RESUMEN
The development of analgesic drugs is still a necessity due to the inefficiency of the current treatments for some pathological conditions and also due to the adverse effects produced by these drugs. The aim of this study was to deepen the pharmacological study of two new hybrids NSAIDs tetrahydropyran derivatives, regarding their antinociceptive effects on acute pain in mice. Male swiss mice were evaluated in the acetic acid-induced abdominal writhing, formalin, tail-flick, open-field, glutamate- and capsaicin-induced paw licking tests, and in vitro Cox inhibition assay, besides the acute toxicological evaluation. The compounds had an effect on the acetic acid-induced abdominal writhing, formalin (both phases), and tail-flick tests. In the study of the mechanism of action was observed reversion of the antinociceptive effect of the compounds from the previous administration of naloxone, L-NAME (L-nitro-arginine methyl ester), ODQ (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one), glibenclamide, and nor-binaltorphimine, by the intrathecal and intraperitoneal routes. The prior administration of MK-801 suggests that the modulation of NMDA receptor contributes to the antinociceptive effect of compounds. In summary, hybrid compounds presented central antinociceptive effect, demonstrating participation of the NO-cGMP-K+ ATP pathway, κ-opioid, and NMDA receptors. In addition, the compounds showed inhibition of cyclo-oxygenase enzymes and adverse effects were not observed with dose 300 times greater than the dose used experimentally.
Asunto(s)
Analgésicos/farmacología , Antiinflamatorios no Esteroideos/farmacología , Adenosina Trifosfato/metabolismo , Analgésicos Opioides/farmacología , Animales , GMP Cíclico/metabolismo , Inhibidores de la Ciclooxigenasa/farmacología , Maleato de Dizocilpina/farmacología , Formaldehído/farmacología , Gliburida/farmacología , Humanos , Masculino , Ratones , NG-Nitroarginina Metil Éster/farmacología , Naloxona/farmacología , Naltrexona/análogos & derivados , Naltrexona/farmacología , Dolor/tratamiento farmacológico , Dolor/metabolismo , Dimensión del Dolor/métodos , Canales de Potasio/metabolismo , Prostaglandina-Endoperóxido Sintasas/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Transducción de Señal/efectos de los fármacosRESUMEN
BACKGROUND: It is known that dexmedetomidine can reduce opioid requirements and that there is a synergistic effect when dexmedetomidine and morphine (a full mu opioid receptor agonist) are administered together. However, it was unclear whether a synergistic or additive effect would be observed when dexmedetomidine was co-administered with a partial mu opioid receptor agonist. The present study was designed to elucidate such effects by intrathecally co-administering dexmedetomidine and dezocine, a partial mu receptor agonist, in a mouse pain model. METHODS: C57 mice (N = 165) were randomly divided into 19 groups. The tail flick test was adopted to measure the antinociceptive effects of the tested agents. The mice were divided into saline and drug groups to investigate the dose-dependent analgesic effects. Each drug was administered at fixed doses alone and in combination with one of three doses of a second drug. RESULTS: Dezocine (0.3125 - 1.25 µg) and dexmedetomidine (0.04 - 1 µg) both enhanced the tail withdrawal latency in dose-dependent fashions. Dexmedetomidine (0.04 - 1 µg) enhanced the analgesic effect of dezocine. Dezocine (0.3125 - 1.25 µg) enhanced the analgesic effect of dexmedetomidine. Compared with the individual drug effects, the combined effects of dezocine (0.625 µg) and dexmedetomidine (0.04 µg) were more potent 15 - 60 min after injection, but they remained similar to the sum of the effects of the two individual drugs. CONCLUSIONS: Dexmedetomidine and dezocine produce an additive analgesic effect on acute nociception when administered simultaneously.
RESUMEN
Oxytocin (OXT)-containing neurosecretory cells in the parvocellular divisions of the paraventricular nucleus (PVN), which project to the medulla and spinal cord, are involved in various physiological functions, such as sensory modulation and autonomic processes. In the present study, we examined OXT expression in the hypothalamo-spinal pathway, as well as the hypothalamo-neurohypophysial system, which includes the magnocellular neurosecretory cells in the PVN and the supraoptic nucleus (SON), after s.c. injection of saline or formalin into the hindpaws of transgenic rats that express the OXT and monomeric red fluorescent protein 1 (mRFP1) fusion gene. (i) The numbers of OXT-mRFP1 neurones that expressed Fos-like immunoreactivity (-IR) and OXT-mRFP1 intensity were increased significantly in the magnocellular/parvocellular PVN and SON after s.c. injection of formalin. (ii) OXT-mRFP1 neurones in the anterior parvocellular PVN, which may project to the dorsal horn of the spinal cord, were activated by s.c. injection of formalin, as indicated by a significant increases of Fos-IR and mRFP1 intensity intensity. (iii) Formalin injection caused a significant transient increase in plasma OXT. (iv) OXT, mRFP1 and corticotrophin-releasing hormone mRNAs in the PVN were significantly increased after s.c. injection of formalin. (v) An intrathecal injection of OXT-saporin induced hypersensitivity in conscious rats. Taken together, these results suggest that the hypothalamo-neurohypophysial/-spinal OXTergic pathways may be involved in acute nociceptive responses in rats.
