Graduation Semester and Year

Spring 2025

Language

English

Document Type

Thesis

Degree Name

Master of Science in Psychology

Department

Psychology

First Advisor

Linda Perrotti

Second Advisor

Yuan B. Peng

Third Advisor

Tracey Greer

Abstract

The opioid epidemic has led to a surge in opioid use disorder (OUD) and overdose deaths, making opioid withdrawal a critical area of study. Opioid withdrawal is characterized by both somatic and affective symptoms, including anxiety-like behaviors and physical withdrawal signs, yet the underlying neurobiological mechanisms remain insufficiently understood. The kynurenine pathway (KP), a primary metabolic route for tryptophan (TRP), is increasingly implicated in neuroinflammatory responses and neuropsychiatric disorders, yet its involvement in opioid use and withdrawal remains poorly studied, with even less known about potential sex-specific differences. Historically, the predominant use of male subjects in preclinical research has compounded this gap, leaving the KP’s role in modulating opioid withdrawal responses and how it might differ between sexes largely unexplored across both opioid and broader substance use disorder studies. This study aimed to address these deficiencies by investigating the KP’s contribution to sex-specific opioid withdrawal, examining alterations in KP metabolism alongside withdrawal-related behaviors in male and female rodents, while also assessing whether the female estrous cycle further influences these effects. To investigate whether the kynurenine pathway (KP) contributes to sex differences in opioid withdrawal, male and female subjects underwent chronic morphine administration followed by withdrawal. Serum levels of kynurenine (KYN) and tryptophan (TRP) were measured to assess potential neurobiological differences, while behavioral assessments, including anxiety-like behavior (elevated plus maze), writhing, paw tremors, and wet dog shakes, were conducted at 12- and 24-hours post-withdrawal. Results revealed sex-specific alterations in both kynurenine pathway (KP) metabolism and withdrawal-related behaviors following chronic morphine withdrawal. In both males and females, serum TRP levels significantly increased at 12- and 24-hour withdrawal time points compared to controls, reflecting a robust metabolic response to opioid withdrawal. However, KYN levels increased significantly only in females at both time points, suggesting a more pronounced activation of the KP in females during withdrawal. These metabolic shifts coincided with distinct behavioral profiles. Females displayed heightened anxiety-like behavior, spending significantly less time in the open arms of the elevated plus maze (EPM) at 12 hours compared to males, with a trend toward reduced time at 24 hours, alongside greater paw tremors at 12 hours relative to both control females and males in the 12-hour withdrawal group. In contrast, males exhibited more pronounced somatic withdrawal symptoms, including significantly greater wet dog shakes at 24 hours compared to control males, 12-hour withdrawal males, and 24-hour withdrawal females, as well as elevated face rubbing at 12 hours relative to control males. These findings highlight a sex-dependent interplay between KP metabolism and withdrawal symptomatology, with females showing a stronger metabolic and anxiety-related response, while males exhibit more intense physical withdrawal signs. The estrous cycle did not significantly influence serum KYN or TRP levels, though anxiety-like behaviors were more pronounced in proestrus/estrus females during late withdrawal. No significant estrous cycle effects were observed for writhing, wet dog shakes, paw tremors, or body weight. These findings illuminate sex-specific metabolic and behavioral responses to opioid withdrawal, revealing distinct neurobiological profiles that underscore the complexity of OUD pathophysiology. The consistent elevation of serum tryptophan (TRP) in both sexes at 12- and 24-hour withdrawal points suggests a broad upregulation of tryptophan metabolism following opioid withdrawal. However, the selective increase in kynurenine (KYN) levels in females points to a more pronounced sex-specific shift toward KP activation, potentially reflecting greater sensitivity to withdrawal-induced neuroinflammation in females. This metabolic divergence aligns with behavioral outcomes: females exhibited heightened anxiety-like behavior and early somatic signs like paw tremors, which may be linked to KYN’s downstream neurotoxic metabolites, such as quinolinic acid (QUIN), known to exacerbate excitotoxicity and negative affect. Conversely, males displayed more intense physical withdrawal symptoms, such as wet dog shakes and face rubbing, without corresponding KYN elevations, suggesting alternative pathways. These sex-dependent patterns emphasize the critical need to integrate sex as a biological variable in OUD research, as they reveal differential vulnerabilities that could inform tailored interventions. For instance, targeting KP enzymes like IDO or kynurenine monooxygenase (KMO) might preferentially mitigate neuroinflammation and anxiety in females, while strategies addressing somatic symptoms could be prioritized for males. Collectively, these results advocate for a nuanced approach to withdrawal management, highlighting the KP as a promising, sex-specific therapeutic target to alleviate distinct facets of OUD symptomatology.

Keywords

Opioid withdrawal, opioid use disorder, sex differences, tryptophan, kynureniune.

Disciplines

Substance Abuse and Addiction

License

Creative Commons Attribution 4.0 International License
This work is licensed under a Creative Commons Attribution 4.0 International License.

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