RESUMO
PURPOSE: Neuropathic pain is a common diabetic complication. It is characterized by symptoms of spontaneous and stimulus-evoked pain including hyperalgesia and allodynia. L-Arginine is a common precursor of many metabolites of biological interest, in particular, nitric oxide (NO), ornithine, and hence polyamines. In central nervous system, NO, glutamate, and polyamines share an N-methyl-D-aspartate (NMDA) receptor-mediated effect. We hypothesized that a variation in arginine metabolism caused by diabetes may contribute to development and maintenance of neuropathic pain and to the worsening of clinical and biological signs of diabetes. METHODS: We examined whether oral L-arginine supplementation (2.58 ± 0.13 g/l in drinking water for 3 weeks) could improve the development of neuropathic pain and the clinical, biological, and metabolic complications of diabetes in streptozocin (STZ)-induced diabetic (D) rats. RESULTS: STZ administration induced classical symptoms of type 1 diabetes. Diabetic rats also displayed mechanical hypersensitivity, tactile, and thermal allodynia. Plasma citrulline and NO levels were increased in diabetic hyperalgesic/allodynic rats. L-Arginine supplementation failed to reduce hyperglycaemia, polyphagia, and weight loss. Moreover, it abolished hyperalgesia and allodynia by normalizing NO plasma concentration and increasing plasma agmatine concentration. CONCLUSIONS: L-Arginine supplementation prevented the development of mechanical hyperalgesia, tactile, and thermal allodynia in painful diabetic neuropathy with concomitant reduction of NO and increased agmatine production, offering new therapeutic opportunities for the management of diabetic neuropathic pain.
Assuntos
Agmatina/sangue , Arginina/farmacologia , Neuropatias Diabéticas/prevenção & controle , Hiperalgesia/prevenção & controle , Óxido Nítrico/sangue , Administração Oral , Animais , Diabetes Mellitus Experimental/complicações , Neuralgia/prevenção & controle , Ratos , Ratos Sprague-Dawley , EstreptozocinaRESUMO
Neuropathic pain is a common diabetic complication affecting 8-16% of diabetic patients. It is characterized by aberrant symptoms of spontaneous and stimulus-evoked pain including hyperalgesia and allodynia. Magnesium (Mg) deficiency has been proposed as a factor in the pathogenesis of diabetes-related complications, including neuropathy. In the central nervous system, Mg is also a voltage-dependent blocker of the N-methyl-d-aspartate receptor channels involved in abnormal processing of sensory information. We hypothesized that Mg deficiency might contribute to the development of neuropathic pain and the worsening of clinical and biological signs of diabetes and consequently, that Mg administration could prevent or improve its complications. We examined the effects of oral Mg supplementation (296 mg l(-1) in drinking water for 3 weeks) on the development of neuropathic pain and on biological and clinical parameters of diabetes in streptozocin (STZ)-induced diabetic rats. STZ administration induced typical symptoms of type 1 diabetes. The diabetic rats also displayed mechanical hypersensitivity and tactile and thermal allodynia. The level of phosphorylated NMDA receptor NR1 subunit (pNR1) was higher in the spinal dorsal horn of diabetic hyperalgesic/allodynic rats. Magnesium supplementation failed to reduce hyperglycaemia, polyphagia and hypermagnesiuria, or to restore intracellular Mg levels and body growth, but increased insulinaemia and reduced polydipsia. Moreover, it abolished thermal and tactile allodynia, delayed the development of mechanical hypersensitivity, and prevented the increase in spinal cord dorsal horn pNR1. Thus, neuropathic pain symptoms can be attenuated by targeting the Mg-mediated blockade of NMDA receptors, offering new therapeutic opportunities for the management of chronic neuropathic pain.
Assuntos
Diabetes Mellitus Experimental/complicações , Neuropatias Diabéticas/prevenção & controle , Hiperalgesia/prevenção & controle , Magnésio/uso terapêutico , Neuralgia/prevenção & controle , Receptores de N-Metil-D-Aspartato/metabolismo , Administração Oral , Animais , Neuropatias Diabéticas/metabolismo , Neuropatias Diabéticas/fisiopatologia , Modelos Animais de Doenças , Temperatura Alta , Hiperalgesia/metabolismo , Hiperalgesia/fisiopatologia , Magnésio/administração & dosagem , Masculino , Neuralgia/metabolismo , Neuralgia/fisiopatologia , Fosforilação , Ratos , Ratos Sprague-Dawley , Estreptozocina , Estresse MecânicoRESUMO
Benzodiazepines are potentially addictive drugs: psychological and physical dependence can develop within a few weeks or years of regular or repeated use. The socioeconomic costs of the present high level of long-term benzodiazepine use are considerable. These consequences could be minimised if prescriptions for long-term benzodiazepines were decreased. However, many physicians continue to prescribe benzodiazepines and patients wishing to withdraw receive little advice or support. Particular care should be taken in prescribing benzodiazepines for vulnerable patients such as elderly persons, pregnant women, children, alcohol- or drug-dependent patients and patients with comorbid psychiatric disorders. The following update gives recent research results on the withdrawal pathophysiology and practical information in order to treat or prevent benzodiazepine withdrawal syndrome.