Asunto(s)
Hiperalgesia/inducido químicamente , Hiperalgesia/fisiopatología , Hipotálamo/metabolismo , Oxitocina/fisiología , Neurohipófisis/metabolismo , Animales , Hormona Liberadora de Corticotropina/biosíntesis , Formaldehído , Inyecciones Espinales , Proteínas Luminiscentes/genética , Masculino , Neuronas/metabolismo , Oxitocina/administración & dosificación , Oxitocina/análogos & derivados , Oxitocina/biosíntesis , Oxitocina/sangre , Oxitocina/farmacología , Dimensión del Dolor , Núcleo Hipotalámico Paraventricular/metabolismo , Núcleo Hipotalámico Paraventricular/fisiología , Proteínas Proto-Oncogénicas c-fos/metabolismo , Ratas , Ratas Transgénicas , Proteínas Inactivadoras de Ribosomas Tipo 1/administración & dosificación , Proteínas Inactivadoras de Ribosomas Tipo 1/farmacología , Saporinas , Núcleo Supraóptico/metabolismo , Núcleo Supraóptico/fisiología , Proteína Fluorescente RojaRESUMEN
OBJECTIVE: To determine the acute anti-nociceptive and the minimal alveolar concentration (MAC) sparing effects of metamizole sodiummonohydrate (dipyrone) in dogs for possible perioperative analgesia. STUDY DESIGN: Two groups of seven adult dogs were used in two separate randomised, blinded, controlled, cross-over studies. In each study, each dog received metamizole 50 mg kg(-1) intravenously (IV) and placebo (saline 0.9%) IV. METHODS: Sevoflurane MAC was determined using the bracketing technique and electrical stimulation (50 V, 50 Hz, 10 milliseconds) at a thoracic limb, before treatment and 1 and 4 hours post treatment. In conscious dogs, thermal thresholds were determined by ramped contact heat at the thoracic wall. Mechanical thresholds (MTs) were measured by constantly rising force pressing against the radial bone. Thresholds were determined pre and 45, 75, 105, 135, 165, 195, 225, 255, 285, 315, 345, 375, 435, 495, 555, 615, 675, 735 minutes and 24 hours post treatment. Parametric data were analyzed by analysis of variance for repeated measurements and paired t-tests. Friedman test was used for nonparametric data. Level of significance was set to <5%. RESULTS: Metamizole did not change MAC of sevoflurane significantly compared to baseline values [mean ± SD Vol%; 2.7 ± 0.5 (BL); 2.8 ± 0.6 (1 hour); 2.8 ± 0.4 (4 hours)] and placebo [2.8 ± 0.5 (BL); 2.9 ± 0.5 (1 hour); 2.9 ± 0.4 (4 hour)]. Metamizole caused a significant rise in % TE up to 105 minutes (66.5 ± 12.1%) and in MT up to 75 minutes (12.7 ± 5.0 N) compared to baseline (55 ± 10%; 7.9 ± 1.8 N). There were no significant differences between treatments. CONCLUSION AND CLINICAL RELEVANCE: Metamizole did not induce an anaesthetic sparing effect. In awake dogs metamizole induced only mild and short cutaneous anti-nociception. Metamizole as the sole analgesic drug in the perioperative periode is not recommended.
Asunto(s)
Anestésicos por Inhalación/farmacocinética , Antiinflamatorios no Esteroideos/farmacología , Dipirona/farmacología , Éteres Metílicos/farmacocinética , Nocicepción/efectos de los fármacos , Alveolos Pulmonares/metabolismo , Animales , Estudios Cruzados , Perros , Femenino , Masculino , Alveolos Pulmonares/efectos de los fármacos , Sevoflurano , Método Simple CiegoRESUMEN
We determined the role of chloride-bicarbonate anion exchanger 3 in formalin-induced acute and chronic rat nociception. Formalin (1%) produced acute (first phase) and tonic (second phase) nociceptive behaviors (flinching and licking/lifting) followed by long-lasting evoked secondary mechanical allodynia and hyperalgesia in both paws. Local peripheral pre-treatment with the chloride-bicarbonate anion exchanger inhibitors 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid and 4-acetamido-4'-isothiocyanato-2,2'-stilbenedisulfonic acid prevented formalin-induced nociception mainly during phase 2. These drugs also prevented in a dose-dependent fashion long-lasting evoked secondary mechanical allodynia and hyperalgesia in both paws. Furthermore, post-treatment (on day 1 or 6) with 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid reversed established hypersensitivity. Anion exchanger 3 was expressed in dorsal root ganglion neurons and it co-localized with neuronal nuclei protein (NeuN), substance P and purinergic P2X3 receptors. Furthermore, Western blot analysis revealed a band of about 85 kDa indicative of anion exchanger 3 protein expression in dorsal root ganglia of naïve rats, which was enhanced at 1 and 6 days after 1% formalin injection. On the other hand, this rise failed to occur during 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid exposure. These results suggest that anion exchanger 3 is present in dorsal root ganglia and participates in the development and maintenance of short and long-lasting formalin-induced nociception.
