RESUMO
AIMS: Investigate the involvement of the histaminergic projections from tuberomammillary nucleus (TMN) to the spinal cord in the modulation of nociception and peripheral edema in a model of monoarthritis. MAIN METHODS: Subacute monoarthritis was induced by an intraarticular injection of carrageenan followed by LPS 72 h later. Disability and joint edema were assessed at the 3rd hour after LPS and at every hour up to 6 h. KEY FINDINGS: Intrathecal administration of histamine potentiated joint incapacitation and edema, while the H1R antagonist cetirizine decreased both. The H3R agonist immepip decreased both incapacitation and edema, while the H3R antagonist thioperamide had the opposite effect. The microinjection of glutamate into the ventral TMN (vTMN) caused an increase of incapacitation and articular edema, whereas the blockade of this nucleus by cobalt chloride inhibited both parameters. Intrathecal administration of cetirizine prevented the increase of incapacitation and joint edema caused by glutamate microinjection into the vTMN. Similarly, an intrathecal injection of the NKCC1 cotransporter inhibitor bumetanide prevented the effects of glutamate microinjection into the vTMN, whereas coadministration of histamine with bumetanide only inhibited the potentiation of joint edema. A microinjection of orexin B into the vTMN potentiated incapacitation and joint edema, while coadministration of the OX1/2 receptor antagonist almorexant with orexin B did not. SIGNIFICANCE: These data support the notion that TMN participates in the modulation of a peripheral inflammatory process by means of histaminergic projections to the spinal cord, and the hypothalamus may trigger TMN activation by means of glutamate and orexin.
Assuntos
Artrite Experimental/fisiopatologia , Edema/patologia , Região Hipotalâmica Lateral/metabolismo , Nociceptividade/fisiologia , Medula Espinal/metabolismo , Acetamidas/farmacologia , Animais , Feminino , Histamina/administração & dosagem , Isoquinolinas/farmacologia , Orexinas/administração & dosagem , Ratos , Ratos WistarRESUMO
The results of this study show that the oral administration of ivermectin (48 mg/L) repeatedly for 72 h used in accordance with the present protocol is a safe and highly effective treatment for Giardia spp. and Hymenolepis nana in laboratory rat colonies. The drug can be easily and safely administered using drinking water. This simple regimen should control pinworm infection (Syphacia muris), a problem that can be endemic in laboratory colonies. Experiments using healthy animals are likely to generate more consistent results, thereby requiring a reduced number of animals per group.
Assuntos
Antiparasitários/uso terapêutico , Giardíase/veterinária , Himenolepíase/veterinária , Ivermectina/uso terapêutico , Oxiuríase/veterinária , Ratos , Doenças dos Roedores/tratamento farmacológico , Administração Oral , Animais , Antiparasitários/farmacologia , Feminino , Trato Gastrointestinal/parasitologia , Giardia/efeitos dos fármacos , Giardíase/tratamento farmacológico , Giardíase/parasitologia , Himenolepíase/tratamento farmacológico , Himenolepíase/parasitologia , Hymenolepis nana/efeitos dos fármacos , Ivermectina/farmacologia , Masculino , Oxiuríase/tratamento farmacológico , Oxiuríase/parasitologia , Oxyuroidea/efeitos dos fármacos , Contagem de Ovos de Parasitas/veterinária , Ratos Wistar , Doenças dos Roedores/parasitologia , RoedoresRESUMO
Anxiety and/or fear can alter the nociceptive response in humans and animals. Slight stimulation of the dorsal periaqueductal gray matter (DPAG) produced anxiety/fear-related behaviour and hyponociception in escapable, non-anxiogenic nociceptive models. Our aim was to investigate the role of the DPAG in models of persistent, anxiogenic nociception. GLY (1, 10, 20, and 80 nmol/0.3 microl/60s) was injected into the DPAG of rats, 5 min before formalin (2%/50 microl) injection either into the knee-joint or hind paw. In the knee-joint incapacitation test, GLY caused hypernociception at lower doses and hyponociception at higher doses. In the paw shacking test, GLY produced only hypernociception with the higher dose. Co-injecting GLY with 7-chlorokynurenic acid (7-CLK) or (+/-)-3-amino-1-hydroxy-2-pyrrolidone (HA-966) completely prevented the GLY effects in incapacitation and paw shacking tests, respectively. GLY injections outside the periaqueductal gray matter (PAG) did not change the nociception. Behavioural analysis indicated that formalin paw injection produced higher stress signals than knee-joint injection, as diminished exploratory behaviour, and stereotypy. The results suggest that activation of the DPAG through the GLY(B)/NMDA receptor is able to produce either facilitation or inhibition of nociception depending on the nociceptive context.
