Author ORCID Identifier

0000-0002-8936-4550

Date of Award

8-9-2022

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Neuroscience Institute

First Advisor

Anne Murphy

Abstract

Opioids are among the most potent and widely used drugs for the management of chronic pain. Chronic pain is exceedingly prevalent in individuals over 65 years of age but is under-managed in this population, due in part to a lack of knowledge regarding the suitable dosing of opioids for chronic pain management. The present experiments first seek to characterize the impact of advanced age on opioid potency in male and female rats using intraplantar Complete Freund's adjuvant (CFA), a clinically relevant model of inflammatory pain. We report that advanced age and sex alter morphine modulation of persistent inflammatory pain, specifically, morphine potency was highest in adult male rats (2mos), with a 2-fold rightward shift in the dose-response curve for aged males (18mos), and females regardless of age. These findings suggest that opioids have decreased anti-hyperalgesic potency in aged rodents compared to adults, prompting us to determine the neural mechanisms underlying this attenuated response.

Morphine-induced analgesia is mediated primarily via binding to μ-opioid receptors (MOR) within the midbrain periaqueductal gray (PAG), a critical site for descending pain modulation. The present studies use cellular and pharmacological techniques to examine MOR binding and signaling within the PAG. The data in this thesis thoroughly characterize the impact of advanced and biological sex on PAG MOR expression, binding, and signaling within the PAG in the presence of chronic inflammatory pain, and thus have significant implications for pain management in the aged population. These studies contribute to our understanding of how advanced age and sex alter morphine anti-hyperalgesia and enhance our knowledge of age- and sex-induced changes in PAG MOR signaling. Our findings identify novel therapeutic targets to improve opioid signaling in the aged brain and develop effective chronic pain management strategies.

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