Assuntos
Benzodiazepinas/efeitos adversos , Síndrome de Abstinência a Substâncias/psicologia , Transtornos Relacionados ao Uso de Substâncias/psicologia , Adulto , Idoso , Envelhecimento/psicologia , Alcoolismo/complicações , Feminino , Humanos , Masculino , Transtornos Mentais/complicações , Pessoa de Meia-Idade , Gravidez , Síndrome de Abstinência a Substâncias/terapia , Transtornos Relacionados ao Uso de Substâncias/reabilitaçãoRESUMO
BACKGROUND: While data from USA and Canada demonstrate an opioid overdose epidemic, very little nation-wide European studies have been published on this topical subject. METHODS: Using a nationally representative sample of the French Claims database (>700,000 patients), the exhaustive nationwide hospital discharge database, and national mortality registry, all patients dispensed at least one prescription opioid (PO) in 2004-2017 were identified, to describe trends in PO analgesic use, shopping behaviour, opioid-related hospitalizations and deaths. Annual prevalence of PO use and shopping behaviour (≥1 day of overlapping prescriptions from ≥2 prescribers, dispensed by ≥3 pharmacies) was estimated. RESULTS: In 2004-2017, the annual prevalence of weak opioid use codeine, tramadol and opium rose by 150%, 123%, and 244%, respectively (p < 0.05). Strong opioid use increased from 0.54% to 1.1% (+104%, p < 0.05), significantly for oxycodone (+1950%). Strong opioid use in chronic noncancer pain rose by 88% (p < 0.05) and 1180% for oxycodone. Opioid shopping increased from 0.50% to 0.67% (+34%, p < 0.05), associated with higher mortality risk HR = 2.8 [95% confidence interval (CI): 1.2-6.4]. Opioid-related hospitalizations increased from 15 to 40 per 1,000,000 population (+167%, 2000-2017), and opioid-related deaths from 1.3 to 3.2 per 1,000,000 population (+146%, 2000-2015). CONCLUSIONS: This study provided a first European approach to a nationwide estimation with complete access to several national registries. In 2004-2017 in France, PO use excluding dextropropoxyphene more than doubled. The increase in oxycodone and fentanyl use, and nontrivial increasing trend in opioid-related morbidity-mortality should prompt authorities to closely monitor PO consumption in order to prevent alarming increases in opioid-related morbidity-mortality. SIGNIFICANCE: In 2004-2017, prescription opioid use in France at least doubled and oxycodone use increased particularly, associated with a nontrivial increase in opioid-related morbidity-mortality. Although giving no indication for an 'opioid epidemic,' these findings call for proper monitoring of opioid use.
Assuntos
Analgésicos Opioides/uso terapêutico , Dor Crônica/tratamento farmacológico , Mortalidade , Transtornos Relacionados ao Uso de Opioides/epidemiologia , Adulto , Idoso , Codeína/uso terapêutico , Bases de Dados Factuais , Dextropropoxifeno/uso terapêutico , Feminino , Fentanila/uso terapêutico , França/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Ópio/uso terapêutico , Oxicodona/uso terapêutico , Prevalência , Modelos de Riscos Proporcionais , Tramadol/uso terapêuticoRESUMO
BACKGROUND: Histamine H3 receptors are mainly expressed on CNS neurons, particularly along the nociceptive pathways. The potential involvement of these receptors in pain processing has been suggested using H3 receptor inverse agonists. METHODS: The antinociceptive effect of S 38093, a novel inverse agonist of H3 receptors, has been evaluated in several neuropathic pain models in rat and compared with those of gabapentin and pregabalin. RESULTS: While S 38093 did not change vocalization thresholds to paw pressure in healthy rats, it exhibited a significant antihyperalgesic effect in the Streptozocin-induced diabetic (STZ) neuropathy model after acute and chronic administration and, in the chronic constriction injury (CCI) model only after chronic administration, submitted to the paw-pressure test. Acute S 38093 administration at all doses tested displayed a significant cold antiallodynic effect in a model of acute or repeated administration of oxaliplatin-induced neuropathy submitted to cold tail immersion, cold allodynia being the main side effect of oxaliplatin in patients. The effect of S 38093 increased following chronic administration (i.e. twice a day during 5 days) in the CCI and STZ models except in the oxaliplatin models where its effect was already maximal from the first administration The kinetics and size of effect of S 38093 were similar to gabapentin and/or pregabalin. Finally, the antinociceptive effect of S 38093 could be partially mediated by α2 adrenoreceptors desensitization in the locus coeruleus. CONCLUSIONS: These results highlight the interest of S 38093 to relieve neuropathic pain and warrant clinical trials especially in chemotherapeutic agent-induced neuropathic pain. SIGNIFICANCE: S 38093, a new H3 antagonist/inverse agonist, displays antiallodynic and antihyperalgesic effect in neuropathic pain, especially in oxaliplatin-induced neuropathy after chronic administration. This effect of S 38093 in neuropathic pain could be partly mediated by α2 receptors desensitization in the locus coeruleus.
