RESUMEN
BACKGROUND: P2X7 receptors are responsible for triggering inflammatory responses contributing to processes of pain in articular tissues. This study aimed to investigate whether the activation of the P2X7 receptor located in the temporomandibular joint (TMJ) tissues induces nociception through an inflammatory mechanisms and/or the activation of C-fibres (small-diameter primary afferents) of rats' TMJ. METHODS: The TMJ hypernociception induced by the activation of P2X7 receptor was assessed by measuring the behavioural nociceptive responses. After behavioural experiments, the animals were terminally anaesthetized and periarticular tissues were removed and homogenate for enzyme-linked immunosorbent assay, leukocyte infiltration and western blotting analysis. RESULTS: The nonselective P2X7 receptor agonist BzATP induced a dose-dependent TMJ nociception, which was blocked by the selective P2X7 receptor antagonist A-438079. The co-administration of the selective ß2-adrenoceptor antagonist (ICI-118,551) and the pre-treatment with cyclooxygenase inhibitor indomethacin or with the nonspecific selectin inhibitor Fucoidan significantly reduced BzATP-induced TMJ nociception. BzATP also induced an increase of pro-inflammatory cytokines TNFα, IL-1ß and CINC-1 levels, as well as leukocyte recruitment in TMJ tissue, effects that were reduced by A-438079. Moreover BzATP-induced TMJ nociception was inhibited in rats neonatal-treated with Capsaicin (depleting C-fibers). Finally, BzATP-induced an increase in TRPV1 expression in TMJ tissue. CONCLUSIONS: These findings suggest that P2X7 receptor activation in TMJ of rats induces nociceptive responses mediated by sympathomimetic amines, prostaglandins, leukocyte migration and increased levels of pro-inflammatory cytokines. Furthermore, the P2X7 receptor activation induces nociceptive responses dependent on the activation of the primary afferent nociceptors of rats' TMJ. SIGNIFICANCE: The activation of P2X7 receptors has an essential role in TMJ nociception and could be an interesting target to control the inflammatory pain in temporomandibular disorders.
Asunto(s)
Nocicepción , Trastornos de la Articulación Temporomandibular , Animales , Dolor , Ratas , Ratas Wistar , Articulación Temporomandibular , Trastornos de la Articulación Temporomandibular/inducido químicamenteRESUMEN
The mechanism underlying the role of tumor necrosis factor alpha (TNF-α) in the development of inflammatory hyperalgesia has been extensively studied, mainly the role of TNF-α in the release of pro-inflammatory cytokines. The current concept relies in the fact that TNF-α stimulates the cascade release of other pro-inflammatory cytokines, such as IL-1ß, IL-6, and IL-8 (CINC-1 in rats), triggering the release of the final inflammatory mediator prostaglandin E2 (PGE2 ) and sympathetic amines that directly sensitize the nociceptors. However, this may not be the sole mechanism involved as the blockade of TNF-α synthesis by thalidomide prevents hyperalgesia without interrupting the synthesis of IL-1ß, IL-6, and CINC-1. Therefore, we hypothesized that activation of TNF-α receptor type 1 (TNFR1) by TNF-α increases nociceptors' susceptibility to the action of PGE2 and dopamine. We have found out that intrathecal administration of oligodeoxynucleotide-antisense (ODN-AS) against TNFR1 or thalidomide prevented carrageenan-induced hyperalgesia. The co-administration of TNF-α with a subthreshold dose of PGE2 or dopamine that does not induce hyperalgesia by itself in the hind paw of Wistar rats pretreated with dexamethasone (to prevent the endogenous release of cytokines) induced a robust hyperalgesia that was prevented by intrathecal treatment with ODN-AS against TNFR1. We consider that the activation of neuronal TNFR1 by TNF-α decisively increases the susceptibility of the peripheral afferent neuron to the action of final inflammatory mediators - PGE2 and dopamine - that ultimately induce hyperalgesia. This mechanism may also underlie the analgesic action of thalidomide.
