RESUMO
In clinical use, a single infusion of oxaliplatin, widely used to treat metastatic colorectal cancer, induces specific sensory neurotoxicity signs triggered or aggravated by exposure to cold. To study the pathophysiology of these symptoms, we developed and characterized an animal model that reproduces the effects of a single intraperitoneal oxaliplatin administration (3, 6 and 12 mg/kg). Significant allodynia and hyperalgesia to cold stimuli were rapidly observed from 24 h to day 5 with a maximum lowering of 76% at t+30 h versus control. Other behavioral assessments revealed rapid persistent mechanical allodynia, but no thermal hyperalgesia or allodynia to heat and no hyperalgesia to mechanical stimuli. An immunohistochemical study in the superficial layers of the spinal dorsal horn revealed a marked increase in substance P immunoreactivity versus controls (12% versus 4%), whereas calcitonin gene-related peptide (CGRP) immunoreactivity was unchanged. This new animal model for the first time closely mimics the effects observed in humans after a single oxaliplatin infusion, especially onset and highly intense sensory disturbances, hypersensitivity to cold with allodynia and hyperalgesia signs. This model may help to elucidate the mechanisms of this thermal hypersensitivity, especially the possible involvement of small-diameter A-fibers in cold allodynia symptoms. These selective effects may clue up the mechanistic basis for the acute oxaliplatin neuropathy leading to a better understanding of the clinical condition and to optimize its treatment.
Assuntos
Antineoplásicos , Comportamento Animal/efeitos dos fármacos , Compostos Organoplatínicos , Dor/etiologia , Dor/psicologia , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/psicologia , Analgésicos não Narcóticos/farmacologia , Animais , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Carbamazepina/farmacologia , Hiperalgesia/induzido quimicamente , Hiperalgesia/psicologia , Imuno-Histoquímica , Magnésio/farmacologia , Masculino , Neurônios Aferentes/efeitos dos fármacos , Oxaliplatina , Medição da Dor/efeitos dos fármacos , Doenças do Sistema Nervoso Periférico/patologia , Células do Corno Posterior/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Substância P/metabolismoRESUMO
Nociceptin/orphanin FQ (noci/OFQ), the endogenous ligand for the orphan ORL1 (opioid receptor-like1), has been shown to be anti- or pronociceptive and modify morphine analgesia in rats after central administration. We comparatively examined the effect of noci/OFQ on hyperalgesia and morphine analgesia in two experimental models of neuropathic pain: diabetic (D) and mononeuropathic (MN) rats. Noci/OFQ, when intrathecally (i.t.) injected (0.1, 0.3, or 1, to 10 microg/rat) was ineffective in normal rats, but reduced and suppressed mechanical hyperalgesia (paw-pressure test) in D and MN rats, respectively. This spinal inhibitory effect was suppressed by naloxone (10 microg/rat, i.t.) in both models. Combinations of systemic morphine with spinal noci/OFQ resulted in a strong potentiation of analgesia in D rats. In MN rats, an isobolographic analysis showed that the morphine+noci/OFQ association (i.t.) suppressed mechanical hyperalgesia in a superadditive manner. In summary, the present findings reveal that spinal noci/OFQ produces a differential antinociception in diabetic and traumatic neuropathic pain according to the etiology of neuropathy, an effect possibly mediated by opioid receptors. Moreover, noci/OFQ combined with morphine produces antinociceptive synergy in experimental neuropathy, opening new opportunities in the treatment of neuropathic pain.
Assuntos
Diabetes Mellitus Experimental/fisiopatologia , Mononeuropatias/fisiopatologia , Peptídeos Opioides/fisiologia , Dor/fisiopatologia , Receptores Opioides/metabolismo , Animais , Comportamento Animal , Peso Corporal , Diabetes Mellitus Experimental/induzido quimicamente , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Interações Medicamentosas , Hiperalgesia/fisiopatologia , Masculino , Mononeuropatias/metabolismo , Morfina/farmacologia , Naloxona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Dor/metabolismo , Medição da Dor/métodos , Ratos , Ratos Sprague-Dawley , Receptores Opioides/agonistas , Nervo Isquiático/lesões , Estreptozocina , Fatores de Tempo , Vocalização Animal/efeitos dos fármacos , Receptor de Nociceptina , NociceptinaRESUMO
The purpose of this study was to assess, in rats, the antinociceptive effects of levetiracetam (i.p.), a novel antiepileptic drug, in acute pain tests and in two models of human neuropathic pain. Levetiracetam and carbamazepine contrasted morphine by an absence of effect in the tail flick and hot plate tests. In normal rats, carbamazepine failed to modify the vocalisation thresholds to paw pressure whereas levetiracetam slightly increased this threshold only at the highest dose (540 mg/kg) for 30 min. In the sciatic nerve with chronic constriction injury model, the highest dose of levetiracetam (540 mg/kg) and carbamazepine (30 mg/kg) reversed the hyperalgesia. In streptozocin-induced diabetic rats, levetiracetam dose-dependently increased the vocalization threshold from 17 to 120 mg/kg reaching a similar effect as 10 mg/kg of carbamazepine. These results indicate that levetiracetam induces an antihyperalgesic effect in two models of human neuropathic pain, suggesting a therapeutic potential in neuropathic pain patients.