Assuntos
Analgésicos/uso terapêutico , Antagonistas dos Receptores Histamínicos/uso terapêutico , Hiperalgesia/tratamento farmacológico , Neuralgia/tratamento farmacológico , Aminas/farmacologia , Aminas/uso terapêutico , Analgésicos/farmacocinética , Animais , Ácidos Cicloexanocarboxílicos/farmacologia , Ácidos Cicloexanocarboxílicos/uso terapêutico , Modelos Animais de Doenças , Gabapentina , Antagonistas dos Receptores Histamínicos/farmacologia , Hiperalgesia/induzido quimicamente , Masculino , Neuralgia/induzido quimicamente , Compostos Organoplatínicos , Oxaliplatina , Limiar da Dor/efeitos dos fármacos , Pregabalina/farmacologia , Pregabalina/uso terapêutico , Ratos , Ratos Sprague-Dawley , Ácido gama-Aminobutírico/farmacologia , Ácido gama-Aminobutírico/uso terapêuticoRESUMO
BACKGROUND: T-type calcium channels have been shown to play an important role in the initiation and maintenance of neuropathic pain and represent a promising therapeutic target for new analgesic treatments. Ethosuximide (ETX), an anticonvulsant and a T-type channel blocker has shown analgesic effect in several chronic pain models but has not yet been evaluated in patients with neuropathic pain. METHODS: This proof-of-concept, multicentre, double-blind, controlled and randomized trial compared the efficacy and safety of ETX (given as add-on therapy) to an inactive control (IC) in 114 patients with non-diabetic peripheral neuropathic pain. After a 7-day run-in period, eligible patients aged over 18 years were randomly assigned (1:1) to ETX or IC for 6 weeks. The primary outcome was the difference between groups in the pain intensity (% of change from the baseline to end of treatment) assessed in the intention-to-treat population. This study is registered with EudraCT (2013-004801-26) and ClinicalTrials.gov (NCT02100046). RESULTS: The study was stopped during the interim analysis due to the high number of adverse events in the active treatment group. ETX failed to reduce total pain and showed a poor tolerance in comparison to IC. In the per-protocol analysis, ETX significantly reduced pain intensity by 15.6% (95% CI -25.8; -5.4) from baseline compared to IC (-7.8%, 95% CI -14.3; -1.3; p = 0.033), but this result must be interpreted with caution because of a small subgroup of patients. CONCLUSION: Ethosuximide did not reduce the severity of neuropathic pain and induces, at the doses used, many adverse events. SIGNIFICANCE: This article shows that ETX is not effective to treat neuropathic pain. Nevertheless, per-protocol analysis suggests a possible analgesic effect of ETX. Thus, our work adds significant knowledge to preclinical and clinical data on the benefits of T-type calcium channel inhibition for the treatment of neuropathic pain.
Assuntos
Bloqueadores dos Canais de Cálcio/uso terapêutico , Dor Crônica/tratamento farmacológico , Etossuximida/uso terapêutico , Neuralgia/tratamento farmacológico , Adulto , Idoso , Analgésicos/uso terapêutico , Anticonvulsivantes/uso terapêutico , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudo de Prova de ConceitoRESUMO
Irinotecan is a cytotoxic agent used in the treatment of metastatic colorectal cancer. Irinotecan is a prodrug when is converted in vivo to an active metabolite SN38, which has potent pharmacological activity. SN38 is then inactivated and excreted as SN38-glucuronide. High-performance liquid chromatography-mass spectrometry is a widely used bioanalysis technique that can be coupled to the turbulent-flow extraction line to shorten preparation time. A technique was developed to quantify irinotecan and its metabolite by liquid chromatography-tandem mass spectrometry coupled with a turbulent-flow online extraction method. Assays were performed on 100 µL of plasma after protein precipitation. The supernatant is injected directly into the extraction column, transferred to the chromatographic column, and analyzed by tandem mass spectrometry. Linearity, reproducibility and repeatability of the method were validated on a concentration range of 25-2500 ng/mL for irinotecan and 5-500 ng/mL for SN38. For the low limit of quantification of irinotecan and SN38, precision is 6.31% and 8.73%, and accuracy is 84.0% and 91.8%, respectively. The SN38-glucuronide determination protocol included a hydrolyzation step. This method was successfully used to quantify irinotecan, SN38 and SN38-G in human plasma in a clinical trial.