Assuntos
Glicina/farmacologia , Medição da Dor/métodos , Dor/tratamento farmacológico , Substância Cinzenta Periaquedutal/fisiologia , Animais , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Interações Medicamentosas , Formaldeído , Glicina/administração & dosagem , Glicina/antagonistas & inibidores , Ácido Cinurênico/administração & dosagem , Ácido Cinurênico/análogos & derivados , Ácido Cinurênico/farmacologia , Masculino , Microinjeções , Dor/induzido quimicamente , Substância Cinzenta Periaquedutal/efeitos dos fármacos , Pirrolidinonas/administração & dosagem , Pirrolidinonas/farmacologia , Ratos , Ratos WistarRESUMO
OBJECTIVE: Nonsteroidal anti-inflammatory drugs constitute the primary therapeutic approach in reactive arthritis. Here, we compared etoricoxib, a specific COX-2 inhibitor, with other cyclooxygenase inhibitors on articular incapacitation, edema, leukocyte migration, and gastric damage, in a model of LPS-induced reactive arthritis in rats. METHODS: E. coli Lipopolysaccharide was injected into a carrageenan-primed knee-joint of rats. The effects of etoricoxib, piroxicam, indomethacin, as well the combination of etoricoxib either with piroxicam or indomethacin, were evaluated on articular incapacitation and edema. Afterwards, the synovial leukocyte ontent and the stomach bleeding points were counted. RESULTS: Etoricoxib, piroxicam, and indomethacin dose-dependently inhibited incapacitation and edema. However, only etoricoxib inhibited both mononuclear and polymorphonuclear leukocyte migration. Piroxicam inhibited only mononuclear migration, while indomethacin even increased polymorphonuclear content in inflamed synovia. Associating etoricoxib with either subeffective doses of piroxicam or indomethacin did not enhance the hyponociceptive or the antiedematogenic effect, but prevented the anti-leukocyte migration effect and increased gastric damage. CONCLUSION: The present results suggest that the selective COX-2 inhibitor etoricoxib could be a better option than non-selective COX inhibitors, since it presented a potent inhibitory effect on the clinical signals and also a potent inhibition on cell migration.
Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Artrite Experimental/tratamento farmacológico , Artrite Experimental/imunologia , Inibidores de Ciclo-Oxigenase/uso terapêutico , Lipopolissacarídeos/imunologia , Piridinas/uso terapêutico , Sulfonas/uso terapêutico , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Artrite Experimental/patologia , Carragenina/imunologia , Inibidores de Ciclo-Oxigenase/farmacologia , Etoricoxib , Mucosa Gástrica/efeitos dos fármacos , Mucosa Gástrica/patologia , Indometacina/farmacologia , Indometacina/uso terapêutico , Articulação do Joelho/imunologia , Articulação do Joelho/patologia , Leucócitos/citologia , Leucócitos/imunologia , Masculino , Medição da Dor , Piroxicam/farmacologia , Piroxicam/uso terapêutico , Piridinas/farmacologia , Ratos , Ratos Wistar , Sulfonas/farmacologia , Líquido Sinovial/citologiaRESUMO
Electrical or glutamate stimulation of the dorsal periaqueductal gray matter (DPAG) of rats induces overt defensive behavior, such as freezing or flight, and hyponociception, while glycine and D-serine, a specific NMDA/GLY(B)-site ligand, produced only subtle defensive behavior related to risk assessment and avoidance from the open arms in the elevated plus-maze test. In order to verify whether the GLY(B) site in the DPAG could also be involved in hyponociception, glycine (GLY; 10, 20, 50, and 80 nmol/0.3 microl) and (+/-)-3-amino-1-hydroxy-2-pyrrolidone (HA966; 10 nmol/0.3 microl), a GLY(B)-site antagonist, were microinjected in rats submitted to the radiant heat-induced tail-flick test. GLY increased tail-flick latencies in a dose-dependent way. This hyponociceptive effect was completely reversed by co-administration with HA966. GLY given in the deep layer of superior colliculus did not produce changes in tail-flick latencies. Therefore, the results suggest that the activation of GLY(B) receptors in the DPAG is also involved in the hyponociception elicited by this brain area.
