Enkephalins: Endogenous Analgesics with an Emerging Role in Stress Resilience

Abstract

Psychological stress is a state of mental or emotional strain or tension that results from adverse or demanding circumstances. Chronic stress is well known to induce anxiety disorders and major depression; it is also considered a risk factor for Alzheimer's disease. Stress resilience is a positive outcome that is associated with preserved cognition and healthy aging. Resilience presents psychological and biological characteristics intrinsic to an individual conferring protection against the development of psychopathologies in the face of adversity. How can we promote or improve resilience to chronic stress? Numerous studies have proposed mechanisms that could trigger this desirable process. The roles of enkephalin transmission in the control of pain, physiological functions, like respiration, and affective disorders have been studied for more than 30 years. However, their role in the resilience to chronic stress has received much less attention. This review presents the evidence for an emerging involvement of enkephalin signaling through its two associated opioid receptors, μ opioid peptide receptor and δ opioid peptide receptor, in the natural adaptation to stressful lifestyles.

Figure 1

Cartography of main connectivities involved in fear, stress, and resilience, as well as demonstrated ENK pathways between areas and expression of ENK, MOPr, and DOPr. Pink circles represent brain regions of interest. Full arrows correspond to circuitries of stress, fear, and resilience. Dotted arrows represent demonstrated ENK circuitries. The black dot corresponds to expression of pro-enkephalin, and purple and blue triangles correspond to MOPr and DOPr expression, respectively. AMG: amygdala; HPC: hippocampus; HPT: hypothalamus; LC: locus ceruleus; mPFC: medial prefrontal cortex; NAc: nucleus accumbens; PAG: periaqueducal grey; PGi: paragigantocellularis nucleus; VTA: ventral tegmental area.