Hippocampal TNF-α Signaling Mediates Heroin Withdrawal-Enhanced Fear Learning and Withdrawal-Induced Weight Loss

There is significant comorbidity of opioid use disorder (OUD) and post-traumatic stress disorder (PTSD) in clinical populations. However, the neurobiological mechanisms underlying the relationship between chronic opioid use and withdrawal and development of PTSD are poorly understood. Our previous work identified that chronic escalating heroin administration and withdrawal can produce enhanced fear learning, an animal model of hyperarousal, and is associated with an increase in dorsal hippocampal (DH) interleukin-1 beta (IL-1 beta). However, other cytokines, such as TNF-alpha, work synergistically with IL-1 beta and may have a role in the development of enhanced fear learning. Based on both translational rodent and clinical studies, TNF-alpha has been implicated in hyperarousal states of PTSD, and has an established role in hippocampal-dependent learning and memory. The first set of experiments tested the hypothesis that chronic heroin administration followed by withdrawal is capable of inducing alterations in DH TNF-alpha expression. The second set of experiments examined whether DH TNF-alpha expression is functionally relevant to the development of enhanced fear learning. We identified an increase of TNF-alpha immunoreactivity and positive cells at 0, 24, and 48 h into withdrawal in the dentate gyrus DH subregion. Interestingly, intra-DH infusions of etanercept (TNF-alpha inhibitor) 0, 24, and 48 h into heroin withdrawal prevented the development of enhanced fear learning and mitigated withdrawal-induced weight loss. Overall, these findings provide insight into the role of TNF-alpha in opioid withdrawal and the development of anxiety disorders such as PTSD.

Automated summary

The study reveals that chronic heroin administration and withdrawal can increase fear learning and DH TNF-alpha, while TNF-alpha inhibitor can prevent the development of enhanced fear learning and mitigate withdrawal-induced weight loss.