Assuntos
Comportamento Animal/efeitos dos fármacos , Glicina/farmacologia , Limiar da Dor/efeitos dos fármacos , Substância Cinzenta Periaquedutal , Animais , Relação Dose-Resposta a Droga , Ligantes , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Microinjeções , Medição da Dor , Substância Cinzenta Periaquedutal/metabolismo , Substância Cinzenta Periaquedutal/fisiologia , Ratos , Ratos Sprague-Dawley , Receptores de Glicina/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Fatores de TempoRESUMO
There are only a few studies on the molecular mechanisms underlying the peripheral antihyperalgesic effect of opioids. The aim of this study was to investigate the molecular bases of the peripheral antihyperalgesic effect of fentanyl in a model of prostaglandin-induced chemical hyperalgesia. Prostaglandin E2 (1.4 nmol) injected into one hind paw of male Wistar rats (200-250 g, N = 6 in each experimental or control group) pretreated with indomethacin (2.5 mg/kg) potentiated the nocifensive response to formalin (1%) injection made 60 min later. Drugs applied locally 30 min after prostaglandin E2 induced the following effects: fentanyl (0.1-1.0 nmol) caused a dose-dependent reversal of the hyperalgesic state, naloxone (2 nmol) co-injected with fentanyl (1 nmol) completely reversed the antihyperalgesic effect, Nomega-nitro-L-arginine (NOARG, 0.05-0.2 mol) in combination with fentanyl (1.0 nmol) caused a dose-dependent inhibition of the antihyperalgesic effect of fentanyl, co-administration of L-arginine (0.5 mol) with NOARG (0.2 mol) plus fentanyl (1.0 nmol) fully restored the antihyperalgesic effect, and the cyclic-GMP phosphodiesterase inhibitor UK-114,542-27 (5-[2-ethoxy-5-(morpholinylacetyl) phenyl]-1,6-dihydro-1-methyl-3-propyl-7H-pyrazolo [4,3-d]-pyrimidin-7-one methanesulfonate monohydrate; 0.5-2.0 mol) potentiated a subeffective dose of fentanyl (0.1 nmol) in a dose-dependent manner. However, UK-114,542-27 (2.0 mol) injected alone did not produce this antihyperalgesic effect. Systemically administered fentanyl (1.0 nmol, sc) did not cause antinociception. Taken together, these results support the view that fentanyl reverses prostaglandin E2-induced hyperalgesia, probably by activating an opioid receptor at the periphery, and furthermore the L-arginine/nitric oxide/cyclic-GMP pathway may mediate this peripheral effect of fentanyl.
Assuntos
Analgésicos Opioides/farmacologia , Arginina/fisiologia , GMP Cíclico/fisiologia , Fentanila/farmacologia , Hiperalgesia/tratamento farmacológico , Óxido Nítrico/fisiologia , Animais , Dinoprostona , Relação Dose-Resposta a Droga , Formaldeído , Hiperalgesia/induzido quimicamente , Masculino , Óxido Nítrico Sintase/antagonistas & inibidores , Ocitócicos , Ratos , Ratos WistarRESUMO
There are only a few studies on the molecular mechanisms underlying the peripheral antihyperalgesic effect of opioids. The aim of this study was to investigate the molecular bases of the peripheral antihyperalgesic effect of fentanyl in a model of prostaglandin-induced chemical hyperalgesia. Prostaglandin E2 (1.4 nmol) injected into one hind paw of male Wistar rats (200-250 g, N = 6 in each experimental or control group) pretreated with indomethacin (2.5 mg/kg) potentiated the nocifensive response to formalin (1 percent) injection made 60 min later. Drugs applied locally 30 min after prostaglandin E2 induced the following effects: fentanyl (0.1-1.0 nmol) caused a dose-dependent reversal of the hyperalgesic state, naloxone (2 nmol) co-injected with fentanyl (1 nmol) completely reversed the antihyperalgesic effect, Nomega-nitro-L-arginine (NOARG, 0.05-0.2 æmol) in combination with fentanyl (1.0 nmol) caused a dose-dependent inhibition of the antihyperalgesic effect of fentanyl, co-administration of L-arginine (0.5 æmol) with NOARG (0.2 æmol) plus fentanyl (1.0 nmol) fully restored the antihyperalgesic effect, and the cyclic-GMP phosphodiesterase inhibitor UK-114,542-27 (5-[2-ethoxy-5-(morpholinylacetyl) phenyl]-1,6-dihydro-1-methyl-3-propyl-7H-pyrazolo [4,3-d]-pyrimidin-7-one methanesulfonate monohydrate; 0.5-2.0 æmol) potentiated a subeffective dose of fentanyl (0.1 nmol) in a dose-dependent manner. However, UK-114,542-27 (2.0 æmol) injected alone did not produce this antihyperalgesic effect. Systemically administered fentanyl (1.0 nmol, sc) did not cause antinociception. Taken together, these results support the view that fentanyl reverses prostaglandin E2-induced hyperalgesia, probably by activating an opioid receptor at the periphery, and furthermore the L-arginine/nitric oxide/cyclic-GMP pathway may mediate this peripheral effect of fentanyl.
