Dynorphin, stress, and depression

Abstract

Stress is most often associated with aversive states. It rapidly induces the release of hormones and neuropeptides including dynorphin, which activates kappa opioid receptors (KORs) in the central and peripheral nervous systems. In animal models, many aversive effects of stress are mimicked or exacerbated by stimulation of KORs in limbic brain regions. Although KOR signaling during acute stress may increase physical ability (by producing analgesia) and motivation to escape a threat (by producing aversion), prolonged KOR signaling in response to chronic or uncontrollable stress can lead to persistent expression of behavioral signs that are characteristic of human depressive disorders (i.e., "prodepressive-like" signs). Accumulating evidence suggests that KORs contribute to the progressive amplification (sensitization) of stress-induced behaviors that occurs with repeated exposure to stress. Many of the aversive effects of stress are blocked by KOR antagonists, suggesting that these agents may have potential as therapeutics for stress-related conditions such as depression and anxiety disorders. This review summarizes current data on how KOR systems contribute to the acute (rapid), delayed, and cumulative molecular and behavioral effects of stress. We focus on behavioral paradigms that provide insight on interactions between stress and KOR function within each of these temporal categories. Using a simplified model, we consider the time course and mechanism of KOR-mediated effects in stress and suggest future directions that may be useful in determining whether KOR antagonists exert their therapeutic effects by preventing the development of stress-induced behaviors, the expression of stress-induced behaviors, or both.

Figure 1

Simplified model depicting the time course of stress-induced molecular and behavioral effects. Stress activates the release of hormones and neuropeptides, including dynorphin, which activates kappa opioid receptors (KORs) in the central and peripheral nervous systems (Adaptations). Acute exposure to stress (or KOR agonist) initiates rapid changes in neuronal function (red waveform; Type 1) that are mediated in part by KOR-mediated decreases in neuronal excitability (Outcomes). These acute decreases in neuronal excitability, which may increase or decrease the activity of neural networks, are associated with the rapid expression of a number of stress-induced behaviors that do not require prior exposure to stress to occur (red box). Acute exposure to stress also initiates delayed molecular changes (green waveform; Type 2), such as altered gene expression, that produce structural and functional neural adaptations. Stress-induced KOR signaling can be a cause or consequence of these neural adaptations and can contribute to the expression of sensitized stress responses (light green box) that require prior stress exposure to occur. Finally, re-exposure to stress initiates acute KOR signaling (red portion of waveform; Type 3) and additional neural adaptations (green portion of waveform) that are associated with Type 1 and 2 behavioral responses (red and green boxes, respectively), but may also contribute to the emergence of additional stress-sensitized behaviors that require multiple stress exposures to occur (gray box). The antidepressant- and anxiolytic-like properties of KOR antagonists may result from the prevention of acute and delayed effects of KOR signaling.