The delta opioid receptor: an evolving target for the treatment of brain disorders

Abstract

Compared to the better-known mu opioid receptor, delta opioid receptors have been relatively understudied. However, the development of highly selective delta opioid agonists and the availability of genetic mouse models have extended our knowledge of delta opioid receptors in vivo. Here we review recent developments in the characterization of delta opioid receptor biology and aspects of delta opioid receptor function that have potential for therapeutic targeting. Preclinical data have confirmed that delta opioid receptor activation reduces persistent pain and improves negative emotional states; clinical trials have been initiated to assess the effectiveness of delta opioid agonists in chronic pain and depression. Furthermore, a possible role for these receptors in neuroprotection is being investigated. The usefulness of targeting delta opioid receptors in drug abuse remains open and a role for these receptors in impulse control disorders is emerging. Finally, the recent demonstration of biased agonism at the delta opioid receptor in vivo opens novel perspectives towards targeting specific therapeutic effects through drug design.

Figure 1. In vivo consequences of biased agonist-induced trafficking at the delta opioid receptor: two mechanisms towards tolerance

SNC80 binding to the delta opioid receptor results in massive receptor internalization in primary neurons from DOR-eGFP mice (representative neuron from a hippocampal primary culture, top left panel), as well as throughout central and peripheral nervous systems (representative image from a hippocampal section, top right panel). Following internalization, delta opioid receptors are targeted towards degradation (top left panel), as shown by co-localization of DOR-eGFP fluorescence (green) with the lysosomal marker, lysotracker (red). In contrast, ARM390 does not produce significant internalization of DOR-eGFP, either in primary neurons from DOR-eGFP mice (hippocampal primary culture, bottom left panel) or in central and peripheral nervous systems (dorsal root ganglia section bottom right panel). In vivo, a single injection of the high-internalizing, but not the low-internalizing agonist, produces acute behavioral desensitization [15]. However, chronic treatment with both agonists produces analgesic tolerance, regardless of internalization potency. The high-internalizing agonist down-regulates delta opioid receptors throughout the nervous system leading to generalized tolerance. In contrast, the low-internalizing agonist only affects delta responses at the level of the dorsal root ganglia, resulting in a pain-specific tolerance. In this case, non-analgesic delta opioid agonist effects (anxiolytic effects, for example) remain intact after chronic treatment [23]. Drug design for low-internalizing delta opioid agonists may therefore be helpful in therapeutic strategies targeting chronic psychiatric disorders.

Figure 2. Delta opioid receptors in the central and peripheral nervous systems as potential targets for neurologic and psychiatric disorders

A. Schematic representation of delta opioid receptor binding sites. Delta opioid receptors are particularly abundant (black squares) in the olfactory bulb, cortex, amygdala and striatum (caudate putamen and nucleus accumbens). Delta opioid receptors are also expressed at moderate level in the interpeduncular and pontine nuclei, hippocampus as well as spinal cord and dorsal root ganglia (grey squares), and at a much lower level in hypothalamus, thalamus, mesencephalon, and brain stem (open squares) (Adapted from [3]). Brain areas of high delta opioid receptor expression are involved in several neural processes whose dysfunction may lead to neurological or psychiatric conditions, including pain (pain processing and awareness), anxiety and depression (emotional processing), addictive and impulse disorders (motivation and reward, learning and memory, inhibitory controls). There is a high expression of delta opioid receptors in dopaminergic terminals (striatum), and the role of delta opioid receptors in reward and motivation is complex. B. Delta opioid receptor binding sites visualized by ligand autoradiography ([³H]deltorphin I, sagittal section left, courtesy of Ian Kitchen) or in knockin fluorescent delta opioid receptor reporter mice (coronal section, [21]). Abbreviations: Amg: amygdala; Cpu: Caudate putamen; Cx, cortex; DRG: dorsal root ganglia; FC: frontal cortex; Hip: hippocampus; Hyp: hypothalamus; IP, interpeduncular nucleus; LC: locus coeruleus; NAc: nucleus accumbens; OB: olfactory bulb; PN, pontine nucleus; PAG: periaqueductal gray; RN: raphe nucleus; SC: spinal cord; Ssc: somatosensorial cortex; Th: thalamus; Tu: olfactory tubercle; VTA: ventral tegmental area.