Assuntos
Animais , Masculino , Ratos , Analgésicos Opioides , Arginina , GMP Cíclico , Fentanila , Hiperalgesia , Óxido Nítrico , Dinoprostona , Relação Dose-Resposta a Droga , Formaldeído , Hiperalgesia , Óxido Nítrico Sintase , Ocitócicos , Ratos WistarRESUMO
The influence of endothelin-1 on nociception induced by capsaicin was assessed in the mouse hindpaw. Local endothelin-1 injection (1 to 20 pmol/paw) 30 min prior to ipsilateral injection of capsaicin (0.1 microg/paw) increased, in a graded fashion, the time spent licking the injected paw. Maximal hyperalgesia was obtained with 10 pmol/paw of endothelin-1 (capsaicin-induced hindpaw licking time increased from 43 +/- 3 s to 114 +/- 7 s, n = 6), but no hyperalgesia was evident following 30 pmol/paw of endothelin-1. The selective endothelin ET(B) receptor agonists sarafotoxin S6c (< or = 30 pmol/paw) and IRL 1620 (i.e., Suc[Glu9,Ala11,15]endothelin-1-(10-21); < or = 100 pmol/paw) failed to induce hyperalgesia. Local treatment with BQ-123 (i.e., cyclo[DTrp-DAsp-Pro-DVal-Leu] 1 nmol/paw selective endothelin ET(A) receptor antagonist), 10 min before endothelin-1 (10 pmol/paw), fully blocked the hyperalgesic response, whereas similar treatment with the selective endothelin ET(B) receptor antagonist BQ-788 (i.e., N-cis-2,6-dimethylpiperidinocarbonyl-L-gamma-methylleucyl-D- 1-methoxy-carboyl-D-norleucine) was ineffective. Intravenous injection of bosentan (17 and 52 micromol/kg a non-peptidic mixed endothelin ET(A)/ET(B) receptor antagonist) or BMS 182874 (i.e., 5-[dimethylamino]-N-[3,4-dimethyl-5-isoxazolyl]-1-naphthalenesulph onamide; 10 and 30 micromol/kg; a non-peptidic selective endothelin ET(A) receptor antagonist), 1 h before endothelin-1, inhibited its hyperalgesic effect in a graded fashion and abolished the response at the higher doses. None of the antagonists modified nociception induced by capsaicin alone or the hyperalgesia induced by local injection of 5-hydroxytryptamine (5-HT; 2 nmol/paw, 30 min before capsaicin). Hyperalgesia induced by 5-HT was abolished by simultaneous injection of endothelin-1 or the endothelin ET(B) receptor agonist IRL 1620 (each at 30 pmol/paw). Therefore, local endothelin-1 exerts a dual influence in this model: at low doses it causes endothelin ET(A) receptor-mediated hyperalgesia (i.e., it potentiates capsaicin-induced nociception), whereas at higher doses it induces an anti-hyperalgesic effect against 5-HT which seems to be mediated via distinct endothelin ET (possibly ET(B)) receptors.