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Receptores Tipo I de Factores de Necrosis Tumoral , Factor de Necrosis Tumoral alfa , Animales , Citocinas , Hiperalgesia/inducido químicamente , Neuronas Aferentes , Dolor , Ratas , Ratas WistarRESUMEN
Diabetic neuropathic hyperalgesia is one of the most common diabetes complications. The physiopathological mechanism of hyperalgesia and the reason by which this condition affects only part of the diabetic patients still unclear. We tested whether an adaptation of primary afferent neurons to hyperglycemia could prevent the development of hyperalgesia. Hyperglycemia was induced in male Wistar rats by a daily administration of a low dose of streptozotocin (STZ), during five consecutive days. Glycemia and mechanical nociceptive thresholds were measured at days 0, 3, 7 and 14 after starting the streptozotocin treatment. In parallel, dorsal root ganglia (DRG) neurons were collected from healthy male Wistar rats and cultured in different glucose concentrations (mimicking slow or fast increase of hyperglycemia), and used for calcium imaging and Western blot analyses. Rats with a slow increase of glycemia did not develop hyperalgesia, while rats with a fast increase of glycemia developed hyperalgesia. DRG neurons suddenly incubated in DMEM containing a high glucose concentration showed a significant increase of calcium influx. However, DRG neurons incubated in DMEM and receiving increasing doses of glucose had the same calcium influx observed in control neurons. The activation of AMPK (α1/α2) was greater in L5-L6 DRG of hyperglycemic and non-hyperalgesic rats, when compared with hyperglycemic and hyperalgesic rats. Our data suggest that the onset speed of hyperglycemia could be related to the development of diabetic neuropathic hyperalgesia, as a maladaptive consequence associated with low activation of AMPK (α1/α2) in peripheral nociceptive neurons when the glycemia suddenly increases.
Asunto(s)
Diabetes Mellitus Experimental , Hiperglucemia , Animales , Diabetes Mellitus Experimental/inducido químicamente , Diabetes Mellitus Experimental/complicaciones , Ganglios Espinales , Humanos , Hiperalgesia , Hiperglucemia/inducido químicamente , Hiperglucemia/complicaciones , Masculino , Ratas , Ratas Wistar , Estreptozocina/toxicidadRESUMEN
The mechanism of action of Platelet Rich Plasma (PRP) is thought to be related to the biomolecules present in α-granules. However, for the healing process to occur, an inflammatory phase is also deemed necessary. Leukocytes present in the inflammatory phase release both pro- and anti-inflammatory molecules. The latter may play an important role in the process of "inflammatory regeneration". Thus, we propose that in the context of healing, both platelets and leukocytes play an important role, specifically due to the macrophage's plasticity to switch from the M1 to M2 fraction. Therefore, we propose that PRP products derived from the buffy coat may be more beneficial than detrimental from a standpoint of the regenerative potential of PRP.
RESUMEN
BACKGROUND: Although TRPA1, SP, histamine and 5-hydroxytryptamine (5-HT) have recognized contribution to nociceptive mechanisms, little is known about how they interact with each other to mediate inflammatory pain in vivo. In this study we evaluated whether TRPA1, SP, histamine and 5-HT interact, in an interdependent way, to induce nociception in vivo. METHODS AND RESULTS: The subcutaneous injection of the TRPA1 agonist allyl isothiocyanate (AITC) into the rat's hind paw induced a dose-dependent and short lasting behavioral nociceptive response that was blocked by the co-administration of the TRPA1 antagonist, HC030031, or by the pretreatment with antisense ODN against TRPA1. AITC-induced nociception was significantly decreased by the co-administration of selective antagonists for the NK1 receptor for substance P, the H1 receptor for histamine and the 5-HT1A or 3 receptors for 5-HT. Histamine- or 5-HT-induced nociception was decreased by the pretreatment with antisense ODN against TRPA1. These findings suggest that AITC-induced nociception depends on substance P, histamine and 5-HT, while histamine- or 5-HT-induced nociception depends on TRPA1. Most important, AITC interact in a synergistic way with histamine, 5-HT or substance P, since their combination at non-nociceptive doses induced a nociceptive response much higher than that expected by the sum of the effect of each one alone. This synergistic effect is dependent on the H1, 5-HT1A or 3 receptors. CONCLUSION: Together, these findings suggest a self-sustainable cycle around TRPA1, no matter where the cycle is initiated each step is achieved and even subeffective activation of more than one step results in a synergistic activation of the overall cycle.
