Sex Differences in the Development of an Opioid Addiction-Like Phenotype: A Focus on the Telescoping Effect.

ABSTRACT

Background: Women develop addiction and drug-related health consequences after fewer years of drug use than men; this accelerated time course, or telescoping effect, has been observed clinically for multiple drugs, including opioids. Preclinical studies indicate that this is a biologically based phenomenon; however, these studies have focused exclusively on cocaine, and none have considered health effects. Methods: In this study, we used a rat (Sprague Dawley) model to determine sex differences in the time course for the development of an opioid addiction-like phenotype, as defined by the development of physical dependence (withdrawal-induced weight loss) and an increase in motivation for fentanyl (under a progressive-ratio schedule). Effects were determined following either 10 days (optimized, experiment 1) or 3 days (threshold, experiment 2) of extended-access fentanyl self-administration (24 hours/day, fixed ratio 1, 2- to 5-minute trials/hour) or following short-access fentanyl self-administration (subthreshold, experiment 3; fixed ratio 1, up to 40 infusions/day). Opioid-related adverse health effects were also determined (experiment 4). Results: Motivation for fentanyl was similarly increased in males and females following 10 days of extended-access self-administration (experiment 1), was transiently increased in females, but not males, following 3 days of extended-access self-administration (experiment 2) and was not increased in either sex following short-access self-administration (experiment 3). Females developed fentanyl-associated adverse health effects more readily than males (experiment 4), with particularly robust differences during extended-access self-administration and withdrawal. Conclusions: As with findings in humans, female rats developed opioid addiction-like features and adverse health consequences more readily than male rats. These data provide support for a biologically based telescoping effect in females for opioids, particularly for opioid-related adverse health consequences.

In this issue, we explore how female rats develop signs of opioid addiction and related health issues faster than male rats, a phenomenon known as the telescoping effect. This study expands on previous research by using a rat model to assess addiction-like behaviors and health consequences following different withdrawal period and durations of fentanyl self-administration. The findings underline the biological underpinnings of sex differences in addiction trajectories, previously demonstrated in humans but not yet studied in opioids until now.