Haeme oxygenase-1 overexpression via nAChRs and the transcription factor Nrf2 has antinociceptive effects in the formalin test
- 1 November 2009
- journal article
- Published by Ovid Technologies (Wolters Kluwer Health) in Pain
- Vol. 146 (1), 75-83
- https://doi.org/10.1016/j.pain.2009.07.007
Abstract
Epibatidine has shown antinociceptive effects in various pain models, being 200-fold more potent than morphine. Previous results from our laboratory demonstrated that HO-1 overexpression has an antinociceptive effect in the formalin test. Furthermore, epibatidine was able to induce haeme oxygenase-1 (HO-1). So, the aim of this study was to investigate the effect of HO-1 overexpression induced by epibatidine in nociception elicited by formalin injection in the mice hindpaw. Administration of epibatidine (4 microg/kg) 24h before the test reduced the nociceptive response during the first phase and second phase of the formalin test. This effect was prevented by treatment with tin protoporphyrin (SnPP, an inhibitor of HO-1 activity) administered via intraplantar 5min before the test, suggesting a main role of HO-1. Western blot analysis revealed that epibatidine treatment increased by 2-fold HO-1 expression in the paw; this effect was lost in knockout mice for nuclear factor-erythroid 2-related factor 2 (Nrf2) and was accompanied by the loss of its antinociceptive effect. Furthermore, the antinociceptive effect of epibatidine was related to the activation of alpha7 and/or alpha9 nAChRs since methyllycaconitine (MLA) and mecamylamine but not dihydro-beta-erythroidine (DHbetaE) reverted this effect. Finally, we showed by flow cytometry and by immunofluorescence that white blood cells of the animals injected with epibatidine expressed more HO-1 than control animals, and this expression was also reverted by MLA pre-treatment. These findings demonstrate that HO-1 induction by epibatidine has antinociceptive and anti-inflammatory effects by the activation of MLA-sensitive nAChRs.Keywords
This publication has 48 references indexed in Scilit:
- The alpha7 nicotinic acetylcholine receptor as a pharmacological target for inflammationBritish Journal of Pharmacology, 2007
- Nicotinic receptor activation by epibatidine induces heme oxygenase‐1 and protects chromaffin cells against oxidative stressJournal of Neurochemistry, 2007
- The Vagus Nerve: A Tonic Inhibitory Influence Associated With Inflammatory Bowel Disease in a Murine ModelGastroenterology, 2006
- Molecular mechanism activating nrf2–keap1 pathway in regulation of adaptive response to electrophilesFree Radical Biology & Medicine, 2004
- Antihyperalgesic activity of epibatidine in the formalin model of facial painPain, 2001
- Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxinNature, 2000
- Analgesic and toxic effects of ABT-594 resemble epibatidine and nicotine in ratsPain, 2000
- The α7 nicotinic acetylcholine receptor in neuronal plasticityMolecular Neurobiology, 1999
- Constitutive expression of mRNA for the same choline acetyltransferase as that in the nervous system, an acetylcholine-synthesizing enzyme, in human leukemic T-cell linesNeuroscience Letters, 1998
- Choline is a Selective Agonist of α7 Nicotinic Acetylcholine Receptors in the Rat Brain NeuronsEuropean Journal of Neuroscience, 1997