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Inflammation and complex regional pain syndrome: The role of alpha1-adrenoceptors

Wijaya, Linda Kurnia (2020) Inflammation and complex regional pain syndrome: The role of alpha1-adrenoceptors. PhD thesis, Murdoch University.

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A growing number of studies have investigated novel roles of the alpha1-adrenoceptor (α1-AR; a receptor for sympathetic neurotransmitter catecholamines) in inflammation. Stimulation of 1-AR in immune cells modulates cellular functions, including migration and inflammatory cytokine production. However, whether α1-ARs in the skin play a role in cutaneous inflammation is not well understood. Complex regional pain syndrome (CRPS) is a complex and debilitating type of neuropathic pain. In the acute stage of CRPS, excessive inflammation persists in the affected limb. Moreover, α1-AR expression is heightened in the skin of the affected limb. However, the causes of this upregulation of cutaneous α1-AR expression and whether this upregulation contributes to the persistent inflammation are unknown.

In this study, the role of α1-AR in cutaneous inflammation was explored, in both normal and pathological conditions, utilizing in vitro, in vivo and ex vivo approaches. It was hypothesized that inflammatory mediators produced by keratinocytes, as a response to injury, would up-regulate α1-AR expression in these cells, and that heightened expression of α1-AR would increase α1-AR sensitivity to stimulation, leading to further release of inflammatory mediators from keratinocytes. Moreover, in CRPS, it was hypothesized that this feedback loop would be amplified and the response stronger than in healthy controls.

A positive feedback interaction between α1-AR and inflammatory mediators in keratinocytes was demonstrated. In particular, α1-AR expression increased after exposure to the primary proinflammatory cytokine tumour necrosis factor α (TNF α). Furthermore, activation of α1-AR further induced a pro-inflammatory cytokine, interleukin 6 (IL-6), expression, thereby suggesting a positive feedback loop between α1-AR and IL-6 in keratinocytes. Interestingly, the interaction was stronger in keratinocytes obtained from CRPS patients, particularly those with high baseline levels of α1-AR expression, compared to healthy controls.

In conclusion, this study demonstrated a positive feedback interaction between α1-AR and IL-6 in the skin, which may play an important role in normal cutaneous inflammation. Maintaining homeostasis of this interaction could be crucial to prevent the development of persistent inflammation underlying pathophysiology in chronic diseases, such as CRPS.

Item Type: Thesis (PhD)
Murdoch Affiliation(s): Psychology, Counselling, Exercise Science and Chiropractic
Supervisor(s): Drummond, Peter and Stumbles, Phil
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