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Biomed Pharmacother ; 174: 116524, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38574622

RESUMO

This study evaluates the antiallodynic and antihyperalgesic effects of LMH-2, a new haloperidol (HAL) analog that acts as sigma-1 receptor (σ1 R) antagonist, in diabetic mice using a model of neuropathic pain induced by chronic hyperglycemia. Additionally, we compared its effects with those of HAL. Hyperglycemia was induced in mice by nicotinamide-streptozotocin administration (NA-STZ, 50-130 mg/kg). Four weeks later, mechanical allodynia was assessed using the up-down method, and hyperalgesia was evoked with formalin 0.5%. We evaluated antiallodynic and antihyperalgesic effects of LMH-2 (5.6-56.2 mg/kg), HAL (0.018-0.18 mg/kg) and gabapentin (GBP, 5.6-56.2 mg/kg). The results showed that LMH-2 had a more significant antiallodynic effect compared to HAL and GBP (90.4±8.7 vs 75.1±3.1 and 41.9±2.3%, respectively; P<0.05), as well as an antihyperalgesic effect (96.3±1.2 vs 86.9±7.41 and 86.9±4.8%, respectively; P<0.05). Moreover, the antiallodynic and antihyperalgesic effect of both LMH-2 and HAL were completely abolished by PRE-084 (σ1 R agonist); and partially by pramipexole (a D2-like receptor agonist). Finally, the effect of all treatments on the rotarod test, barra, open field and exploratory behaviors showed that LMH-2 did not alter the animals' balance or the exploratory behavior, unlike as HAL or GBP. The molecular docking included indicate that LMH-2 has lower affinity to the D2R than HAL. These results provide evidence that LMH-2 exerts its antinociceptive effects as a σ1 R antagonist without the adverse effects induced by HAL or GBP. Consequently, LMH-2 can be considered a good and safe strategy for treating neuropathic pain caused by hyperglycemia in patients with diabetes.


Assuntos
Analgésicos , Diabetes Mellitus Experimental , Haloperidol , Hiperalgesia , Neuralgia , Receptores sigma , Receptor Sigma-1 , Animais , Receptores sigma/antagonistas & inibidores , Receptores sigma/metabolismo , Haloperidol/farmacologia , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/complicações , Masculino , Camundongos , Analgésicos/farmacologia , Neuralgia/tratamento farmacológico , Hiperalgesia/tratamento farmacológico , Neuropatias Diabéticas/tratamento farmacológico , Simulação de Acoplamento Molecular , Estreptozocina , Relação Dose-Resposta a Droga , Gabapentina/farmacologia
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