Asunto(s)
Histamina/metabolismo , Dolor/metabolismo , Serotonina/metabolismo , Sustancia P/metabolismo , Canales Catiónicos TRPC/metabolismo , Acetanilidas/farmacología , Animales , Antagonistas de los Receptores Histamínicos H1/farmacología , Isotiocianatos , Masculino , Oligonucleótidos Antisentido/farmacología , Dolor/inducido químicamente , Piperazinas/farmacología , Purinas/farmacología , Pirilamina/farmacología , Quinuclidinas/farmacología , Ratas Wistar , Receptor de Serotonina 5-HT1A/metabolismo , Receptores Histamínicos H1/metabolismo , Receptores de Neuroquinina-1/metabolismo , Receptores de Serotonina 5-HT3/metabolismo , Antagonistas de la Serotonina/farmacología , Canal Catiónico TRPA1 , Canales Catiónicos TRPC/agonistas , Canales Catiónicos TRPC/antagonistas & inhibidores , Canales Catiónicos TRPC/genética , p-Metoxi-N-metilfenetilamina/farmacologíaRESUMEN
AIMS: Although evidence suggest that TRPA1 mediates some effects of prostaglandins, it is not known whether TRPA1 contributes to the in vivo nociceptive effects of prostaglandin E2 (PGE2), a key mediator of inflammatory pain. MAIN METHODS: To address this issue, the effect of the pharmacological blockade of TRPA1 or of its gene silencing on the hyperalgesia induced in the rat paw by PGE2 or its downstream signaling molecules, protein kinase A (PKA) or protein kinase C-epsilon (PKCε), was evaluated. TRPA1 expression on dorsal root ganglia cells was assessed by western blot. KEY FINDINGS: The pharmacological blockade of local TRPA1 by its selective antagonist, HC 030031 decreased and reversed PGE2-induced hyperalgesia. The TRPA1 gene silencing induced by intrathecal pre-treatment with antisense oligodeoxynucleotide blocked PGE2-induced hyperalgesia and strongly reduced TRPA1 expression in dorsal root ganglia cells (L5 and L6). PGE2 injection into the hind paw did not significantly increase TRPA1 expression in dorsal root ganglia cells. Treatment with either HC 030031 or antisense oligodeoxynucleotide significantly decreased the hyperalgesia induced by PKA or PKCε. Since both kinases are the major components of PGE2-induced intracellular signal transduction, the modulation of TRPA1 function by PGE2 may be downstream PKA and PKC-epsilon. SIGNIFICANCE: These findings show that TRPA1 is essential to the in vivo nociceptive effects induced by one of the most important mediators of inflammatory pain, PGE2. This is one of the crucial findings necessary to support TRPA1 as a promising target for the development of future drugs to pain treatment and control.
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Dinoprostona/metabolismo , Ganglios Espinales/metabolismo , Nocicepción/fisiología , Canales Catiónicos TRPC/metabolismo , Acetanilidas/farmacología , Análisis de Varianza , Animales , Western Blotting , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Factores de Crecimiento de Fibroblastos , Silenciador del Gen , Proteína Quinasa C-epsilon/metabolismo , Purinas/farmacología , Ratas , Canal Catiónico TRPA1 , Canales Catiónicos TRPC/antagonistas & inhibidores , Canales Catiónicos TRPC/genéticaRESUMEN
UNLABELLED: Acupuncture-induced analgesia depends on the activation of endogenous pain modulation pathways. In this study, we asked whether ascending nociceptive control (ANC), a form of pain-induced analgesia, contributes to the antinociceptive effect of acupuncture. To answer this question, we tested the ability of procedures that block ANC-induced analgesia, at peripheral, spinal, nucleus accumbens and rostral ventral medulla levels, to block acupuncture-induced analgesia. Acupuncture at ST36 (Zusanli), a widely used acupoint located in the hind limb, induced potent heterosegmental antinociception in the orofacial formalin test. The magnitude of this antinociceptive effect was similar to that induced by an intraplantar injection of capsaicin, a procedure classically used to activate ANC. The antinociceptive effect of acupuncture was blocked by sciatic C-fibers depletion (1% perineural capsaicin), spinal administration of a µ-opioid (Cys2,Tyr3,Orn5,Pen7amide, .2 µg) or of a GABAA (bicuculline, .3 µg) receptor antagonist, intra-nucleus accumbens administration of a µ-opioid receptor antagonist (Cys2,Tyr3,Orn5,Pen7amide, 1 µg), or intrarostral ventral medulla administration of a nicotinic acetylcholine receptor antagonist (mecamylamine, .6 µg). In addition, acupuncture at ST36 and/or upper lip formalin induced c-Fos expression in the nucleus accumbens and in rostral ventral medulla. On the basis of these results, we propose that ANC contributes to the antinociceptive effect of acupuncture. PERSPECTIVE: This article presents a novel mechanism of acupuncture analgesia, contributing to the understanding of its scientific basis. Because ANC is a pain modulation pathway activated by peripheral noxious stimulation that ascends to supraspinal regions, it could be the link between acupoint stimulation and the central mechanisms underlying acupuncture analgesia.
