Morgan, Oakley; (2023) Exacerbation of inflammatory pain states and migraine by stress exposure: a role for the stress regulator FKBP51. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Chronic pain is a global health burden, affecting up to 20% of the world population at any one time. Current pain therapeutics are low in efficacy and often accompanied by negative side effects. As such, there is a great need for novel treatment approaches. An alternative strategy for pain management could rely on the identification of individual risk to chronic pain development. Stress exposure has been recognised as a predisposing factor for pain chronicity, but the underlying mechanisms by which this occurs are unknown. This thesis explored the hypothesis that FKBP51, a significant regulator of the stress axis and persistent pain states, drives the mechanisms that govern the interactions between stress exposure and pain. To test this hypothesis, we combined preclinical models of stress exposure and pain. Mice experienced stress in adulthood, via sub-chronic restraint, or in early life, by disruption of neonatal maternal interactions. These paradigms were then followed by inflammatory or migraine pain models, respectively. Both forms of stress exposure influenced the manifestation of subsequent pain experiences, with stress exposed mice showing enhanced sensory and affective responses to the respective pain states. Crucially, the hypersensitive pain states were significantly prolonged, suggesting that stress exposure had increased the susceptibility to pain chronicity. Manipulation of FKBP51, via pharmacological and genetic tools, resulted in the prevention of the stress-induced exacerbation of pain, suggesting that FKBP51 was driving this effect. Furthermore, DNA methylation analysis provided initial evidence for the involvement of epigenetic regulation of FKBP5 expression by stress exposure in the mechanisms of predisposition to persistent pain. In conclusion, the findings from this thesis suggest that stress exposure exacerbates pain via FKBP51-dependent mechanisms, increasing chronic pain vulnerability. Moreover, this research suggests that FKBP51 inhibition could become an effective preventive intervention for those at high risk of stress-driven pain chronicity.

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