Assuntos
Camptotecina/análogos & derivados , Pró-Fármacos/análise , Espectrometria de Massas em Tandem/métodos , Camptotecina/sangue , Cromatografia Líquida/métodos , Humanos , IrinotecanoRESUMO
Visceral pain and intestinal dysbiosis are associated with Irritable Bowel Syndrome (IBS), a common functional gastrointestinal disorder without available efficient therapies. In this study, a decrease of Faecalibacterium prausnitzii presence has been observed in an IBS-like rodent model induced by a neonatal maternal separation (NMS) stress. Moreover, it was investigated whether F. prausnitzii may have an impact on colonic sensitivity. The A2-165 reference strain, but not its supernatant, significantly decreased colonic hypersensitivity induced by either NMS in mice or partial restraint stress in rats. This effect was associated with a reinforcement of intestinal epithelial barrier. Thus, F. prausnitzii exhibits anti-nociceptive properties, indicating its potential to treat abdominal pain in IBS patients.
Assuntos
Faecalibacterium prausnitzii/fisiologia , Mucosa Intestinal , Síndrome do Intestino Irritável/etiologia , Animais , Colo/imunologia , Colo/metabolismo , Colo/microbiologia , Modelos Animais de Doenças , Síndrome do Intestino Irritável/metabolismo , Síndrome do Intestino Irritável/microbiologia , Masculino , Privação Materna , Camundongos , Permeabilidade , Estresse FisiológicoRESUMO
The effect of ICS 205-930 (ICS), a specific 5-HT3 antagonist, was studied on carrageenan (CAR)-induced rat paw inflammation to assess the involvement of endogenous released serotonin (5-HT) in the observed hyperalgesia. Studies were performed using a behavioural test, measuring the threshold stimulus necessary to elicit vocalization by gradually increasing pressure applied to the paw. When administered (s.c., in the CAR-injected paw) either 20 min before, simultaneously or 20 min after CAR, ICS (10(-11) mol/kg, i.e., 3.2 ng/kg) completely prevented the hyperalgesia in both the injected and non-injected hind paws. This effect was prolonged for 90 min, equivalent to the effect on CAR on 5-HT release. Moreover, ICS increased the vocalization threshold over the pre-drug values in normal and CAR-treated rats when injected both 20 min before and simultaneously with the polysaccharide. On the contrary, it did not reduce the hyperalgesia, when injected 2 h after CAR. ICS had no effect at any time of administration on paw oedema. These results suggest that the early inflammatory sensitization of peripheral nociceptors is mainly dependent on the release of serotonin and that the hyperalgesic effect of the monoamine involves 5-HT3(M) receptors which do not seem to be involved in the early development of oedema.
Assuntos
Hiperalgesia/fisiopatologia , Hiperestesia/fisiopatologia , Indóis/farmacologia , Animais , Carragenina , Limiar Diferencial , Edema/induzido quimicamente , Edema/metabolismo , Membro Posterior , Hiperalgesia/induzido quimicamente , Masculino , Estimulação Física , Ratos , Ratos Endogâmicos , Antagonistas da Serotonina/farmacologia , Tropizetrona , Vocalização AnimalRESUMO
Most pain tests used for the assessment of drug analgesic activity in animal chronic pain models are based on the measurement of the response to an external acute stimulation (thermal, mechanical or electrical). But these stimuli are not related to the chronic pain experienced by the animal. Quantitative analysis of the spontaneous behaviour induced by the chronic pain state is needed. Several authors have suggested that ultrasonic vocalisations (USVs) emitted by rats in painful situations might reflect expression of affective pain. In a first study, we recorded spontaneous USVs in sub-chronic and chronic pain models: inflammation induced by carrageenan, arthritis induced by Freund's adjuvant and diabetes induced by streptozotocin. The USVs were analysed when naive Sprague-Dawley rats were alone and during non-agonistic interaction with a conspecific. When the rats were alone they did not emit any USV. During social interaction, no difference in either the frequency or the duration was observed between the emissions of healthy rats and rats in pain. In a third study, the influence of three parameters, degree of confrontation between the rats, age of the conspecific and housing conditions (isolated or collective) was studied in the arthritic rat model. Arthritic rats did not emit more USVs than controls in any of our experimental conditions. A fourth study showed that Aspirin (200 mg/kg) had no effect on the USVs, this data confirms the lack of direct relationship between USVs and experimental chronic pain in rats in our conditions.