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Analgesia por Acupuntura , Dolor Agudo/fisiopatología , Vías Aferentes/fisiología , Nocicepción/fisiología , Dolor Nociceptivo/fisiopatología , Dolor Agudo/terapia , Animales , Modelos Animales de Enfermedad , Masculino , Dolor Nociceptivo/terapia , Dimensión del Dolor , Ratas , Ratas WistarRESUMEN
The aim of this study was to investigate the mechanisms that contribute to hyperalgesia and edema induced by TRPA1 activation. The injection of allyl isothiocyanate (AITC, 50, 100, or 300 µg/paw) into the rat's hind paw induced dose and time-dependent hyperalgesia and edema, which were blocked by the selective TRPA1 antagonist, HC 030031 (1,200 µg/paw), or by treatment with antisense oligodeoxynucleotide (four daily intrathecal injections of 5 nmol). These results demonstrate that the hyperalgesia and edema induced by AITC depend on TRPA1 activation. AITC-induced hyperalgesia and edema were significantly reduced by treatment with neurokinin 1 (L-703,606, 38 µg/paw) or calcitonin gene-related peptide (CGRP8-37 , 5 µg/paw) receptor antagonists, with a mast cell degranulator (compound 48/80, four daily injections of 1, 3, 10, and 10 µg/paw) or with H1 (pyrilamine, 400 µg/paw), 5-HT1A (wAy-100,135, 450 µg/paw) or 5-HT3 (tropisetron, 450 µg/paw) receptor antagonists. Pre-treatment with a selectin inhibitor (fucoidan, 20 mg/kg) significantly reduced AITC-induced hyperalgesia, edema, and neutrophil migration. Finally, a cyclooxygenase inhibitor (indomethacin, 100 µg/paw), a ß1 (atenolol, 6 µg/paw) or a ß2 (ICI 118, 551, 1.5 µg/paw) adrenoceptor antagonist also significantly reduced AITC-induced hyperalgesia and edema. Together, these results demonstrate that TRPA1 mediates some of the key inflammatory mechanisms, suggesting a key role of this receptor in pain and inflammation.
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Edema/complicaciones , Hiperalgesia/metabolismo , Canales Catiónicos TRPC/metabolismo , Acetanilidas/toxicidad , Análisis de Varianza , Animales , Péptido Relacionado con Gen de Calcitonina/farmacología , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Edema/inducido químicamente , Edema/tratamiento farmacológico , Extremidades/patología , Regulación de la Expresión Génica/efectos de los fármacos , Hiperalgesia/inducido químicamente , Hiperalgesia/tratamiento farmacológico , Masculino , Oligodesoxirribonucleótidos Antisentido/uso terapéutico , Fragmentos de Péptidos/farmacología , Peroxidasa/metabolismo , Piperazinas/farmacología , Purinas/toxicidad , Quinuclidinas/farmacología , Ratas , Ratas Wistar , Antagonistas de la Serotonina/farmacología , Canal Catiónico TRPA1 , Canales Catiónicos TRPC/antagonistas & inhibidoresRESUMEN
Transient receptor potential ankyrin 1 (TRPA1) is a nonselective cation channel important in setting nociceptive threshold. It is expressed in nociceptive C-fibers and in non-neuronal cells involved in pro-inflammatory mediators' release. We asked whether TRPA1 contributes to carrageenan-induced hyperalgesia in rats, and if so, whether this contribution is mediated by mechanisms involved in inflammation such as cytokine release and neutrophil migration and/or by a direct sensitization of the primary afferent nociceptors. Pharmacological blockade of local TRPA1 by its selective antagonist HC 030031 prevented and reversed carrageenan-induced hyperalgesia, which was detected either by a mechanical or chemical (low dose of capsaicin) stimulus. However, it did not affect either carrageenan-induced cytokines expression or neutrophil migration. The neuronal TRPA1 gene silencing induced by intrathecal pre-treatment with antisense oligodoexynucleotide completely prevented carrageenan-induced hyperalgesia over 24 h and significantly reduced TRPA1 expression in the dorsal root ganglia cells (L5-6), which was not affected by carrageenan treatment. We conclude that TRPA1 plays an important role in the development and maintenance of carrageenan-induced inflammatory hyperalgesia by directly contributing to nociceptor excitability.
