Nociceptin/orphanin FQ, hedonic state and the response to abused drugs

The mesolimbic dopamine and endogenous opioid systems are foremost in our understanding of the neurochemical systems implicated in the control of motivation and reward. Several decades of study indicate that these systems interact to balance hedonic state and drive seeking for both natural and artificial and rewarding stimuli, such as food and abused drugs. Several classes of endogenous opioids have been identified, of which nociceptin (known also as orphanin FQ) is the most recently discovered. The relative contribution that each class of endogenous opioid peptides makes in determining basal and drug-stimulated changes in hedonic state is still unclear. mu and delta opioid receptor agonists induce increases in hedonic state and are therefore rewarding. Kappa opioid receptor agonists, on the other hand, typically decrease hedonic state and are aversive. Although nociceptin is mostly devoid of hedonic properties when administered centrally, it effectively blocks the acquisition of conditioned place preferences to various rewarding drugs, suggesting that nociceptin reverses stimulated increases in hedonic state. Nociceptin also blocks the seeking of some rewarding stimuli in drug self-administration paradigms. Neurobiological explanations for these behavioral effects are incomplete; though a key finding has been that nociceptin suppresses basal and drug-stimulated activity in the mesolimbic dopamine system. Thus far, little is known about the role of naturally occurring endogenous nociceptin in the control of reward and motivated behaviors. Gaining an understanding in this area could contribute significantly to our understanding of how the brain regulates hedonic balance and motivation in both normal and perturbed states. have formed a strong impression that augmentation therapy, especially with milnacipran plus lithium, is likely to be effective if the first-line antidepressant is ineffective. Investigation of more cases will be needed to confirm or refine details of the algorithm and, more generally, to determine the best approach to antidepressant medication.