Assuntos
Medição da Dor/métodos , Dor/diagnóstico , Vocalização Animal , Analgésicos/farmacologia , Analgésicos/uso terapêutico , Animais , Artrite Experimental/diagnóstico , Artrite Experimental/tratamento farmacológico , Artrite Experimental/fisiopatologia , Doença Crônica/tratamento farmacológico , Masculino , Dor/tratamento farmacológico , Dor/fisiopatologia , Ratos , Ratos Sprague-Dawley , Ultrassom , Vocalização Animal/efeitos dos fármacos , Vocalização Animal/fisiologiaRESUMO
The effect of clomipramine (CMI), a tricyclic antidepressant, was studied on an acute inflammatory pain model in an attempt to understand its potential antinociceptive activity, the involvement of a central and/or peripheral component and its influence on the inflammatory process. When administered (i.v.) before the inflammatory agent, carrageenan (CAR), CMI (0.125, 0.25 and 0.5 mg/kg) completely prevented the development of the hyperalgesia for 70-120 min according to the doses. This antinociceptive effect was suppressed by naloxone (100 micrograms/kg i.v.) for 65 min. Neither higher doses (1, 2 and 20 mg/kg, i.v.) nor CMI injected into the inflamed paw (15 min before CAR) modified pain thresholds. Moreover, CMI (0.5 and 2 mg/kg, i.v.) administered 15 min before CAR markedly increased the volume of the CAR-induced oedema. These results (1) demonstrate an opioid-dependent antinociceptive effect of CMI on this model, the doses used being lower than those active in thermal or electrical tests, and (2) tend to exclude a peripheral mechanism and an NSAID-like anti-inflammatory activity suggested by previous in vitro studies.
Assuntos
Analgésicos , Sistema Nervoso Central/efeitos dos fármacos , Clomipramina/farmacologia , Nervos Periféricos/efeitos dos fármacos , Animais , Edema/induzido quimicamente , Edema/prevenção & controle , Pé , Injeções , Injeções Intravenosas , Masculino , Naloxona/farmacologia , Dor/fisiopatologia , Ratos , Ratos Endogâmicos , Limiar Sensorial/efeitos dos fármacosRESUMO
The present study was designed to investigate which subtypes of spinal 5-HT receptors are involved in 5-HT-induced antinociception using the mechanical pain test. Serotonin and various selective antagonists or agonists for 5-HT receptor subtypes (5-HT(1A), 5-HT(1B), 5-HT(2A), 5-HT(2C), 5-HT(3) and 5-HT(4)) were administered intrathecally (i.t.) in rats. The i.t. injection of 5-HT (1 microg) produced significant antinociceptive effects using the paw pressure test. Pretreatment with the 5-HT(2C) receptor antagonist mesulergine (1 and 10 microg) and the 5-HT(3) receptor antagonist tropisetron (1 and 10 microg) reversed totally the antinociception induced by 5-HT. Furthermore, at a dose of 10 microg, both the 5-HT(2A) receptor antagonist ketanserin and the 5-HT(1B) receptor antagonist penbutolol, but neither the 5-HT(1A) receptor antagonist WAY 100635 nor the 5-HT(4) receptor antagonist GR113808, attenuated the antinociceptive effect induced by 5-HT. In addition, an i.t. injection of the 5-HT(3) agonist mCPBG induced significant antinociceptive effects whereas the 5-HT(2) agonist DOI did not produce analgesia. These results suggest that although the precise degree of the involvement of spinal serotonergic 5-HT(3) receptors remains to be elucidated due to some differences in the effect of agonists or antagonists, these receptors seem to play a role in the antinociceptive effect of 5-HT against a mechanical acute noxious stimulus. The involvement of 5-HT(2C) is more questionable due to the observed discrepancies between the effects of the used agonist and antagonist. 5-HT(1A) and 5-HT(4) receptors do not seem to be involved. In addition, a possible functional interaction between spinal serotonergic receptors may exist.
Assuntos
Analgésicos/farmacologia , Receptores de Serotonina/efeitos dos fármacos , Serotonina/farmacologia , Analgésicos/administração & dosagem , Animais , Relação Dose-Resposta a Droga , Injeções Espinhais , Masculino , Medição da Dor/efeitos dos fármacos , Limiar da Dor/efeitos dos fármacos , Piperazinas/farmacologia , Piridinas/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores 5-HT3 de Serotonina , Receptores 5-HT4 de Serotonina , Serotonina/administração & dosagem , Antagonistas da Serotonina/farmacologia , Agonistas do Receptor de Serotonina/farmacologiaRESUMO
Painful diabetic neuropathy is one of the most common complications of insulin-dependent diabetes in man. Conflicting results have been obtained in experimentally diabetic animals subjected to pain stimuli. This work aimed to systematically study the response of rats made diabetic (hyperglycemia > or = 14 mM) by injection of streptozocin (STZ) (75 mg/kg, i.p.), to various pain stimuli: mechanical, thermal (warm and cold) and chemical. The time course of the scores was followed for 4 weeks simultaneously with the clinical symptoms (weight, body and skin temperature, motility) and hyperglycemia. A decrease in reaction thresholds to noxious heat stimuli (44 degrees C and 46 degrees C) and to non-painful thermal (cold: 10 degrees C, and warm: 38-42 degrees C) and mechanical stimulation (paw pressure) was observed. This can be considered as evidence for hyperalgesia and allodynia, respectively. These troubles appeared gradually and required at least 2 weeks of diabetes to reach statistical significance. Four weeks after the induction of diabetes, the scores obtained in diabetic rats injected with formalin were greater than those in normal rats, indicating hyperalgesia. Variation in sensitivity to pain occurred at the same time as arrested weight increase, fall in skin temperature, some amyotrophy measured in terms of hind-paw volume, and the usual polyuria-polydipsia syndrome. Spontaneous motor activity of the rats was lowered. This model is thus of interest as the observed reactions to noxious and non-noxious stimuli correspond to hyperalgesia and allodynia, symptoms encountered in painful diabetic neuropathy in man. Operating conditions for this model are discussed.