Asunto(s)
Carragenina/toxicidad , Hiperalgesia/inducido químicamente , Hiperalgesia/metabolismo , Canales Catiónicos TRPC/antagonistas & inhibidores , Canales Catiónicos TRPC/fisiología , Acetanilidas/farmacología , Animales , Silenciador del Gen/efectos de los fármacos , Silenciador del Gen/fisiología , Hiperalgesia/genética , Masculino , Dimensión del Dolor/efectos de los fármacos , Dimensión del Dolor/métodos , Purinas/farmacología , Ratas , Ratas Wistar , Canal Catiónico TRPA1RESUMEN
We have previously demonstrated that activation of kappa-opioid receptor located in the temporomandibular joint (TMJ) of rats induces a significantly greater TMJ antinociception in diestrus females than in proestrus females (higher estradiol serum levels than diestrus) and males. These findings indicate that gonadal hormones decrease TMJ kappa-mediated antinociception. The aim of this study was to investigate some of the mechanisms by which gonadal hormones decrease TMJ kappa-mediated antinociception. Western blot analysis demonstrated a significantly lower kappa-opioid receptor expression in the trigeminal ganglia of intact males than in intact and ovariechtomized (OVX) females and orchidectomized (ORX) males. In females, kappa-opioid receptor expression in the trigeminal ganglia was significantly lower in proestrus than in diestrus and OVX females. Taken together these findings suggest that gonadal hormones, especially male gonadal hormones, down-regulate kappa-opioid receptor expression. Co-application of the NOS inhibitor L-NMMA or the NO-sensitive guanylyl cyclase inhibitor ODQ with the kappa-opioid receptor agonist U50,488 blocked TMJ kappa-mediated antinociception in males and females. These findings suggest that antinociception induced by activation of kappa opioid receptors in the TMJ region is mediated by the L-arginine/NO/cGMP pathway in both sexes. Despite the involvement of the L-arginine/NO/cGMP pathway in TMJ kappa-mediated antinociception in both sexes, gonadal hormones do not diminish the activity of this pathway to decrease TMJ kappa-mediated antinociception. Alternatively, they significantly reduce kappa-opioid receptor expression in the trigeminal ganglia.
Asunto(s)
Analgésicos/farmacología , Regulación hacia Abajo/efectos de los fármacos , Hormonas Gonadales/metabolismo , Dolor/metabolismo , Receptores Opioides kappa/metabolismo , Articulación Temporomandibular/metabolismo , Ganglio del Trigémino/metabolismo , Analgésicos/uso terapéutico , Animales , Arginina/metabolismo , GMP Cíclico/metabolismo , Femenino , Humanos , Masculino , Óxido Nítrico/metabolismo , Oxadiazoles/farmacología , Dolor/tratamiento farmacológico , Quinoxalinas/farmacología , Ratas , Ratas Wistar , Receptores Opioides kappa/agonistas , Caracteres Sexuales , Transducción de Señal/efectos de los fármacos , Ganglio del Trigémino/efectos de los fármacos , omega-N-Metilarginina/farmacologíaRESUMEN
The duration of noxious stimulus-induced antinociception (NSIA) has been shown to outlast the pain stimulus that elicited it, however, the mechanism that determines the duration of analgesia is unknown. We evaluated the role of spinal excitatory and inhibitory receptors (NMDA, mGluR(5), mu-opioid, GABA(A), and GABA(B)), previously implicated in NSIA initiation, in its maintenance. As in our previous studies, the supraspinal trigeminal jaw-opening reflex (JOR) in the rat was used for nociceptive testing because of its remoteness from the region of drug application, the lumbar spinal cord. NSIA was reversed by antagonists for two inhibitory receptors (GABA(B) and mu-opioid) but not by antagonists for either of the two excitatory receptors (NMDA and mGluR(5)), indicating that NSIA is maintained by ongoing activity at inhibitory synapses in the spinal cord. Furthermore, spinal administration of the GABA(B) agonist baclofen mimicked NSIA in that it could be blocked by prior injection of the mu-opioid receptor antagonist H-D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH(2) (CTAP) in nucleus accumbens. CTAP also blocked baclofen antinociception when administered in the spinal cord. We conclude that analgesia induced by noxious stimulation is maintained by activity in spinal inhibitory receptors.
