Document Type

Dissertation - Open Access

Award Date

2016

Degree Name

Doctor of Philosophy (PhD)

Department / School

Pharmaceutical Sciences

First Advisor

Shafiqur Rahman

Keywords

Hippocampus, mice, microglia, neuroinflammatory pain, α7 NICOTINIC ACETYLCHOLINE RECEPTOR

Abstract

Neuroinflammatory pain affects about 1.5% of the United States population. Around 20-40% patients having neurological disorders are affected with neuroinflammatory pain. As a part of the limbic system, hippocampus is known to play a critical role in pain perception and processing, and is densely populated with microglial cells and α7 nicotinic acetylcholine receptors (nAChRs). Given the role of microglial α7 nAChRs in neuroinflammation, the α7 nAChRs have emerged as potential target for neuroinflammatory pain treatment. We hypothesized that microglial α7 nAChRs positive allosteric modulation in the hippocampus will decrease neuroinflammatory pain at behavioral, cellular, biochemical, and molecular level. The primary objective of current study was to examine the role of an α7 nAChR positive allosteric modulator (PAM), TQS, in neuroinflammatory pain and to determine biochemical, cellular, and molecular mechanisms associated with neuroinflammatory pain in the hippocampus using mouse models. We demonstrated that TQS reduced neuroinflammatory pain-like symptoms, including tactile allodynia and thermal hyperalgesia in mice. Methyllcaconitine, an α7 nAChR antagonist, reversed antiallodynic and antihyperalgesic effects of TQS suggesting the involvement of α7 nAChR. The TQS decreased the expression of ionized calcium binding adapter molecule 1 and cluster of differentiation 11b, microglial activation markers, in the hippocampus. We determined that TQS reduced inhibitor of kappa B, a downstream mediator that decreases due to nuclear factor-κB (NF-κB) inactivation, and p-NF-κB p65 expression in the hippocampus. In addition, TQS reduced the expression of tumor necrosis factor (TNF) and increased the level of norepinephrine in the hippocampus. We determined that TQS decreased the expression of brain-derived neurotrophic factor (BDNF). Similarly, we determined that TQS reduced the activation of Na-K-Cl cotransporter 1 and increased K-Cl co-transporter 2 expression. Taken together, our results indicated that TQS decreased microglial TNF and BDNF expression and associated signaling in neuroinflammatory pain involving α7 nAChR and microglial activation. Our findings provided strong and novel evidence that microglial α7 nAChR positive allostetric modulation-mediated signaling regulate behavioral, cellular, biochemical, and molecular mechanisms underlying neuroinflammatory pain. Therefore, targeting microglial α7 nAChR positive allosteric modulation in the hippocampus might be a novel strategy for the treatment of neuroinflammatory pain.

Library of Congress Subject Headings

Nicotinic receptors.
Neuroprotective agents.
Inflammation.
Microglia.
Nervous system -- Diseases.
Hippocampus (Brain)

Description

Includes bibliographical references (pages 161-201)

Format

application/pdf

Number of Pages

219

Publisher

South Dakota State University

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Rights Statement

In Copyright