Table 3. DOR dysregulation in depression.
These data are compiled from preclinical and clinical studies that implicate DOR and ENK in depression using behavioral constructs that relate to the domains of negative valence, positive valence, systems for social processes and arousal/regulatory systems. DOR – delta opioid receptor, ENK – enkephalin, ppENK – preproenkephalin, CeA – central nucleus of the amygdala, NAc – nucleus accumbens, EPM – elevated plus maze, FST – forced swim test, BP – binding potential.
| Domain | Constructs | Behavioral effects | Reference |
|---|---|---|---|
| Negative Valence: | Acute threat (Fear) | DOR agonists attenuated conditioned suppression of activity. | (Jutkiewicz, et al., 2004; Jutkiewicz, et al., 2005a; Jutkiewicz, et al., 2003; Saitoh, et al., 2004; Torregrossa, et al., 2006) |
| Increased efficacy of DOR agonists on conditioned suppression of activity in stressed rats. | (Hebb, et al., 2005) | ||
| Knockdown of ENK in the CeA reduced freezing during the training phase of fear conditioning but did not alter freezing during testing. | (Poulin, et al., 2013) | ||
| Potential threat (Anxiety) | DOR agonists produce anxiolytic effects | (Jutkiewicz, et al., 2004; Saitoh, et al., 2004; Torregrossa, et al., 2006) | |
| DOR antagonists produce anxiogenic effects in mice | (Saitoh, et al., 2011) | ||
| Oprd1−/−mice exhibit increased levels of anxiety | (Filliol, et al., 2000) | ||
| Sustained threat (Aversive emotional state) | DOR agonists produce antidepressant-like activity in the FST. | (Jutkiewicz, et al., 2005a; Jutkiewicz, et al., 2005b; Jutkiewicz, et al., 2003) | |
| Oprd1−/−mice exhibit increased levels of immobility in the FST. | (Filliol, et al., 2000) | ||
| Increased trafficking of vesicles containing DORs to the cell surface of mice exposed to cold swim stress. | (Commons, 2003) | ||
| Acute stress increases ENK release. | (Henry et al., 2017) | ||
| Chronic or severe stress exposure decreases ENK levels. | (Berube, et al., 2013; Berube, et al., 2014; Poulin, et al., 2013) | ||
| Enkephalinase inhibitors reduced immobility scores in the FST. | (Jutkiewicz, et al., 2006) | ||
| ENK knockdown in the CeA increased exploration on the EPM. | (Poulin, et al., 2013) | ||
| Positive Valence: | Reward Responsiveness | Chronic restraint stress decreased ppENK in the NAc of rats that exhibited decreased sucrose preference | (Poulin, et al., 2013) |
| Systems for social processes | Affiliation and Attachment | Following stress exposure, there is increased trafficking of DOR containing vesicles and increased efficacy of DOR agonists in reducing suppression of activity following social instability and social defeat. | (Commons, 2003) |
| Perception and Understanding of Others | DOR activation produces stimulant effects in socially dominant and singly housed rats, but elicited depressant effects in subdominant rats | (Pohorecky, et al., 1999) | |
| Arousal/Regulatory systems | Sleep and Wakefulness | Sleep deprivation decreases DOR BP | (Fadda, et al., 1991) |