Abstract
Despite the large comorbidity between PTSD and opioid use disorders, as well as the common treatment of physical injuries resulting from trauma with opioids, the ability of opioid treatments to subsequently modify PTSD-related behavior has not been well studied. Using the stress-enhanced fear learning (SEFL) model for PTSD, we characterized the impact of chronic opioid regimens on the sensitization of fear learning seen following traumatic stress in mice. We demonstrate for the first time that chronic opioid pretreatment is able to robustly augment associative fear learning. Highlighting aversive learning as the cognitive process mediating this behavioral outcome, these changes were observed after a considerable period of drug cessation, generalized to learning about multiple aversive stimuli, were not due to changes in stimulus sensitivity or basal anxiety, and correlated with a marker of synaptic plasticity within the basolateral amygdala. Additionally, these changes were not observed when opioids were given after the traumatic event. Moreover, we found that neither reducing the frequency of opioid administration nor bidirectional manipulation of acute withdrawal impacted the subsequent enhancement in fear learning seen. Given the fundamental role of associative fear learning in the generation and progression of PTSD, these findings are of direct translational relevance to the comorbidity between opioid dependence and PTSD, and they are also pertinent to the use of opioids for treating pain resulting from traumas involving physical injuries.
Highlights
Post-traumatic stress disorder (PTSD) is highly comorbid with substance use disorder (SUD), with nearly 40% of individuals with PTSD having SUD [1,2,3,4,5,6]
We have previously demonstrated that stress-enhanced fear learning (SEFL) captures several lasting anxiogenic changes in response to traumatic stress, including augmented fear learning, increased anxiety and startle responses, and altered glucocorticoid cycling [10,11,12,13,14]
We found that opioid exposure was able to markedly potentiate the ability of trauma to augment fear learning, and that this persisted at least a week after opioid cessation, a time in which weight changes, anxiety-like differences and differences in shock reactivity, were not apparent
Summary
Post-traumatic stress disorder (PTSD) is highly comorbid with substance use disorder (SUD), with nearly 40% of individuals with PTSD having SUD [1,2,3,4,5,6]. We have previously demonstrated that SEFL captures several lasting anxiogenic changes in response to traumatic stress, including augmented fear learning, increased anxiety and startle responses, and altered glucocorticoid cycling [10,11,12,13,14] This model has recently been used to characterize long-lasting trauma-induced changes in drug seeking [15], making it optimal to study bidirectional interactions between trauma and drug use. We found that opioid exposure was able to markedly potentiate the ability of trauma to augment fear learning, and that this persisted at least a week after opioid cessation, a time in which weight changes, anxiety-like differences and differences in shock reactivity, were not apparent. This change appears to be a direct ramification of opioid exposure rather than acute withdrawal
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