RESUMO
The present study assessed the possible pronociceptive role of peripheral and spinal 5-HT(6) receptors in the formalin test. For this, local peripheral administration of selective 5-HT(6) receptor antagonists N-[3,5-dichloro-2-(methoxy)phenyl]-4-(methoxy)-3-(1-piperazinyl)-benzenesulphonamide (SB-399885) (0.01-1 nmol/paw) and 4-iodo-N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]benzene-sulfonamide hydrochloride (SB-258585) (0.001-0.1 nmol/paw) significantly reduced formalin-induced flinching. Local peripheral serotonin (5-HT) (10-100 nmol/paw) or 5-chloro-2-methyl-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole hydrochloride (EMD-386088) (0.01-0.1 nmol/paw; a selective 5-HT(6) receptor agonist) augmented 0.5% formalin-induced nociceptive behavior. The local pronociceptive effect of 5-HT (100 nmol/paw) or EMD-386088 (0.1 nmol/paw) was significantly reduced by SB-399885 or SB-258585 (0.1 nmol/paw). In contrast to peripheral administration, intrathecal injection of 5-HT(6) receptor antagonists SB-399885 and SB-258585 (0.1-10 nmol/rat) did not modify 1% formalin-induced nociceptive behavior. Spinal 5-HT (50-200 nmol/rat) significantly reduced formalin-induced flinching behavior during phases 1 and 2. Contrariwise, intrathecal EMD-386088 (0.1-10 nmol/rat) dose-dependently increased flinching during phase 2. The spinal pronociceptive effect of EMD-386088 (1 nmol/rat) was reduced by SB-399885 (1 nmol/rat) and SB-258585 (0.1 nmol/rat). Our results suggest that 5-HT(6) receptors play a pronociceptive role in peripheral as well as spinal sites in the rat formalin test. Thus, 5-HT(6) receptors could be a target to develop analgesic drugs.
Assuntos
Dor/metabolismo , Sistema Nervoso Periférico/metabolismo , Receptores de Serotonina/fisiologia , Medula Espinal/metabolismo , Animais , Feminino , Formaldeído , Membro Posterior , Inflamação/metabolismo , Inflamação/fisiopatologia , Injeções , Terminações Nervosas/metabolismo , Dor/fisiopatologia , Medição da Dor , Ratos , Ratos Wistar , Antagonistas da Serotonina/farmacologia , Agonistas do Receptor de Serotonina/farmacologiaRESUMO
mRNA and protein presence of Na+/H+ exchanger (NHE) 1 (NHE1) and 5 (NHE5) in dorsal root ganglion (DRG) and dorsal spinal cord as well as its possible role in three inflammatory nociception tests were determined. Local peripheral ipsilateral, but not contralateral, administration of NHE inhibitors 5-(N,N-dimethyl)amiloride hydrochloride (DMA, 0.3-30 microM/paw), 5-(N-ethyl-N-isopropyl)amiloride (EIPA, 0.3-30 microM/paw) and amiloride (0.1-10 microM/paw) significantly increased flinching but not licking behavior in the capsaicin and 5-HT tests. Moreover, DMA and EIPA (0.03-30 microM/paw) as well as amiloride (0.1-1 microM/paw) augmented, in a dose-dependent manner, 0.5% formalin-induced flinching behavior during phase II but not during phase I. Reverse transcription-polymerase chain reaction showed the expression of NHE1 and NHE5 in DRG and dorsal spinal cord. Western blot analysis confirmed the presence of NHE1 in DRG and spinal cord. Moreover, NHE5 was expressed in dorsal spinal cord, but not in DRG where a 45 kDa truncated isoform of NHE5 was identified. Collectively, these data suggest that NHE1, but not NHE5, plays an important role reducing inflammatory pain in rats.