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Type: Thesis
Title: Investigation of a Functional Relationship Between Toll-Like Receptor 4 and Transient Receptor Potential Cation Channel Subfamily V Member 1 in Relation to a Novel Neuroimmune Pain Model
Author: Evans, Samuel Greig
Issue Date: 2020
School/Discipline: Adelaide Medical School
Abstract: Chronic pain represents a significant global disease burden, affecting 1 in 5 adults worldwide and costing billions of dollars annually. Due to poor efficacy and undesirable side effects including tolerance, nausea, constipation, diarrhoea, dizziness and addiction; current therapeutic options are less than ideal. In order to improve upon current therapeutic options, an improved mechanistic understanding underlying the generation and maintenance of chronic pain conditions is required. Communication between the immune system and the nervous system is an emerging area of interest in pain research. Known as neuroimmune signalling, this interaction is involved in altering key elements of the nociceptive signalling pathway and therefore represents an interesting target for future novel therapeutics. Recently, an interaction between innate immune receptor toll-like receptor 4 (TLR4), and neuronal ion channel transient receptor potential cation channel subfamily V member 1 (TRPV1) has been suggested as a clinically relevant neuroimmune interaction. A clinical model provides evidence that TLR4 agonist lipopolysaccharide (LPS), potentiates responses mediated by TRPV1 agonist capsaicin. We aim to further clarify the nature of this interaction in an in vitro overexpression system. And secondly, we aim to replicate the clinical findings in a preclinical model that allows investigation of peripheral and central mechanisms. Our in vitro investigations reveal that TLR4 alters TRPV1 mediated calcium influx dynamic and accumulation in HEK293FT cells. The dynamic was not altered by antagonising or activating TLR4 signalling, although both potentiated calcium accumulation. We were unable to back-translate the clinical endotoxin-capsaicin model into BALB/c mice; however, a primed, peripherally targeted LPS challenge potentiated capsaicin-induced mechanical hypersensitivity in a population of BALB/c mice. However, we found that consecutive intraplantar injections result in attenuated capsaicin-induced mechanical hypersensitivity, an effect reversed by both classical and non-classical opioid antagonists (-)- and (+)-naltrexone. Further, (-)- and (+)- naltrexone produced an extended and potentiated capsaicin-induced mechanical hypersensitivity. The effect of naltrexone appeared to be dependent on the state of nociceptive activity at the time of application. We also present a systematic review of the literature analysing capsaicin-induced animal pain models in order to better inform future research decisions. Therefore, we present a study investigating the TLR4/TRPV1 functional interaction in vitro and in vivo; finding TLR4 alters TRPV1 function. Our results agree with previous studies which postulate both a direct physical interaction and indirect interaction via intracellular calcium-induced signalling and/or pro-inflammatory mediators. Therefore, we present evidence suggesting the interaction between TLR4 and TRPV1 warrants further investigation as a relevant neuroimmune signalling element in chronic pain states; representing a novel therapeutic target.
Advisor: Hutchinson, Mark
Mustafa, Sanam
Buisman-Pijlman, Femke
Dissertation Note: Thesis (Ph.D.) -- University of Adelaide, Adelaide Medical School, 2020
Keywords: Chronic pain
pain model
pain hypersensitivity
Provenance: This electronic version is made publicly available by the University of Adelaide in accordance with its open access policy for student theses. Copyright in this thesis remains with the author. This thesis may incorporate third party material which has been used by the author pursuant to Fair Dealing exceptions. If you are the owner of any included third party copyright material you wish to be removed from this electronic version, please complete the take down form located at:
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