Mechanisms underlying midazolam-induced peripheral nerve block and neurotoxicity.

BACKGROUND AND OBJECTIVES: The benzodiazepine midazolam has been reported to facilitate the actions of spinally administrated local anesthetics. Interestingly, despite the lack of convincing evidence for the presence of γ-aminobutyric acid type A (GABAA) receptors along peripheral nerve axons, midazolam also has been shown to have analgesic efficacy when applied alone to peripheral nerves.These observations suggest midazolam-induced nerve block is due to another site of action. Furthermore, because of evidence indicating that midazolam has equal potency at the benzodiazepine site on the GABAA receptor and the 18-kd translocator protein (TSPO), it is possible that at least the nerve-blocking actions of midazolam are mediated by this alternative site of action. METHODS: We used the benzodiazepine receptor antagonist flumazenil, and the TSPO antagonist PK11195, with midazolam on rat sciatic nerves and isolated sensory neurons to determine if either receptor mediates midazolam-induced nerve block and/or neurotoxicity. RESULTS: Midazolam (300 µM)-induced block of nerve conduction was reversed by PK11195 (3 µM), but not flumazenil (30 µM). Midazolam-induced neurotoxicity was blocked by neither PK11195 nor flumazenil. Midazolam also causes the release of Ca from internal stores in sensory neurons, and there was a small but significant attenuation of midazolam-induced neurotoxicity by the Ca chelator, BAPTA. BAPTA (30 µM) significantly attenuated midazolam-induced nerve block. CONCLUSIONS: Our results indicate that processes underlying midazolam-induced nerve block and neurotoxicity are separable, and suggest that selective activation of TSPO may facilitate modality-selective nerve block while minimizing the potential for neurotoxicity.

Ação analgésica da corrente anódica de alta voltagem sobre ciatalgia experimental / Analgesic action of anodic high voltage current on experimental sciatica

JUSTIFICATIVA E OBJETIVOS: A ciatalgia produz grande morbidade, com implicações individuais e sociais, uma das possibilidades terapêuticas é a corrente de alta voltagem, mas possui resultados controversos na literatura devendo ser mais explorada. Assim, o objetivo do estudo foi analisar o quadro álgico de ratos submetidos a um modelo de ciatalgia, tratados com corrente de alta voltagem anódica. MÉTODO: Foram utilizados 12 ratos Wistar, divididos em 2 grupos, simulacro (GS) e tratado com corrente de alta voltagem anódica (GP+). Todos foram submetidos a um modelo de ciatalgia experimental, e 3 dias após iniciou-se o tratamento para GP+, diários, durante 10 dias. As avaliações ocorreram antes da compressão, ao 3º dia (antes e após o 1º tratamento), após o 5º e 10º dias de tratamento. Os métodos utilizados foram o teste de incapacidade funcional e o limiar de retirada, com uso do filamento de Von Frey digital. RESULTADOS: Para o teste de incapacidade funcional, ambos os grupos apresentaram aumento do tempo de elevação da pata,sem redução em nenhum momento. Para o limiar de retirada, foi possível observar apenas para o GP+ aumento do limiar após o 5º e 10º dias de terapia, ocorrendo também aumento significativo ao comparar pós-lesão com após a 5ª terapia. CONCLUSÃO: O uso da corrente anódica de alta voltagem produziu aumento do limiar doloroso à pressão, mas não produziu diminuição na dor que pudesse intervir na claudicação.

BACKGROUND AND OBJECTIVES: The sciatica produces high morbidity, with individual and social implications, one of the therapeutic is the high-voltage current, but has the same controversial results in literature and should be explored further. Thus,the aim of the study was to analyze the pain in rats subjected to a sciatica model treated with the anode high-voltage current. METHOD: A total of 12 Wistar rats were divided into two groups, sham (SG) and treated with the high-voltage anode(PG+). All animals underwent to a sciatica experimental model,and 3 days after treatment began for PG+, daily for 10 days.Assessments occurred prior to compression, the 3rd day (before and after the 1st treatment), after the 5th and 10th treatment days.The methods used were the functional incapacitation test and the withdrawal threshold, using the digital Von Frey filament. RESULTS: for functional incapacitation test, both groups showed increased paw elevation time, without reduction in anytime. For the withdrawal threshold, was observed only for the PG+ threshold increase after the 5th and 10th days of therapy, occurring also increased significantly when compared with postinjury after the 5th treatment. CONCLUSION: the use of anode high-voltage current produced a pain threshold increase to pressure, but produced no reduction in pain that could intervene in claudication.

Venlafaxine-induced depression of wind-up activity in mononeuropathic rats is potentiated by inhibition of brain 5-HT1A receptor expression in vivo.

Antinociceptive effects of inhibiting 5-HT1A receptor expression by intracerebroventricular administration of an antisense oligodeoxynucleotide were studied in mononeuropathic rats. A 7-day period of treatment with the antisense produced: (i) reduction of mechanical hyperalgesia in the neuropathic hindlimb starting from day 5 of treatment, (ii) decrease of the hypothermic effect of 8-OH-DPAT challenge on day 6 of treatment, and (iii) potentiation of the inhibitory effect of velafaxine on spinal wind-up activity on day 7 of treatment. Results suggest a counteracting role of somatodendritic 5-HT1A receptors of raphe nuclei neurons in the antinociceptive efficacy of antidepressants with serotonergic spectrum in neuropathic pain.