Assuntos
Comportamento Animal/efeitos dos fármacos , Diabetes Mellitus Experimental/psicologia , Dor/psicologia , Animais , Glicemia/metabolismo , Doença Crônica , Diabetes Mellitus Experimental/complicações , Modelos Animais de Doenças , Formaldeído/farmacologia , Imersão , Masculino , Atividade Motora/efeitos dos fármacos , Dor/induzido quimicamente , Dor/etiologia , Medição da Dor/efeitos dos fármacos , Estimulação Física , Ratos , Ratos Sprague-Dawley , Temperatura Cutânea/efeitos dos fármacosRESUMO
We describe audible and ultrasonic vocalization elicited in rats by a short electrical pulse applied to the tail. Three types of vocal emissions were recorded: (1) 'peep', characterized by a repartition of energy over a wide range (0-50 kHz) of frequencies without any clear structure; (2) 'chatters', characterized by an audible (frequencies in hearing range of humans) fundamental frequency (2.47 +/- 0.03 kHz) and harmonics; and (3) 'ultrasonic emissions', characterized by a succession of slightly modulated pulses with frequencies in the 20-35 kHz range. Peeps and chatters were never recorded before the application of the stimuli. Several different vocalization patterns were described in terms of these types of responses. Just after the stimulation, all the animals emitted a 1st peep, which was generally (61%) followed by a 2nd one. They appeared with reproducible latencies, durations and envelopes. The envelopes of the audible (peeps and chatters) responses were intensity-dependent. Experimental data (moving the stimulation site, lidocaine injection) indicated that the 1st and 2nd peeps were triggered by two different groups of peripheral fibres with mean conduction velocities of 7.3 +/- 0.8 and 0.7 +/- 0.1 m/sec, respectively. This suggested an involvement of A delta and C fibres. Morphine showed a naloxone-reversible and dose-dependent antinociceptive effect by decreasing the 1st and 2nd peep envelopes. It is concluded that a short stimulus applied to the tail triggers a complex behavioural repertoire. It is proposed that this model will be a useful tool for physiological and pharmacological studies of nociception.
Assuntos
Nociceptores/fisiologia , Cauda/fisiologia , Ultrassom , Vocalização Animal , Anestésicos Locais/farmacologia , Animais , Estimulação Elétrica , Hiperacusia , Injeções Intravenosas , Injeções Subcutâneas , Masculino , Medição da Dor , Ratos , Ratos Sprague-Dawley , Fatores de TempoRESUMO
The streptozocin-induced diabetic rat has been put forward as a model of chronic pain with signs of hyperalgesia and allodynia that may reflect signs observed in diabetic humans. The aim of this work was to assess, in streptozocin-induced diabetic rats, the pharmacological activity to several analgesic drugs known to be effective (clomipramine, amitriptyline, desipramine, clonidine, lidocaine), ineffective (aspirin), or with a doubtful effectiveness (morphine) in human painful diabetic neuropathy. The animals were submitted to a mechanical pain test (paw pressure) and the ability of the drugs to reverse diabetes-induced hyperalgesia was tested. The tested antidepressants (0.125-8 mg/kg, i.v.) were slightly effective in diabetic rats; amitriptyline and clomipramine induced a weak effect, whereas desipramine was more active, suggesting noradrenergic specificity. This was confirmed by the effectiveness of clonidine (50, 100, 150 micrograms/kg, s.c.). Lidocaine (1-9 mg/kg, i.v.) had prolonged efficacy on mechanical hyperalgesia. Aspirin (100 mg/kg, i.v.) was without effect and morphine (0.5-4 mg/kg, i.v.) induced a dose-dependent antinociceptive effect but at doses twice as high as those used in normal rats. These results demonstrate the high pharmacological predictivity of this model of painful diabetes and suggest that in this pathological condition, among the drugs acting on monoaminergic transmission, noradrenergic drugs seem the most active.
