RESUMO
In the current study, we investigated the effect of the activation of the alpha-7 nicotinic acetylcholine receptor (α7 nAchR) on dextran sulphate sodium (DSS)-induced colitis and referred mechanical hyperalgesia in mice. Colitis was induced in CD1 male mice through the intake of 4% DSS in tap water for 7 days. Control mice received unadulterated water. Referred mechanical hyperalgesia was evaluated for 7 days after the beginning of 4% DSS intake. Referred mechanical hyperalgesia started within 1 day after beginning DSS drinking, peaked at 3 days and persisted for 7 days. This time course profile perfectly matched with the appearance of signs of colitis. Both acute and chronic oral treatments with nicotine (0.1-1.0 mg/kg, p.o.) were effective in inhibiting the established referred mechanical hyperalgesia. The antinociceptive effect of nicotine was completely abrogated by cotreatment with the selective α7 nAchR antagonist methyllycaconitine (MLA) (1.0 mg/kg). Consistent with these results, i.p. treatment with the selective α7 nAchR agonist PNU 282987 (0.1-1.0 mg/kg) reduced referred mechanical hyperalgesia at all periods of evaluation. Despite their antinociceptive effects, nicotinic agonists did not affect DSS-induced colonic damage or inflammation. Taken together, the data generated in the present study show the potential relevance of using α7 nAchR agonists to treat referred pain and discomfort associated with inflammatory bowel diseases.
Assuntos
Analgésicos/uso terapêutico , Colite/fisiopatologia , Hiperalgesia/tratamento farmacológico , Terapia de Alvo Molecular , Agonistas Nicotínicos/uso terapêutico , Dor Referida/tratamento farmacológico , Receptores Nicotínicos/metabolismo , Aconitina/efeitos adversos , Aconitina/análogos & derivados , Analgésicos/administração & dosagem , Analgésicos/antagonistas & inibidores , Animais , Comportamento Animal/efeitos dos fármacos , Benzamidas/administração & dosagem , Benzamidas/uso terapêutico , Compostos Bicíclicos com Pontes/administração & dosagem , Compostos Bicíclicos com Pontes/uso terapêutico , Colite/induzido quimicamente , Colite/imunologia , Relação Dose-Resposta a Droga , Antagonismo de Drogas , Hiperalgesia/etiologia , Hiperalgesia/imunologia , Masculino , Camundongos , Camundongos Endogâmicos , Proteínas do Tecido Nervoso/agonistas , Proteínas do Tecido Nervoso/antagonistas & inibidores , Proteínas do Tecido Nervoso/metabolismo , Nicotina/administração & dosagem , Nicotina/antagonistas & inibidores , Nicotina/uso terapêutico , Agonistas Nicotínicos/administração & dosagem , Agonistas Nicotínicos/química , Antagonistas Nicotínicos/efeitos adversos , Limiar da Dor/efeitos dos fármacos , Dor Referida/etiologia , Dor Referida/imunologia , Distribuição Aleatória , Receptores Nicotínicos/química , Receptor Nicotínico de Acetilcolina alfa7RESUMO
BACKGROUND: Nicotine (NIC), the major active component of tobacco, is critical in the maintenance of the smoking habit. The aims of the present study were to analyze the behavioural and neurochemical variations during NIC withdrawal syndrome in mice, and whether they are prevented with baclofen (BAC, GABA(B) receptor agonist). METHODS: Swiss-Webster albino mice received NIC (2.5 mg/kg, s.c.) 4 times daily, for 7 consecutive days. On day 8 (the day of the experiment), NIC-treated mice received the nicotine antagonist mecamylamine (MEC, 2 mg/kg, i.p.) 1h after the last dose of NIC. A second group of dependent mice received BAC (2mg/kg, i.p.) before MEC-precipitated abstinence. The somatic signs were measured for 30 min. Dopamine (DA), serotonin (5-hydroxytryptamine; 5-HT) and its metabolites concentrations were determined by HPLC in the striatum, cortex and hippocampus. RESULTS: The global score was greater in the abstinent group compared to the control group. Moreover, the global score time course showed a higher increase at 10 min compared to the global score at 5 min or 30 min after MEC-precipitated NIC withdrawal. In addition, the global score was attenuated by BAC. The DA and dihydroxyphenyl acetic acid (DOPAC) cortical levels decreased in the abstinent group, while BAC reestablished these levels 10 min after NIC withdrawal. Furthermore, DA and 5-HT striatal levels decreased during NIC withdrawal, and BAC reverted this decrease. CONCLUSION: In conclusion, the prevention of NIC withdrawal signs by BAC could be related to changes in dopaminergic and serotonergic activity.