The α7 nicotinic acetylcholine receptor positive allosteric modulator prevents lipopolysaccharide-induced allodynia, hyperalgesia and TNF-α in the hippocampus in mice

Background: Previous studies have shown that alpha 7 nicotinic acetylcholine receptor (nAChR) has a critical role in the regulation of pain sensitivity and neuroinflammation. However, pharmacological effects of alpha 7 nAChR activation in the hippocampus on neuroinflammatory mechanisms associated with allodynia and hyperalgesia remain unknown. We have determined the effects of 3a,4,5,9b-tetrahydro-4-(1-naphthalenyl)-3H-cyclopentan[c]quinoline-8-sulfonamide (TQS), an alpha 7 nAChR positive allosteric modulator, on lipopolysaccharide (LPS)-induced allodynia and hyperalgesia in mice. We also evaluated the effects of TQS on immunoreactivity of microglial marker ionized-calcium binding adaptor molecule 1 (Iba-1), phospho-nuclear factor-kappa B (p-NF-kappa B p(65)), tumor necrosis factor-alpha (TNF-alpha), and norepinephrine (NE) level. Methods: Mice were treated with (0.25, 1 or 4 mg/kg, ip) followed by LPS (1 mg/kg, ip) administration. Allodynia and hyperalgesia were determined using von Frey filaments and hot plate respectively. Immunoreactivity of Iba-1, p-NF-kappa B p(65), and TNF-alpha, were measured in the hippocampus using immunofluorescence assay. Hippocampal NE level was evaluated using high performance liquid chromatography. Results: LPS administration resulted in allodynia and hyperalgesia in mice after six h. Systemic administration of TQS prevented LPS-induced allodynia and hyperalgesia. TQS pretreatment significantly decreased the immunoreactivity of Iba-1, p-NF-kappa B, and TNF-alpha in CA1 and DG regions of the hippocampus. In addition, TQS reversed LPS-induced NE reduction in the hippocampus. Conclusions: Taken together, our results suggest that TQS prevented LPS-induced allodynia and hyperalgesia, upregulation of TNF-alpha expression and NE level reduction involving microglial alpha 7 nAChR in part in the hippocampus. Therefore, these findings highlight the important effects of alpha 7 nAChR allosteric modulator against symptoms of inflammatory pain. (C) 2019 Maj Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier B.V. All rights reserved.