Early life adversity diminishes the cortisol response to opioid blockade in women: Studies from the Family Health Patterns project

Abstract

Early life adversity (ELA) contributes to behavioral impulsivity along with risk for substance use disorders, both accompanied by blunted stress-axis reactivity. However, the biological contributors to blunted stress reactivity are not known. We took advantage of the fact that women have significant opioid inhibition of cortisol output by using the opioid antagonist, naltrexone, to unmask opioid interactions due to ELA. We administered 50 mg of naltrexone or placebo to 72 healthy women (23 years of age) in a double-blind crossover study and observed deviations in cortisol secretion from placebo over the next 180 minutes. ELA was assessed by reported exposure to physical and sexual abuse or neglect and low socioeconomic status and scored as Low, Medium, or High (0, 1–2, and 3+). The ELA groups all had identical placebo-day cortisol secretion, indicating normal basal regulation of the hypothalamic-pituitary-adrenocortical axis. Cortisol rises to naltrexone were largest in the Low-ELA group and strongly blunted in the High-ELA group (F = 3.51, p = 0.035), indicating a lack of opioid function in women with high degrees of ELA. The Low-ELA women reported dysphoric responses to naltrexone (F = 4.05, p = .022) indicating a mild opioid withdrawal, an effect that was absent in the High-ELA group. Women exposed to ELA have blunted cortisol responses to naltrexone, indicating reduced opioid regulation of the stress axis. Central opioid changes may be one pathway linking ELA to blunted stress reactivity in adulthood.

Low-Dose Estrogens as Neuroendocrine Modulators in Functional Hypothalamic Amenorrhea (FHA): The Putative Triggering of the Positive Feedback Mechanism(s)

“…Moreover, the presence of a cortisol response to naloxone infusion observed after low-dose estradiol administration supports the hypothesis that a specific neuroendocrine modulation took place on the Adreno Corticotropin Hormone (ACTH) pathway [45].…”

The Developmental Origins of Opioid Use Disorder and Its Comorbidities

“…Thus, disturbances in endogenous opioids might also mediate ELA-induced alterations of striatal DA signaling leading to aberrant reward-related behaviors. These ELA-induced opioids and DA-related disruptions suggest a mechanism by which ELA may lead simultaneously or in parallel to psychiatric disorders and enhanced consumption of opioids (Khantzian, 1987 ; Dallman et al, 2005 ; Kim et al, 2015 ; Lovallo et al, 2018 ).…”

Early Life Stress and Risks for Opioid Misuse: Review of Data Supporting Neurobiological Underpinnings

“…The first direct evidence of ELS effects on opioid neurotransmission in humans was reported by Lutz et al [ 92 ], who conducted a postmortem study showing that ELS was associated with the downregulation of kappa receptors in the anterior insula of both depressed individuals who died by suicide and controls who died suddenly from accidental causes. Cortisol response to naltrexone has also been found to be blunted in high vs. low ELS women, which similarly linked ELS with downregulation of endogenous opioid activity [ 265 ]. The authors posited that these effects may reflect an adaptation of the central opioid system that shapes how a person responds to motivationally significant stimuli.…”