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Inhibición Neural/fisiología , Umbral del Dolor/fisiología , Dolor/fisiopatología , Médula Espinal/fisiología , Transmisión Sináptica/fisiología , Analgésicos/antagonistas & inhibidores , Animales , Baclofeno/farmacología , Capsaicina/antagonistas & inhibidores , Interacciones Farmacológicas/fisiología , Agonistas del GABA/farmacología , Antagonistas del GABA/farmacología , Agonistas de Receptores GABA-B , Antagonistas de Receptores de GABA-B , Masculino , Antagonistas de Narcóticos/farmacología , Inhibición Neural/efectos de los fármacos , Dolor/inducido químicamente , Umbral del Dolor/efectos de los fármacos , Péptidos/farmacología , Ratas , Ratas Sprague-Dawley , Receptores de GABA-B/metabolismo , Receptores Opioides mu/antagonistas & inhibidores , Receptores Opioides mu/metabolismo , Fármacos del Sistema Sensorial/antagonistas & inhibidores , Médula Espinal/efectos de los fármacos , Sinapsis/efectos de los fármacos , Sinapsis/fisiología , Transmisión Sináptica/efectos de los fármacosRESUMEN
UNLABELLED: The aim of this study was to investigate the influence of sex and ovarian hormones on formalin- and glutamate-induced temporomandibular joint (TMJ) nociception in rats. The influence of sex and ovarian hormones on the nociceptive behavior induced by formalin or glutamate was virtually the same. The nociceptive behavior of males was similar to that of females in the proestrus phase of the estrous cycle but was significantly lower than that in the diestrus phase. Since the serum level of estradiol but not of progesterone was significantly higher in the proestrus than in the diestrus phase, these data suggest that females with lower endogenous serum level of estradiol have an exacerbation of TMJ nociception. The nociceptive behavior of ovariectomized rats was similar to that of diestrus females and significantly greater than that of proestrus females. Although the administration of estradiol or progesterone in ovariectomized females significantly reduced TMJ nociception, the combination of both hormones did not increase the antinociceptive effect induced by each of them. These findings suggest that estradiol and progesterone decrease TMJ nociception in an independent way. PERSPECTIVE: We report that ovarian hormones have an antinociceptive effect on the TMJ formalin and glutamate nociceptive behavior models. Therefore, the greater prevalence and severity of TMJ pain in women of reproductive age may be a consequence of hormonal fluctuation during the reproductive cycle, in that during low endogenous estradiol serum level TMJ pain sensitivity is increased, enhancing the risk of females experiencing TMJ pain.
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Estradiol/fisiología , Nociceptores/fisiología , Dolor/fisiopatología , Progesterona/fisiología , Trastornos de la Articulación Temporomandibular/fisiopatología , Animales , Conducta Animal/efectos de los fármacos , Conducta Animal/fisiología , Diestro/fisiología , Estradiol/sangre , Femenino , Formaldehído/administración & dosificación , Formaldehído/toxicidad , Ácido Glutámico/administración & dosificación , Ácido Glutámico/toxicidad , Humanos , Inyecciones Intraarticulares , Inyecciones Intraperitoneales , Masculino , Nociceptores/efectos de los fármacos , Ovariectomía , Dolor/inducido químicamente , Dimensión del Dolor/métodos , Proestro/fisiología , Progesterona/sangre , Radioinmunoensayo , Ratas , Ratas Sprague-Dawley , Ratas Wistar , Factores Sexuales , Articulación Temporomandibular/efectos de los fármacos , Articulación Temporomandibular/fisiopatología , Trastornos de la Articulación Temporomandibular/sangre , Trastornos de la Articulación Temporomandibular/inducido químicamenteRESUMEN
A considerable amount of evidence suggests that temporomandibular joint (TMJ) pain associated with temporomandibular disorder results, at least in part, from an inflammatory episode. Although histamine can cause pain, it is not clear whether this mediator induces nociception in the TMJ. In this study, we investigated the contribution of endogenous histamine to formalin-induced nociception in the TMJ of rats. We also investigated whether the administration of histamine induces nociception in the TMJ and, if so, whether this effect is mediated by an indirect action on primary afferent nociceptors. Local administration of the H1-receptor antagonist pyrilamine prevented formalin-induced nociception in the TMJ in a dose-dependent manner. Local administration of histamine (250 microg) in the TMJ induced nociceptive behavior that was inhibited by co-administration of the lidocaine N-ethyl bromide quaternary salt QX-314 (2%) or the selective H1-receptor antagonist pyrilamine (400 microg). Nociception induced by histamine was also inhibited by pre-treatment with sodium cromoglycate (800 microg) and by co-administration of the 5-HT(3) receptor antagonist tropisetron (400 mug), while pyrilamine (400 mug) did not inhibit nociception induced by 5-hydroxytryptamine (5-HT, 250 microg) in the TMJ. Furthermore, histamine, in a dose that did not induce nociception by itself, strongly enhanced 5-HT-induced nociception. Finally, the administration of a sub-threshold dose of 5-HT (100 microg), but not of histamine (100 microg), elicited nociception in the TMJ previously challenged with the inflammatory agent carrageenan (100 microg). In conclusion, these data suggest that histamine induces TMJ nociception by an indirect mechanism involving endogenous release of 5-HT and activation of 5-HT(3) receptors on sensory afferents. It is proposed that histamine activates the H1 receptor to induce the release of 5-HT which depolarizes the nociceptor by activating 5-HT(3) receptor.
