Abstract
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-1β (IL-1β). However, other cytokines, such as TNF-α, work synergistically with IL-1β and may have a role in the development of enhanced fear learning. Based on both translational rodent and clinical studies, TNF-α 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-α expression. The second set of experiments examined whether DH TNF-α expression is functionally relevant to the development of enhanced fear learning. We identified an increase of TNF-α 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-α 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-α in opioid withdrawal and the development of anxiety disorders such as PTSD.
Highlights
Post-traumatic stress disorder (PTSD), a devastating mental illness, is highly comorbid with substance use disorder (SUD), as nearly 40% of individuals diagnosed with PTSD are diagnosed with SUD [1]
TNF-α immunoreactivity was increased during 0-h heroin withdrawal (t(18) = −2.727, p = .029) (Fig. 1c), 24-h heroin withdrawal (t(21) = −3.416, p = .003) (Fig. 1d), and 48h heroin withdrawal (t(21) = −3.190, p = .008) (Fig. 1e) relative to saline controls, but no difference was observed at 72-h withdrawal (t(21) = −.277, p = −0.603) (Fig. 1f)
These results show that both a combination of chronic heroin administration and subsequent withdrawal is necessary for increased TNF-α immunoreactivity within the dentate gyrus (DG) as TNF-α immunoreactivity was increased 0, 24, and 48 h following heroin administration and withdrawal
Summary
Post-traumatic stress disorder (PTSD), a devastating mental illness, is highly comorbid with substance use disorder (SUD), as nearly 40% of individuals diagnosed with PTSD are diagnosed with SUD [1]. Opioid abuse has one of the highest prevalence rates of any comorbid SUD. It has been reported that 33.2% of individuals with an opioid use disorder (OUD) currently meet criteria for comorbid PTSD and 41% of those have a lifetime history of PTSD [2, 3]. Comorbidity estimates of heroin use disorder and PTSD are as high as 66% [4], and this has substantial clinical consequences. Co-occurring PTSD in heroin use disorder is associated with an earlier addiction onset age, longer addiction durations, higher rates of attempted suicide, and poorer occupational functioning [4]. The mechanisms surrounding this comorbidity present an important area of research in order to improve the treatment, recovery, and outcomes of clinical populations with these psychopathologies
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