Asunto(s)
Antiportadores de Cloruro-Bicarbonato/metabolismo , Formaldehído/efectos adversos , Ganglios Espinales/efectos de los fármacos , Ganglios Espinales/metabolismo , Dolor/inducido químicamente , Dolor/metabolismo , Animales , Femenino , Formaldehído/antagonistas & inhibidores , Regulación de la Expresión Génica/efectos de los fármacos , Nocicepción/efectos de los fármacos , Dolor/fisiopatología , Transporte de Proteínas/efectos de los fármacos , Ratas , Ratas Wistar , Ácidos Sulfónicos/farmacologíaRESUMEN
Lipocalin-2 (LCN2) is an acute-phase protein induced by injury, infection, or other inflammatory stimuli. LCN2 binds small hydrophobic ligands and interacts with cell surface receptor to regulate diverse cellular processes. The role of LCN2 as a chemokine inducer in the central nervous system (CNS) has been previously reported. Based on the previous participation of LCN2 in neuroinflammation, we investigated the role of LCN2 in formalin-induced nociception and pathological pain. Formalin-induced nociceptive behaviors (licking/biting) and spinal microglial activation were significantly reduced in the second or late phase of the formalin test in Lcn2 knockout mice. Likewise, antibody-mediated neutralization of spinal LCN2 attenuated the mechanical hypersensitivity induced by peripheral nerve injury in mice. Taken together, our results suggest that LCN2 can be therapeutically targeted, presumably for both prevention and reversal of acute inflammatory pain as well as pathological pain.
RESUMEN
Lipocalin-2 (LCN2) is an acute-phase protein induced by injury, infection, or other inflammatory stimuli. LCN2 binds small hydrophobic ligands and interacts with cell surface receptor to regulate diverse cellular processes. The role of LCN2 as a chemokine inducer in the central nervous system (CNS) has been previously reported. Based on the previous participation of LCN2 in neuroinflammation, we investigated the role of LCN2 in formalin-induced nociception and pathological pain. Formalin-induced nociceptive behaviors (licking/biting) and spinal microglial activation were significantly reduced in the second or late phase of the formalin test in Lcn2 knockout mice. Likewise, antibody-mediated neutralization of spinal LCN2 attenuated the mechanical hypersensitivity induced by peripheral nerve injury in mice. Taken together, our results suggest that LCN2 can be therapeutically targeted, presumably for both prevention and reversal of acute inflammatory pain as well as pathological pain.
Asunto(s)
Animales , Ratones , Proteínas de Fase Aguda , Sistema Nervioso Central , Hipersensibilidad , Ligandos , Ratones Noqueados , Microglía , Nocicepción , Dimensión del Dolor , Traumatismos de los Nervios Periféricos , Médula EspinalRESUMEN
BACKGROUND: Spinal anticholinesterase has been shown to have an antinociceptive action to acute noxious stimuli. The purpose of this study was to determine the effect of intrathecal anticholinesterase on the facilitated state developed after tissue injury evoked by formalin injection. METHODS: Rats were implanted with lumbar intrathecal catheters. For nociceptive test, 50 microliter of 5% formalin solution was injected into the hindpaw. The effect of pretreatment with intrathecal neostigmine, physostigmine and edrophonium, administered 10 min before formalin injection, was observed for 60 min. For the evaluation of the effect of posttreatment with intrathecal anticholinesterase, administered 9 min after formalin injection, the response was observed for 50 min. RESULTS: Formalin injection into the paw resulted in a biphasic incidence of flinching of the injected paw. Intrathecal pretreatment with neostigmine, physostigmine and edrophonium produced a dose- dependent suppression of the flinching during phase 1 and phase 2 on the formalin test. Posttreatment with three intrathecal anticholinesterases reduced the phase 2 flinching response. CONCLUSIONS: Both pretreatment and posttreatment with intrathecal anticholinesterase produced an antinociception on the formalin test. These results point out the usefulness of anticholinesterase to acute nociception and facilitated state.