Assuntos
Analgésicos/uso terapêutico , Diabetes Mellitus Experimental/complicações , Neuropatias Diabéticas/complicações , Dor/tratamento farmacológico , Animais , Antidepressivos Tricíclicos/uso terapêutico , Aspirina/uso terapêutico , Clonidina/uso terapêutico , Modelos Animais de Doenças , Humanos , Lidocaína/uso terapêutico , Masculino , Morfina/uso terapêutico , Dor/etiologia , Ratos , Ratos Sprague-Dawley , Sensibilidade e EspecificidadeRESUMO
The effects of various i.v. doses of diclofenac sodium (Voltaren, 1.5, 3, 6 and 9 mg/kg) were evaluated by measuring the vocalization threshold in response to paw pressure in normal and in Freund's adjuvant-induced arthritic rats. An electrophysiological study performed in parallel in arthritic rats considered the effects of 6 mg/kg i.v. diclofenac on ventrobasal thalamic neuronal responses driven by mild stimulation of an inflamed joint. In normal rats, 6 and 9 mg/kg i.v. diclofenac raised vocalization thresholds significantly (maximum vocalization thresholds were respectively 135.67 +/- 3.30% and 157.41 +/- 4.62% of the preinjection control at 30 min, n = 9 in each group), while no effect was observed with 3 mg/kg. In arthritic rats, i.v. doses of 3, 6 and 9 mg/kg diclofenac induced a clear analgesic effect (maximum vocalization thresholds were respectively 172.22 +/- 4.26, 201.78 +/- 4.76, 222.33 +/- 5.10% of the control at 25 min, n = 9 in each group), whereas a dose of 1.5 mg/kg i.v. did not raise the threshold. In arthritic rats, the VB neuronal responses were depressed by about 50% 20 min after an injection of 6 mg/kg i.v. diclofenac. These results clearly establish that diclofenac produces a dose-dependent analgesic effect, which is more potent in arthritic than in normal rats.
Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Artrite/tratamento farmacológico , Diclofenaco/uso terapêutico , Dor/tratamento farmacológico , Núcleos Talâmicos/fisiopatologia , Potenciais de Ação , Animais , Artrite/fisiopatologia , Relação Dose-Resposta a Droga , Masculino , Dor/etiologia , Dor/fisiopatologia , Medição da Dor , Ratos , Ratos Endogâmicos , Núcleos Talâmicos/efeitos dos fármacosRESUMO
The formalin test is a valuable tool widely used in animal pain studies. We offer a new automated technique based on continuous recording of movements of animals injected in a hindpaw with formalin (5%). This method, based on image processing, allows the discrimination of specific pain-induced behaviors and general motor activity. The comparison of the pain scores evaluated by manual and automated methods showed the same biphasic response. This new process was validated by using compounds known to alter pain responses to formalin: morphine and a non-steroidal anti-inflammatory drug (ketoprofen). Morphine dose-dependently usually affects the two phases of formalin response with ED50 of 2.0 +/- 0.5 and 1.5 +/- 0.5 mg/kg s.c. for the first and the second phase, respectively. The injection of ketoprofen significantly decreased pain scores of the second phase but not those of the first phase. The specificity of the method was studied by determining the effect of diazepam. This sedative compound induced a decrease in pain scores as well as a decrease in motor activity parameters. These data show that this automated technique can be considered as a relevant, sensitive and specific tool which allows the easier use of the formalin test especially for the screening of analgesic drugs.
Assuntos
Processamento de Imagem Assistida por Computador , Medição da Dor , Analgésicos Opioides/farmacologia , Animais , Automação , Cetoprofeno/farmacologia , Masculino , Morfina/farmacologia , Ratos , Ratos Sprague-Dawley , Sensibilidade e EspecificidadeRESUMO
BACKGROUND AND AIMS: Short-chain fatty acid (SCFA) (especially butyrate) enemas are widely used to reduce symptoms associated with human inflammatory bowel disease. The purpose of this study was to evaluate their real effect on colonic sensitivity in rats. METHODS: The effects of saline and SCFA enemas (acetate, propionate and particularly butyrate) were studied on visceral pain thresholds following colonic distension in control rats and in rats with colitis (instilled with trinitrobenzene sulfonic acid (TNBS)). RESULTS: Butyrate enemas (40 mM twice daily for 14 days) decreased colonic pain thresholds in control rats; they did not reduce the TNBS-induced hypersensitivity, but on the contrary increased its duration (without modifying the inflammation score). This pronociceptive effect was confirmed in control rats receiving twice daily enemas of 80 mM for 3 days and two enemas of 240 mM of a butyrate solution. The other SCFA enemas did not modify the hypersensitivity of rats with colitis and induced proinflammatory effects. CONCLUSIONS: The beneficial effect of SCFA (especially butyrate) enemas on hypersensitivity and inflammation in inflammatory bowel disease is questionable and needs to be thoroughly investigated in humans.
