the GC kinase domain and acts as the NP clearance receptor. In addition, NPR–C can couple to specific Gái–βã–mediated intracellular signaling cascades in numerous cell types. Recent studies suggest that NPs are also involved in the regulation of pain sensitivity, although the underlying mechanisms remain largely unknown. In Aim 1, I show that CNP acutely sensitized the excitation of mouse dorsal root ganglia (DRG) sensory neurons that is dependent on the transient receptor potential vanilloid–1 (TRPV1). CNP potentiated capsaicin– and proton–activated TRPV1 currents in cultured mouse DRG neurons and increased neuronal firing frequency, an effect that was absent in DRG neurons from TRPV1−/−mice. Further, CNP injection into mouse hind paw led to the development of thermal hyperalgesia, which was absent in TRPV1−/−mice. In Aim 2, I dissected the signaling mechanism underlying TRPV1 sensitization by CNP. My results show that all 3 functional NPRs are expressed in mouse DRG neurons; however NPR–A/B–cGMP signaling is not involved in CNP–mediated sensitization of TRPV1. Interestingly, I observed that sensitization of TRPV1 by CNP is dependent on protein kinase C (PKC) activity. Furthermore, I found that NPR–C is co–expressed in TRPV1–expressing mouse DRG neurons and can be co–immunoprecipitated with Gαi, but not with Gαq/11 or Gαs subunits. CNP treatment induced translocation of PKCå to the plasma membrane of these neurons, which was attenuated by pertussis toxin pre–treatment. Accordingly, CNP–induced sensitization of TRPV1 was attenuated by pre–treatment of DRG neurons with the specific inhibitors of Gβã, phospholipase–Cβ (PLCβ) or PKC, but not of protein kinase A (PKA), and by mutations at two PKC phosphorylation sites, S502 and S800, in the TRPV1 protein. Furthermore, the development of thermal hyperalgesia in CNP–injected hindpaw was attenuated by administration of specific inhibitors of Gβã or PKC. Thus, my work identifies the Gβã–PLCâ–PKC–dependent potentiation of TRPV1 as a novel signaling cascade recruited by CNP in mouse DRG neurons that can lead to enhanced nociceptor excitability and thermal hypersensitivity. Such signaling cascade could presumably constitute one of the mechanisms underlying chronic inflammatory joint pain associated with RA.