Research ArticlePosttraumatic Stress Disorder

Amygdala-Dependent Fear Is Regulated by Oprl1 in Mice and Humans with PTSD

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Science Translational Medicine  05 Jun 2013:
Vol. 5, Issue 188, pp. 188ra73
DOI: 10.1126/scitranslmed.3005656

Blocking PTSD with an Opioid Receptor Agonist

There are currently no approved pharmacological preventive treatments for posttraumatic stress disorder (PTSD), an anxiety disorder with altered fear learning that occurs in some individuals after exposure to a highly traumatic event. Andero et al. now demonstrate that the opioid receptor–like 1 gene (Oprl1), encoding the nociceptin (NOP)/orphanin FQ receptor, is involved in stress-mediated enhancement of amygdala-dependent fear in mouse models and humans with PTSD. These findings build on published data showing that opioid activity appears to be involved in fear inhibition and may block the consolidation of fear memories. Recent clinical observations suggest that opioid analgesia, provided shortly after trauma, may decrease the development of PTSD. Here, Andero et al. use a gene discovery approach to identify a specific member of the opioid receptor family, Oprl1, which may be involved in this process. Using a mouse model of dysregulated fear, the authors found altered expression of Oprl1 in the amygdala, the part of the brain where fear memories are consolidated. Systemic infusion of SR-8993, a new highly selective NOP receptor agonist, or injection into the central amygdala of mice impaired the consolidation of fear memories. Additionally, in humans, a single-nucleotide polymorphism (SNP) was found within Oprl1 and may be associated with PTSD symptoms. The authors show that this SNP is associated with physiological startle measures of fear discrimination and correlates with functional connectivity between the amygdala and insula. Together, these data suggest that Oprl1 is associated with amygdala function, fear processing, and PTSD symptoms. Furthermore, activation of the NOP receptor encoded by Oprl1 may block fear memory consolidation, with implications for preventing PTSD after traumatic events.

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