RESUMO
Sympathetic fibres maintain some forms of neuropathic pain, but the underlying mechanisms are poorly understood. Therefore, this study investigated the possible involvement of transient receptor potential ankyrin 1 (TRPA1) and the role of the sympathetic nervous system (involved in sympathetically maintained neuropathic pain) in a model of neuropathic pain induced by sciatic nerve chronic constriction injury (CCI) in mice. Systemic injection of the selective TRPA1 antagonist HC-030031 reversed the mechanical and cold allodynia that was induced by sciatic nerve chronic constriction injury (CCI). Nerve injury also sensitised mice to nociception, which was induced by the intraplantar injection of a low dose of the TRPA1 agonist allyl isothiocyanate without changing TRPA1 immunoreactivity in the injected paw. Furthermore, chemical sympathectomy produced by guanethidine largely prevented CCI-induced mechanical and cold allodynia. CCI also induced a norepinephrine-triggered nociception that was inhibited by an α-adrenoceptor antagonist, norepinephrine transporter block and monoamine oxidase inhibition. Finally, the peripheral injection of HC-030031 also largely reduced CCI-induced norepinephrine nociception and mechanical or cold allodynia. Taken together, the present findings reveal a critical role of TRPA1 in mechanical and cold hypersensitivity and norepinephrine hypersensitivity following nerve injury. Finally, our results suggest that TRPA1 antagonism may be useful to treat patients who present sympathetically maintained neuropathic pain.
Assuntos
Neuralgia/metabolismo , Sistema Nervoso Simpático/fisiopatologia , Canais de Potencial de Receptor Transitório/metabolismo , Acetanilidas/farmacologia , Analgésicos/farmacologia , Animais , Constrição , Modelos Animais de Doenças , Hiperalgesia/etiologia , Hiperalgesia/metabolismo , Hiperalgesia/fisiopatologia , Hiperalgesia/prevenção & controle , Masculino , Camundongos , Neuralgia/etiologia , Neuralgia/fisiopatologia , Neuralgia/prevenção & controle , Nociceptividade/efeitos dos fármacos , Purinas/farmacologia , Nervo Isquiático/efeitos dos fármacos , Nervo Isquiático/lesões , Nervo Isquiático/fisiopatologia , Sistema Nervoso Simpático/efeitos dos fármacos , Canal de Cátion TRPA1 , Canais de Potencial de Receptor Transitório/antagonistas & inibidoresRESUMO
Monoamine oxidase (MAO) inhibitors were the first antidepressant drugs to be prescribed and are still used today with great success, especially in patients resistant to other antidepressants. In this study, we evaluated the MAO inhibitory properties and the potential antidepressant action of 2-(3,4-dimethoxy-phenyl)-4,5-dihydro-1H-imidazole (2-DMPI) in mice. We found that 2-DMPI inhibited both MAO isoforms (K(i) values were 1.53 (1.3-1.8) µM and 46.67 (31.8-68.4) µM for MAO-A and MAO-B, respectively) with 30-fold higher selectivity toward MAO-A. In relation to the nature of MAO-A inhibition, 2-DMPI showed to be a mixed and reversible inhibitor. The treatment with 2-DMPI (100-1000 µmol/kg, s.c.) caused a significant decrease in immobility time in the tail suspension test (TST) without affecting locomotor activity, motor coordination or anxiety-related activities. Conversely, moclobemide (1000 µmol/kg, s.c.) caused a significant increase in immobility time in the TST, which appeared to be mediated by a nonspecific effect on motor coordination function. 2-DMPI (300 µmol/kg, s.c.) decreased serotonin turnover in the cerebral cortex, hippocampus and striatum, whereas dopamine turnover was diminished only in the striatum, and norepinephrine turnover was not changed. The antidepressant-like effect of 2-DMPI was inhibited by the pretreatment of mice with methysergide (2 mg/kg, s.c., a non-selective serotonin receptor antagonist), WAY100635 (0.1 mg/kg, s.c., a selective 5-HT(1A) receptor antagonist) or haloperidol (0.05 mg/kg, i.p., a non-selective dopamine receptor antagonist). These results suggest that 2-DMPI is a prototype reversible and preferential MAO-A inhibitor with potential antidepressant activity, due to its modulatory effect on serotonergic and dopaminergic systems.