Modulation of the central opioid system as an antidepressant target in rodent models

There has been a resurgence in interest in the central opioid system as a target in the treatment of depression. Using a range of laboratory rodent tests, potential antidepressant properties have been most associated with kappa opioid receptor antagonists, delta opioid receptor agonists, and nociceptin/orphanin FQ receptor antagonists. Although most studies to date have assessed acute behavioral effects, more elaborate investigations have demonstrated activity following repeated administration. Concerns over adverse effects have meant that opioid candidates need to be examined for their abuse potential, locomotor stimulant, and other adverse effects that might reside by activating a certain receptor subtype. The interplay between the central opioid and monoaminergic systems has been established with many clinically used antidepressants exhibiting affinity for opioid receptors that could contribute to their therapeutic effect. Similarly currently marketed opioid drugs such as tramadol possess antidepressant properties. More recent investigations have begun to examine combining of opioid agents, conferring unique profiles. This approach acknowledges that targeting a single opioid receptor may not be sufficient to produce the balanced profile of therapeutic effects, while minimizing adverse effects. As these compounds begin to reach the clinical stage, hopefully they will represent an important addition to the armamentarium to treat depression.