Assuntos
Analgesia , Endotelina-1/farmacologia , Hiperalgesia/tratamento farmacológico , Animais , Bosentana , Capsaicina , Compostos de Dansil/farmacologia , Relação Dose-Resposta a Droga , Antagonistas dos Receptores de Endotelina , Endotelina-1/administração & dosagem , Endotelinas/farmacologia , Membro Posterior , Hiperalgesia/induzido quimicamente , Masculino , Camundongos , Oligopeptídeos/farmacologia , Fragmentos de Peptídeos/farmacologia , Peptídeos/farmacologia , Peptídeos Cíclicos/farmacologia , Piperidinas/farmacologia , Receptor de Endotelina A , Receptor de Endotelina B , Receptores de Endotelina/agonistas , Serotonina/farmacologia , Sulfonamidas/farmacologia , Venenos de VíborasRESUMO
This study assessed the possible local nociceptive and hyperalgesic properties of endothelin-1 (ET-1) in the rat knee-joint incapacitation test, in which animals are placed for 1 min/h on a revolving (3 rpm) metal cylinder and nociception is measured as the time the hindpaw of the injected limb was off the cylinder (i.e., paw elevation time, PET). Carrageenan (Cg; 150 micrograms/joint), E. coli LPS (1 microgram/joint), and ET-1 (120 or 240 pmol/joint) each increased PET persistently, unlike sarafotoxin S6c (120-240 pmol/joint) or PBS. ET-1 (15 and 30 pmol/joint, 30 min before) did not cause incapacitation per se but potentiated PET induced by Cg, increasing the area under the curve (AUC in arbitrary units, 0-6 h) from 105 +/- 9 to 165 +/- 10 and 169 +/- 25, respectively. Prior Cg injection (300 micrograms/joint, 72 h before) sensitized the joint to incapacitation triggered by restimulation with either Cg (300 micrograms/joint), LPS (1 microgram/joint), or ET-1 (30 pmol/joint). Treatment with bosentan (10 mg/kg i.v., 15 min before joint stimulation) did not affect PET values in naive animals to Cg or LPS, but significantly reduced the upregulated response evoked by restimulation with LPS (but not Cg), from 465 +/- 24 to 290 +/- 49 (AUC 0-12 h). Therefore, ET-1 triggers nociception and hyperalgesia in the naive knee joint of the rat, perhaps via ETA receptors. Although local endogenous ETs may not have a role in inflammatory nociception in the naive joint, they may participate in articular incapacitation induced by restimulation with LPS. This latter finding could be relevant to the etiology of pain associated with chronic arthritic diseases.
Assuntos
Artrite Experimental/patologia , Endotelina-1/toxicidade , Membro Posterior/patologia , Hiperalgesia/induzido quimicamente , Articulações/patologia , Animais , Artrite Experimental/induzido quimicamente , Bosentana , Carragenina , Antagonistas dos Receptores de Endotelina , Endotoxinas , Hiperalgesia/patologia , Lipopolissacarídeos , Masculino , Ratos , Ratos Wistar , Sulfonamidas/farmacologia , Vasoconstritores/farmacologia , Venenos de Víboras/farmacologiaRESUMO
The present study investigates the influence of endothelin (ET) related peptides (0.3-30 pmol/paw) on both phases of nociception and on edema induced by intraplantar injection of formalin (0.5% in 20 microL) in the mouse hind paw. The first phase of nociception (0-5 min after injection) was significantly potentiated by simultaneous injection of either ET-1 (10 or 30 pmol/paw) or ET-3 (10 pmol/paw), but not of the selective ET3 receptor agonist sarafotoxin S6c (SRTX-c; up to 30 pmol/paw). All three peptides potentiated the second phase (10-30 min after injection) of formalin-induced nociception (at 3-30, 1-30, and 10-30 pmol/paw for ET-1, ET-3, and SRTX-c, respectively), whereas only ET-1 (10 or 30 pmol/paw) effectively enhanced edema caused by formalin (30 min after injection). Histamine also potentiated all three responses triggered by formalin, but was 30- to 100-fold less potent than ET-1. Treatment with the mixed ETA/ETB receptor antagonist bosentan (10 mg/kg i.p., 1 h beforehand) did not influence nociceptive and edematogenic responses to formalin or their potentiation by histamine (3 nmol/paw), but did inhibit the potentiations induced by ET-1 (10 pmol/paw). Thus, ET-1 potentiates formalin-induced nociception and edema in the mouse. These actions are possibly mediated via ETB and ETA receptors, respectively, but their true identity and the mechanisms involved still remain to be fully elucidated.