What Is DADLE? Definition and What Research Reports
DADLE, short for [D-Ala2, D-Leu5]-enkephalin, is a synthetic five-amino-acid peptide modelled on the natural opioid peptide leu-enkephalin. Two D-amino acid substitutions make it more stable and more selective for the delta opioid receptor. It is used in laboratories as a delta receptor agonist tool compound, and it has been studied in animal and tissue models of ischemia-reperfusion, organ preservation, hypothermia and pain. It is a research chemical, not an approved medicine, and human clinical evidence is absent from the studies summarised here.
Definition
DADLE is the common laboratory abbreviation for [D-Ala2, D-Leu5]-enkephalin, a synthetic pentapeptide derived from the naturally occurring opioid peptide leu-enkephalin (Tyr-Gly-Gly-Phe-Leu). In DADLE, two of the five residues are replaced with their mirror-image D-form counterparts: D-alanine at position 2 and D-leucine at position 5. Those substitutions slow enzymatic breakdown and shift the peptide's binding preference toward the delta opioid receptor rather than the mu receptor targeted by most clinical opioids. DADLE is therefore classified as a delta opioid receptor (DOR) agonist and is handled as a research chemical; it is not an approved drug in any jurisdiction and the literature described below is preclinical.
This page is for educational purposes only and is not medical advice; consult a licensed physician about any medical question or before making any health decision.
What Class of Molecule Is It, and Where Does It Come From?
DADLE belongs to the opioid peptide family — short chains of amino acids that bind the same receptors as morphine-type small molecules but are produced biologically rather than synthetically in nature. The parent compound, leu-enkephalin, is an endogenous neurotransmitter identified in mammalian brain and gut. DADLE itself is made by solid-phase peptide synthesis; it does not occur in the body and is not extracted from tissue.
Its historical notoriety comes from a separate line of work: DADLE was investigated as a candidate "hibernation-inducing" factor after opioid-like activity was described in plasma from hibernating animals. That framing persists in reviews of hypometabolic and suspended-animation research, including a review of hibernation-based strategies examined in hemorrhagic shock models (PMID 29283978).
Naming and synonyms
- DADLE — the abbreviation used in most papers
- [D-Ala2, D-Leu5]-enkephalin — the formal chemical name
- DADL, delta opioid peptide (DOP) — occasional variants in older or applied literature
Some papers use the broader phrase "delta opioid peptide" when describing DADLE's role in tissue-protection experiments (PMID 36678674).
How the Term Is Used in Peptide Research
In practice, "DADLE" appears in three fairly distinct contexts in published work:
| Context | How the term functions |
|---|---|
| Receptor pharmacology | A selective delta opioid receptor agonist used as a tool to probe DOR signalling in cells, slices and animals |
| Ischemia and organ preservation | A test compound in models of reduced blood flow, cold storage or machine perfusion of organs |
| Hypometabolism / "hibernation" research | A historical candidate mediator of torpor-like states, discussed in reviews of suspended-animation approaches |
A 2018 review catalogued the range of nervous-system conditions in which delta opioid receptors and DADLE had been examined, describing the receptor's effects as multifaceted across neuroprotection, neurodegeneration and related models (PMID 29032758).
Doing the math on a vial? The PeptideU app does reconstitution, units and dilution for you.
Try it freeWhat the Published Literature Reports
The published record on DADLE is overwhelmingly animal, tissue and cell based. The summary below reflects what researchers reported in those settings; none of it describes outcomes in people.
Brain and cerebral ischemia models
An ex vivo study using brain slices reported that the delta opioid peptide [D-Ala2, D-Leu5]enkephalin exerted protective effects in a model of ischemia/reperfusion (PMID 22943142). In rats, researchers reported that activation of the delta opioid receptor relieved cerebral ischemic injury and implicated EGFR transactivation as a contributing signalling step (PMID 33667516). A separate rat study on global ischemia reported that delta opioid receptor activation with DADLE contributed to synaptic improvement in the hippocampus (PMID 34470528). Work published in 2022 reported that the delta opioid peptide targeted brain microvascular endothelial cells and reduced apoptosis in a hypoxic-ischemic/reperfusion model (PMID 36678674).
Liver preservation and hepatic injury
A 2019 study reported that [D-Ala(2), D-Leu(5)] enkephalin improved liver preservation during normothermic ex vivo perfusion (PMID 31071481). In cirrhotic rats, the study reported that the same peptide attenuated hepatic ischemia-reperfusion injury (PMID 35599785). Earlier work on hypothermic preservation reported protective effects of a hibernation-inducer against hepatocyte injury (PMID 17909722).
Cardiac and pain models
Researchers reported that a delta opioid receptor agonist attenuated lipopolysaccharide-induced myocardial injury in a model where autophagy regulation was the proposed mechanism (PMID 28647372). In a rat study of affective pain, activation of delta opioid receptors in the anterior cingulate cortex was reported to alleviate the affective dimension of pain (PMID 35569643).
