Enkephalins: Endogenous Analgesics with an Emerging Role in Stress Resilience

Table 2

Evidence for ENK signaling involvement under different stress paradigms.

Paradigm	Principles and procedures	Evidence for involvement of ENK signaling
Single housing	Given the social behavior of rodents, chronic or acute single housing is used to mimic the stress due to social isolation. The animal is placed alone in its home cage.	(i) Prolonged single housing in early life decreases ENK immunoreactivity in AMG, SN, HPT, and PAG [63].
Restraint stress	The animal is placed in a tube in such a way that all movements are prevented. The psychological and physiological effects due to restraint stress result from the distress and aversive nature of the forced immobility.	(i) After acute restraint stress, ENK-degrading activity is reduced in AMG and increased in HPC [46]; (ii) After chronic restraint stress, ENK knockout (KO) mice do not exhibit anxiety nor depression-like behavior [67]; (iii) After chronic restraint stress, rats showing increased anhedonia present a reduced expression of ENK mRNA in the NAc [70].
Social defeat stress (or resident-intruder paradigm)	This task exploits the social conflict between two individuals to initiate psychological stress. This experiment can be related to the intimidation or victimization in humans. An intruder is placed in the home cage of a resident each day for a given period of time.	(i) After a chronic social defeat, Oprm1 A112G mice show a strong resilience [71]; (ii) After a chronic social defeat, resilient rats demonstrate a high recruitment of ENK afferents from PGi to LC [72]; (iii) After a chronic social defeat in rats and mice, ENK mRNA levels decrease in BLA of vulnerable individuals [17, 81].
Chronic unpredictable stress	This test allows to mimic the unpredictable disruptions of daily life. An animal is subjected to different stressors each day for a given period of time. Stressors can include restraint stress, electric footschocks, wet bedding, group housing, mild shaking of the home cage, cold water swim, etc.	(i) ENK knockdown (KD) in BLA increases anxiety; reproducing behavioral responses encountered in individuals vulnerable to chronic unpredictable stress [18].