Delta Opioid receptor

The δ-opioid receptors, also known as delta opioid receptor or simply delta receptor, abbreviated DOR, is an opioid receptor that has enkephalins as their endogenous ligands.

Function
Until comparatively recently, there were few pharmacological tools for the study of δ receptors. As a consequence, our understanding of their function is much more limited than those of the other opioid receptors for which selective ligands have long been available.

However there are now several selective delta opioid agonists available, including peptides such as DPDPE and deltorphin II, and non-peptide drugs such as SNC-80, the more potent (+)-BW373U86, a newer drug DPI-287 which does not produce the problems with convulsions seen with the earlier agents, and the mixed mu/delta agonist DPI-3290 which is a much more potent analgesic than the more highly selective delta agonists. Selective antagonists for the delta receptor are also available, with the best known being the opiate derivative naltrindole.

Activation of delta receptors produces some analgesia, although less than that of mu-opioid agonists. Many delta agonists may also cause seizures at high doses, although not all delta agonists produce this effect.

Evidence for whether delta agonists produce respiratory depression is mixed; high doses of the delta agonist peptide DPDPE produced respiratory depression in sheep, but in tests on mice the non-peptide delta agonist SNC-80 produced respiratory depression only at the very high dose of 40 mg/kg. In contrast both the peptide delta agonist Deltorphin II and the non-peptide delta agonist (+)-BW373U86 actually stimulated respiratory function and blocked the respiratory depressant effect of the potent mu-opioid agonist alfentanil, without affecting pain relief. It thus seems likely that while delta opioid agonists can produce respiratory depression at very high doses, at lower doses they have the opposite effect, a fact which may make mixed mu/delta agonists such as DPI-3290 potentially very useful drugs which might be much safer than the mu agonists currently used for pain relief.

Of most interest however is the potential for delta agonists to be developed for use as a novel class of antidepressant drugs, following robust evidence of both antidepressant effects and also upregulation of BDNF production in the brain in animal models of depression. These antidepressant effects have been linked to endogenous opioid peptides acting at delta and mu opioid receptors, and so can also be produced by enkephalinase inhibitors such as RB-101.

Recent work indicates that exogenous ligands which activate the delta receptors mimic the phenomenon known as ischemic preconditioning. Experimentally, if short periods of transient ischemia are induced the downstream tissues are robustly protected if longer-duration interruption of the blood supply is then effected. Opiates and opioids with delta activity mimic this effect. In the rat model introduction of delta active ligands results in significant cardioprotection.