Δ-opioid receptor

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

Function
Activation of δ receptors produces is_associated_with::analgesia, much more significantly than that of mu-opioid agonists, however it seems like mu agonism provides heavy potentiation to any d agonism, so even selective mu agonists can cause analgesia under the right conditions, others can cause none whatsoever though. Many δ agonists may also cause is_associated_with::seizures at high doses, although not all δ agonists produce this effect.

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

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

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

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



Agonists

 * Peptides
 * is_associated_with::Leu-enkephalin
 * is_associated_with::Met-enkephalin
 * Deltorphins

is_associated_with::Mitragyna speciosa (kratom) indole derivatives:
 * Non-peptides
 * is_associated_with::7-Spiroindanyloxymorphone
 * is_associated_with::N-Phenethyl-14-ethoxymetopon
 * is_associated_with::ADL-5859
 * is_associated_with::BU-48
 * is_associated_with::SNC-80
 * is_associated_with::BW373U86
 * is_associated_with::DPI-221
 * is_associated_with::DPI-287
 * is_associated_with::DPI-3290
 * is_associated_with::TAN-67
 * is_associated_with::RWJ-394674
 * is_associated_with::Norbuprenorphine
 * is_associated_with::Cannabidiol
 * is_associated_with::Tetrahydrocannabinol
 * is_associated_with::Mitragynine
 * is_associated_with::Mitragynine pseudoindoxyl

Antagonists

 * is_associated_with::Buprenorphine
 * is_associated_with::Trazodone
 * is_associated_with::Naltriben
 * is_associated_with::Naltrindole

Interactions
δ−opioid receptors have been shown to interact with β2 adrenergic receptors, arrestin β1 and GPRASP1.