Assuntos
Colite/tratamento farmacológico , Ácidos Graxos Voláteis/farmacologia , Acetatos/farmacologia , Animais , Comportamento Animal , Butiratos/farmacologia , Colite/induzido quimicamente , Colite/imunologia , Doenças Funcionais do Colo/induzido quimicamente , Doenças Funcionais do Colo/tratamento farmacológico , Doenças Funcionais do Colo/imunologia , Enema , Masculino , Pressão , Propionatos/farmacologia , Ratos , Ratos Sprague-Dawley , Cloreto de Sódio/farmacologia , Ácido TrinitrobenzenossulfônicoRESUMO
1. Magnesium (Mg)-deficient rats develop a mechanical hyperalgesia which is reversed by a N-Methyl-D-Aspartate (NMDA) receptor antagonist. Given that functioning of this receptor-channel is modulated by Mg, we wondered whether facilitated activation of NMDA receptors in Mg deficiency state may in turn trigger a cascade of specific intracellular events present in persistent pain. Hence, we tested several antagonists of NMDA and non-NMDA receptors as well as compounds interfering with the functioning of intracellular second messengers for effects on hyperalgesia in Mg-deficient rats. 2. Hyperalgesic Mg-deficient rats were administered intrathecally (10 microl) or intraperitoneally with different antagonists. After drug injection, pain sensitivity was evaluated by assessing the vocalization threshold in response to a mechanical stimulus (paw pressure test) over 2 h. 3. Intrathecal administration of MgSO4 (1.6, 3.2, 4.8, 6.6 micromol) as well as NMDA receptor antagonists such as MK-801 (0.6, 6.0, 60 nmol), AP-5 (10.2, 40.6, 162.3 nmol) and DCKA (0.97, 9.7, 97 nmol) dose-dependently reversed the hyperalgesia. Chelerythrine chloride, a protein kinase C (PKC) inhibitor (1, 10.4, 104.2 nmol) and 7-NI, a specific nitric oxide (NO) synthase inhibitor (37.5, 75, 150 micromol x kg(-1), i.p.) induced an anti-hyperalgesic effect in a dose-dependent manner. SR-140333 (0.15, 1.5, 15 nmol) and SR-48968 (0.17, 1.7, 17 nmol), antagonists of neurokinin receptors, produced a significant, but moderate, increase in vocalization threshold. 4. These results demonstrate that Mg-deficiency induces a sensitization of nociceptive pathways in the spinal cord which involves NMDA and non-NMDA receptors. Furthermore, the data is consistent with an active role of PKC, NO and, to a lesser extent substance P in the intracellular mechanisms leading to hyperalgesia.
Assuntos
Antagonistas de Aminoácidos Excitatórios/farmacocinética , Ácido Cinurênico/análogos & derivados , Receptores de N-Metil-D-Aspartato/metabolismo , Coluna Vertebral/metabolismo , 2-Amino-5-fosfonovalerato/farmacocinética , Alcaloides , Analgésicos/farmacocinética , Animais , Benzofenantridinas , Maleato de Dizocilpina/farmacocinética , Hiperalgesia/induzido quimicamente , Indazóis/farmacocinética , Injeções Espinhais , Ácido Cinurênico/farmacocinética , Sulfato de Magnésio/farmacologia , Masculino , Neurônios/metabolismo , Óxido Nítrico Sintase/antagonistas & inibidores , Medição da Dor , Fenantridinas/farmacocinética , Proteína Quinase C/antagonistas & inibidores , Ratos , Ratos Wistar , Receptores de N-Metil-D-Aspartato/antagonistas & inibidoresRESUMO
The benefit of antidepressant treatment in human neuropathic pain is now well documented, but the effect is limited and slow to appear. It has been demonstrated that the association of a 5-HT(1A) antagonist and a serotoninergic antidepressant reduced the delay of action and increases the thymoanaleptic effect of the drug. The purpose of this work was to evaluate the combination of an antidepressant and a 5-HT(1A) antagonist in animal models of chronic neuropathic pain. We studied the antinociceptive effect of the co-administration of clomipramine and a 5-HT(1A) antagonist (WAY 100,635) in a pain test applied in normal rats and in two models of neurogenic sustained pain (mononeuropathic and diabetic rats). The results show an increase in the antinociceptive effect of acutely injected clomipramine due to WAY 100,635 in these models, which is majored when the two drugs are repeatedly injected. The 5-HT(1A) antagonist reduced the delay of onset and increased the maximal antinociceptive effect of clomipramine. These new findings argue for using the combination of an antidepressant and a 5-HT(1A) antagonist in human neuropathic pain therapy.