Sex-dependent impact of pain-induced negative affective states on alcohol relapse: role of the dynorphinergic/kor signaling in the nucleus accumbens and amygadala
- Autores: Jesus David Lorente Erenas
- Directores de la Tesis: Lucía Teresa Hipólito Cubedo (dir. tes.)
- Lectura: En la Universitat de València ( España ) en 2024
- Idioma: inglés
- Número de páginas: 247
- Tribunal Calificador de la Tesis: Ignacio Morón Henche (presid.), María José Cano Cebrián (secret.), Jerôme Janblanc (voc.)
- Programa de doctorado: Programa de Doctorado en Neurociencias por la Universitat de València (Estudi General)
- Materias:
- Enlaces
- Tesis en acceso abierto en: TESEO
- Resumen
Alcohol use has been normalized in social contexts, leading to high consumption rates and the risk of suffering alcohol use disorders (AUDs). Stress and anxiety disorders contribute to AUD, involving the hypothalamic-pituitary-adrenal axis. Over time, alcohol use shifts from positive to negative reinforcement, contributing to an allostatic state and promoting dependence. Additionally, chronic pain influences the reward system through these negative affective states, which entail changes in the interplay of CRF and dynorphinergic systems. Moreover, sex differences in neurobiology affect addiction and pain, but many studies overlook it.
This thesis proposes that inflammatory pain alters the mesolimbic dopaminergic pathway, impacting reward processing and contributing to alcohol relapse. Objectives include studying inflammatory pain's impact on alcohol intake patterns, natural reinforcer and alcohol processing, and negative affective states in male and female rats, focusing on the dynorphinergic system in the SMCL. Herein, we explore inflammatory pain's impact on alcohol relapse, revealing sex-specific responses in the nucleus accumbens (NAc).
We show that pain exacerbates anxiety and increases alcohol consumption after withdrawal, particularly in females. Blocking kappa opioid receptors in NAc prevents pain-induced alcohol consumption increase in females. We also delve into sex differences in pain-induced alterations in motivated behaviors and alcohol reward processing. In this sense, inflammatory pain affects motivation differently in males and females. Males experience decreased sucrose motivation, while females exhibit increased dynorphin expression in the amygdala. Contrary to males, females show elevated dopamine release in the NAc core in response to pain. Moreover, inflammatory pain induces behavioral anhedonia in both sexes, with anxiety persisting in females. Dynorphinergic system hyperactivation in NAcSh produces anxiety in females, as blocking kappa opioid receptors alleviates this pain-induced behavior. Finally, we observe sexdependent effects of pain on female mice, emphasizing the dynorphinergic projection from the central amygdala to NAc. In fact, we revealed dynorphinergic projections exclusively from CeA to NAcSh that exhibits sex-dependent adaptations after pain induction.