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Histamina/farmacología , Dolor , Receptores Histamínicos H1/metabolismo , Trastornos de la Articulación Temporomandibular , Articulación Temporomandibular , Animales , Antiinflamatorios no Esteroideos/farmacología , Conducta Animal/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Histamina/metabolismo , Antagonistas de los Receptores Histamínicos H1/farmacología , Masculino , Dolor/inducido químicamente , Dolor/tratamiento farmacológico , Dolor/metabolismo , Dolor/fisiopatología , Dimensión del Dolor , Ratas , Ratas Wistar , Serotonina/metabolismo , Serotonina/farmacología , Serotonina/fisiología , Antagonistas de la Serotonina/farmacología , Articulación Temporomandibular/efectos de los fármacos , Articulación Temporomandibular/metabolismo , Trastornos de la Articulación Temporomandibular/inducido químicamente , Trastornos de la Articulación Temporomandibular/tratamiento farmacológico , Trastornos de la Articulación Temporomandibular/metabolismo , Trastornos de la Articulación Temporomandibular/fisiopatologíaRESUMEN
UNLABELLED: The lower prevalence of many pain conditions, including temporomandibular dysfunctions, in men than in women has not as yet been clarified. The aim of this study was to investigate the effect of testosterone on the risk of development of temporomandibular joint (TMJ) pain and on acute persistent TMJ pain. The TMJ formalin test was used as an experimental assay in the rat. Intra-TMJ 0.5% formalin induced a significant nociceptive behavior in naive female rats and gonadectomized male rats but not in naive male rats, suggesting that naive male rats have a lower risk for development of TMJ pain. The finding that the serum level of testosterone but not of estrogen and progesterone significantly decreased in gonadectomized male rats suggests that testosterone is the hormone underlying the decreased naive male rat's risk for development of TMJ pain. The magnitude of the nociceptive behaviors induced by intra-TMJ 1.5% formalin was similar in gonadectomized and naive male rats. Therefore, in contrast to the protective role of testosterone in TMJ pain development, testosterone, at physiological serum levels, does not appear to modulate acute persistent TMJ pain induced by the TMJ injection of 1.5% formalin. At a supraphysiological serum level, however, testosterone significantly attenuated 1.5% formalin-induced nociception in male rats but not in female rats. This antinociceptive effect was not mediated by estrogen derived from testosterone aromatization, because estrogen administration did not affect 1.5% formalin-induced TMJ nociception in gonadectomized male rats. PERSPECTIVE: The present findings not only help to explain the lower prevalence of TMJ pain in males versus females but also show that testosterone reduces TMJ pain at supraphysiological serum levels.
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Andrógenos/uso terapéutico , Dolor/etiología , Dolor/prevención & control , Trastornos de la Articulación Temporomandibular/complicaciones , Testosterona/uso terapéutico , Análisis de Varianza , Animales , Castración , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Femenino , Formaldehído , Masculino , Dimensión del Dolor , Ratas , Ratas Wistar , Factores Sexuales , Trastornos de la Articulación Temporomandibular/inducido químicamenteRESUMEN
Although interferon-gamma (IFN-gamma) plays a critical role in periodontitis, no information is available regarding the effect of smoking on this cytokine in the periodontium. Therefore, this study aimed to evaluate the effect of smoking on the IFN-gamma levels in gingival tissue from patients with chronic periodontitis. Sixty-two patients were assigned to three groups: healthy [non-smoking and periodontally healthy individuals (probing depth
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Encía/metabolismo , Interferón gamma/metabolismo , Periodontitis/metabolismo , Fumar/metabolismo , Adulto , Antivirales/inmunología , Enfermedad Crónica , Métodos Epidemiológicos , Femenino , Humanos , Interferón gamma/efectos de los fármacos , Masculino , Persona de Mediana Edad , ARN Mensajero/análisis , Fumar/efectos adversosRESUMEN
BACKGROUND AND PURPOSE: Although interferential therapy (IFT) is used widely in the management of many painful conditions, the effectiveness and the mechanism of action of IFT in animal models of inflammatory pain have not been evaluated. The aim of this study was to evaluate the effectiveness of IFT in reducing inflammatory pain and edema in rats. SUBJECTS: Sixty-nine male Wistar rats were used in the study. METHODS: The effect of IFT application (4,000-Hz carrier frequency, 140-Hz amplitude-modulated beat frequency, pulse duration=125 milliseconds, current intensity=5 mA) for 1 hour on the formalin-induced nociceptive response and edema and on carrageenan-induced mechanical hyperalgesia and edema was evaluated. RESULTS: Interferential therapy significantly reduced the formalin-evoked nociceptive response when applied to the paw immediately after but not before the formalin injection. Interferential therapy application at 2 hours after the carrageenan injection significantly prevented a further increase in carrageenan-induced mechanical hyperalgesia only immediately after discontinuation of the electrical current application. The antinociception induced by IFT was not attributable to a reduction in inflammation because IFT did not significantly reduce the edema induced by either formalin or carrageenan. DISCUSSION AND CONCLUSION: The results suggest that, despite its short-duration effect, IFT is effective in reducing inflammatory pain and should be considered primarily for use in the control of acute inflammatory pain.
