Influence of NMDA and non-NMDA antagonists on acute and inflammatory pain in the trigeminal territory: a placebo control study / Influência dos antagonistas dos receptores NMDA e não-NMDA sobre a dor aguda e inflamatória ao nível do território do trigêmeo: um estudo placebo controlado

NMDA and non-NMDA receptors are involved in spinal transmission of nociceptive information in physiological and pathological conditions. Our objective was to study the influence of NMDA and non-NMDA receptor antagonists on pain control in the trigeminal system using a formalin-induced orofacial pain model. Motor performance was also evaluated. Male Rattus norvegicus were pre-treated with topiramate (T) (n=8), memantine (M) (n=8), divalproex (D) (n=8) or isotonic saline solution (ISS) (n=10) intraperitoneally 30 minutes before the formalin test. Formalin 2.5 percent was injected into the right upper lip (V2 branch) and induced two phases: phase I (early or neurogenic) (0-3 min) and phase II (late or inflammatory) (12-30 min). For motor behavior performance we used the open-field test and measured latency to movement onset, locomotion and rearing frequencies, and immobility time. Pre-treatment of animals with M and D only attenuated nociceptive formalin behavior for phase II. T increased locomotion and rearing frequencies and reduced immobility time. Treatment with M increased immobility time and with D reduced locomotion frequency. Our results showed that the NMDA antagonist (M) is more potent than the non-NMDA antagonists (D and T) in the control of pain in the inflammatory phase. The non-NMDA topiramate improved motor performance more than did D and M, probably because T has more anxiolytic properties.

Receptores NMDA e não-NMDA estão envolvidos na transmissão das informações nociceptivas em condições fisiológicas e patológicas. Com o objetivo de estudar a influência dos antagonistas dos receptores NMDA e não-NMDA sobre o controle de dor no sistema trigeminal utilizamos modelo de dor orofacial induzida pela formalina. Testes de desempenho motor foram também avaliados. Ratos machos da espécie Rattus norvegicus foram tratados com topiramato (T) (n=8), memantina (M) (n=8), divalproato de sódio (D) (n=8) ou solução salina isotônica (SSI) (n=10), por via intraperitoneal, 30 minutos antes dos testes com a formalina. Formalina 2.5 por cento foram injetadas na região do lábio superior dos animais (segundo ramo do trigêmeo) induzindo comportamento em duas fases distintas: fase I (precoce ou neurogênica) (0-3 min ) e fase II (tardia ou inflamatória) (12-30 min). Para avaliação da atividade motora utilizou-se o teste do campo aberto mensurando-se a latência para o início dos movimentos, número de casas andadas, freqüência de levantamentos e tempo de imobilidade. Animais pré-tratados com M e D atenuaram a fase inflamatória do teste da formalina. O T aumenta o número de casas andadas, freqüência de levantamentos e reduz o tempo de imobilidade. Nossos resultados mostram que o antagonista NMDA é mais potente do que os antagonistas não-NMDA para o controle da fase inflamatória da dor. O topiramato entretanto aumenta a atividade motora provavelmente porque apresente propriedades ansiolíticas.

N-methyl-D-aspartate (NMDA) and Non-NMDA Receptors are Involved in the Production and Maintenance of Nociceptive Responses by Intraplantar Injection of Bee Venom and Melittin in the Rat

Whole bee venom (WBV) and its major component, melittin, have been reported to induce long-lasting spontaneous flinchings and hyperalgesia. The current study was designed to elucidate the peripheral and spinal mechanisms of N-methyl-D-aspartate (NMDA) and non-NMDA receptors by which intraplantar (i.pl.) injection of WBV and melittin induced nociceptive responses. Changes in mechanical threshold and flinching behaviors were measured after the injection of WBV (0.04 mg or 0.1 mg/paw) and melittin (0.02 mg or 0.05 mg/paw) into the mid-plantar area of a rat hindpaw. MK-801 and CNQX (6-cyano-7-nitroquinoxaline-2, 3-dione disodium) were administered intrathecally (i.t. 10microgram) or i.pl. (15microgram) 15 min before or i.t. 60 min after i.pl. WBV and melittin injection. Intrathecal pre- and post- administration of MK-801 and CNQX significantly attenuated the ability of high dose WBV and melittin to reduce paw withdrawal threshold (PWT). In the rat injected with low dose, but not high dose, of WBV and melittin, i.pl. injection of MK-801 effectively suppressed the decrease of PWTs only at the later time-points, but the inhibitory effect of CNQX (i.pl.) was significant at all time-point after the injection of low dose melittin. High dose WBV- and melittin-induced spontaneous flinchings were significantly suppressed by i.t. administration of MK-801 and CNQX, and low dose WBV- and melittin-induced flinchings were significantly reduced only by intraplantarly administered CNQX, but not by MK-801. These experimental flinchings suggest that spinal, and partial peripheral mechanisms of NMDA and non-NMDA receptors are involved in the development and maintenance of WBV- and melittin-induced nociceptive responses.