Assuntos
Analgésicos/uso terapêutico , Hiperalgesia/prevenção & controle , Dor/tratamento farmacológico , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Piracetam/uso terapêutico , Doença Aguda , Analgésicos/administração & dosagem , Animais , Carbamazepina/administração & dosagem , Carbamazepina/uso terapêutico , Doença Crônica , Constrição Patológica , Diabetes Mellitus Experimental/complicações , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Humanos , Hiperalgesia/etiologia , Injeções Intraperitoneais , Levetiracetam , Masculino , Morfina/uso terapêutico , Dor/etiologia , Medição da Dor , Doenças do Sistema Nervoso Periférico/etiologia , Piracetam/administração & dosagem , Piracetam/análogos & derivados , Ratos , Ratos Sprague-Dawley , Nervo Isquiático , Vocalização AnimalRESUMO
We previously showed that the intraperitoneal (i.p.) administration of 200mg/kg cyclophosphamide, an antitumoral agent, modified the behaviour of rats with cystitis induced by acrolein, a toxic urinary by-product of cyclophosphamide. This behaviour, (namely decreased breathing rate, closing of the eyes, and specific postures), was scored to indirectly assess the nociception elicited by the cystitis and to use this experimental model as a vesical pain model. Here we investigated the involvement of the N-methyl-D-aspartate (NMDA) receptors and thus of the excitatory amino acid system in this model. We administered dizocilpine (0.01 to 0.1mg/kg intravenously (i.v.) and 1 to 20 microg/rat intrathecally (i.t.)) and ketamine (5 and 10mg/kg i.v. and 50 to 1000 microg/rat i.t.), two non-competitive NMDA receptor antagonists that bind to the channel site, and AP-5 (0.01 to 1mg/kg i.v. and 20 to 500 microg/rat i.t), a competitive antagonist that binds to the glutamate site. Whichever the route of administration (i.v. or i.t.), dizocilpine dose-relatedly reduced the behavioural disorders induced by cyclophosphamide. Systemic ketamine also dose-dependently, though transiently, reduced the effects of cyclophosphamide, but ketamine i.t. and AP-5 i.v. and i.t. did not induce any reduction of these effects.These results (i) demonstrate that in the cyclophosphamide-induced vesical pain model NMDA receptors are involved in the nociception, as shown by the effects of dizocilpine and systemic ketamine, (ii) reveal marked differences in the data obtained with various NMDA receptor antagonists, possibly due to their physicochemical properties, to the animal pain model used, to the noxious stimulus applied or to any combination of these factors.
Assuntos
Ciclofosfamida/efeitos adversos , Cistite/complicações , Dor/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Acroleína/efeitos adversos , Animais , Antineoplásicos Alquilantes/efeitos adversos , Comportamento Animal , Cistite/induzido quimicamente , Cistite/metabolismo , Maleato de Dizocilpina/farmacologia , Relação Dose-Resposta a Droga , Injeções Intravenosas , Injeções Espinhais , Ketamina/farmacologia , Masculino , Modelos Animais , Dor/tratamento farmacológico , Dor/etiologia , Ratos , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato/antagonistas & inibidoresRESUMO
Since evidence points to the involvement of cholecystokinin (CCK) in nociception, we examined the effect of intrathecal CI-988, an antagonist of the CCK-B receptors, on mechanical hyperalgesia and allodynia in normal, mononeuropathic and diabetic rats,. Owing to the anti-opioid activity of CCK, it has been suggested that hyperactivity in the spinal CCK system is responsible for the low sensitivity of neuropathic pain to opioids. We therefore also evaluated the effect of the combination of i.t. CI-988 + i.v. morphine on mechanical hyperalgesia in diabetic and mononeuropathic rats using isobolographic analysis. Although ineffective in normal rats, CI-988 induced antinociceptive effects in diabetic (290 +/- 20 g with a cut-off of 750 g) and mononeuropathic (117 +/- 16 g; cut-off 750 g) rats, suggesting an involvement of the CCKergic system in neurogenic pain conditions. The combination of CI-988 and morphine showed a superadditive interaction in the diabetic rats only (477 +/- 16 g; cut-off 750 g), in comparison with the antinociceptive effect of each drug. In addition, CI-988 exhibited a weak anti-allodynic effect in mononeuropathic rats, and no anti-allodynic effect in diabetic rats. These results show the CCK-B receptor blockade-mediated antinociceptive effects and reveals the antinociceptive action of morphine in diabetic rats after CCKergic system inhibition.