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Edema/prevención & control , Inflamación/prevención & control , Dolor/prevención & control , Estimulación Eléctrica Transcutánea del Nervio/métodos , Animales , Carragenina/farmacología , Modelos Animales de Enfermedad , Fijadores , Formaldehído , Hiperalgesia/inducido químicamente , Hiperalgesia/prevención & control , Masculino , Nociceptores , Dimensión del Dolor , Ratas , Ratas Wistar , Factores de TiempoRESUMEN
This study assessed the effect of the kappa opioid receptor agonist U50,488 administered into the rat temporomandibular joint (TMJ) on nociceptive behavioral responses evoked by formalin injected into the same site. Groups consisted of females, stratified into proestrus and diestrus phases of the estrous cycle, and males. Intra-TMJ formalin induced significantly different dose-dependent responses among the three groups, with diestrus females showing greater responses than males or proestrus females; therefore, equi-nociceptive formalin doses were chosen to test the effects of U50,488. U50,488 significantly reduced formalin-induced nociceptive behavior in all groups, but the reduction was significantly greater in females, especially those in diestrus. Pre-injection of the selective kappa opioid receptor antagonist nor-binaltorphimine (nor-BNI) into the same site significantly attenuated the effect of U50488; U50,488 injection into the contralateral TMJ failed to reduce nociceptive behavior. These findings support a role for kappa opioid receptors local to the site of inflammation to modulate inflammatory pain. Furthermore, since plasma levels of ovarian hormones are low during diestrus, these findings are consistent with the suggestion that sex hormones may play an antagonistic role in these peripheral kappa-mediated effects.
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3,4-Dicloro-N-metil-N-(2-(1-pirrolidinil)-ciclohexil)-bencenacetamida, (trans)-Isómero/farmacología , Analgésicos no Narcóticos/farmacología , Naltrexona/análogos & derivados , Receptores Opioides kappa/agonistas , Articulación Temporomandibular/fisiología , Animales , Relación Dosis-Respuesta a Droga , Ciclo Estral/fisiología , Femenino , Formaldehído , Masculino , Naltrexona/farmacología , Dimensión del Dolor/efectos de los fármacos , Ratas , Ratas Wistar , Caracteres Sexuales , Articulación Temporomandibular/efectos de los fármacosRESUMEN
Temporomandibular joint (TMJ) pain conditions are poorly understood. Since formalin is a noxious stimulus widely used in animal behavioral experiments for studying pain mechanisms, the aim of this study was to develop a behavioral model to study the TMJ pain conditions by characterizing the nociceptive behavioral responses induced by the injection of formalin into the TMJ region of rats. NaCl (0.9%) or different concentrations of formalin (0.5, 1.5, 2.5 or 5%) were administrated into the TMJ region. The formalin-induced behavioral responses characterized by moving the mandible, rubbing the orofacial region and flinching the head quickly were quantified for 45 min. The TMJ injection of formalin significantly increased the asymmetrical orofacial rubbing and head flinching behaviors, but not the movement of the mandible with concentrations of 1.5% and above (P<0.05, Dunn's test) when compared with the NaCl (0.9%) injection. These responses were significantly reduced (P<0.05, Mann-Whitney test) by the co-application of lidocaine N-ethyl bromide quaternary salt, QX-314 (2%), and by the administration of intraperitoneal morphine (4 mg/kg) 30 min prior to the TMJ formalin injection. This study demonstrates that the injection of formalin into the TMJ region of rats produces quantitative nociceptive behaviors constituting a novel behavioral model for TMJ pain.