Delivery research
Because peptides cross biological barriers poorly, some groups have studied carriers. One study reported that chitosan nanoparticles served as efficient carriers for delivering biodegradable drugs to neuronal cells (PMID 24357163).
Safety and Tolerability: What Studies Report
The verified literature summarised on this page consists of animal, tissue-slice, perfused-organ and cell studies focused on efficacy endpoints in injury models. Those papers did not report a human safety dataset, and no adverse-event profile in people can be drawn from them. Reviews of the delta opioid receptor field have described the receptor's biology as multifaceted across nervous-system conditions rather than establishing a clinical tolerability picture (PMID 29032758). Discussions of hibernation-based strategies in hemorrhagic shock similarly framed the approach as experimental (PMID 29283978). Readers evaluating claims about DADLE should note the distance between a perfused rat liver and a human patient.
Tracking research? Log entries with dates, lots and notes — records, never plans.
Get the appWhat DADLE Is Not
- Not an approved medicine. No regulatory agency has authorised DADLE as a therapeutic product.
- Not a mu-opioid analgesic. Its receptor preference is delta, which is why it appears in tissue-protection literature more often than in analgesia literature — though delta receptor activation has been studied in affective pain models (PMID 35569643).
- Not a human-tested "hibernation" agent. The torpor association comes from animal and review literature (PMID 29283978).
- Not orally bioavailable in any established form. Delivery remains an active research question (PMID 24357163).
Quick Reference
| Attribute | Description |
|---|---|
| Full name | [D-Ala2, D-Leu5]-enkephalin |
| Class | Synthetic opioid pentapeptide |
| Primary target | Delta opioid receptor (agonist) |
| Origin | Chemically synthesised analogue of leu-enkephalin |
| Main research areas | Ischemia-reperfusion, organ preservation, hypometabolism, pain circuitry |
| Evidence base | Preclinical — animal, tissue and cell models |
| Regulatory status | Not an approved drug; research use |
Anyone comparing DADLE claims across sources will find that most bold statements trace back to the small preclinical set above, and that the peptide's reputation as a "hibernation compound" reflects a research hypothesis rather than a demonstrated human effect (PMID 29283978). This page is for educational purposes only and is not medical advice; consult a licensed physician with any questions about a medical condition.
Want the full course? Every compound, evidence-graded and cited, inside PeptideU.
Start learning freeReferences
- [D-Ala(2), D-Leu(5)] Enkephalin Improves Liver Preservation During Normothermic Ex Vivo Perfusion (The Journal of Surgical Research, 2019)
- Multifaceted Effects of Delta Opioid Receptors and DADLE in Diseases of the Nervous System (Current Drug Discovery Technologies, 2018)
- Delta opioid receptor agonist attenuates lipopolysaccharide-induced myocardial injury by regulating autophagy (Biochemical and Biophysical Research Communications, 2017)
- [D-Ala(2), D-Leu(5)] Enkephalin Attenuates Hepatic Ischemia-Reperfusion Injury in Cirrhotic Rats (Frontiers in Surgery, 2022)
- Delta Opioid Peptide Targets Brain Microvascular Endothelial Cells Reducing Apoptosis to Relieve Hypoxia-Ischemic/Reperfusion Injury (Pharmaceutics, 2022)
- Activation of the δ opioid receptor relieves cerebral ischemic injury in rats via EGFR transactivation (Life Sciences, 2021)
- Hibernation-Based Approaches in the Treatment of Hemorrhagic Shock (Shock, 2018)
- Protective effects of the delta opioid peptide [D-Ala2, D-Leu5]enkephalin in an ex vivo model of ischemia/reperfusion in brain slices (CNS Neuroscience & Therapeutics, 2012)
- Chitosan nanoparticles are efficient carriers for delivering biodegradable drugs to neuronal cells (Histochemistry and Cell Biology, 2014)
- Activation of δ-opioid Receptors in Anterior Cingulate Cortex Alleviates Affective Pain in Rats (Neuroscience, 2022)
- Delta Opioid Receptor Activation with Delta Opioid Peptide [d-Ala2, d-Leu5] Enkephalin Contributes to Synaptic Improvement in Rat Hippocampus against Global Ischemia (Cell Transplantation, 2021)
- Protective effects of a hibernation-inducer on hepatocyte injury induced by hypothermic preservation (Journal of Hepato-Biliary-Pancreatic Surgery, 2007)
Frequently asked questions
What does the abbreviation DADLE stand for?▾
DADLE stands for [D-Ala2, D-Leu5]-enkephalin. It is a five-amino-acid synthetic peptide based on leu-enkephalin, with D-form amino acids substituted at positions 2 and 5. Those substitutions increase stability against enzymes and bias binding toward the delta opioid receptor. Papers sometimes call it a "delta opioid peptide" instead (PMID 36678674).
Is DADLE a natural or synthetic peptide?▾
It is synthetic. The parent molecule, leu-enkephalin, occurs naturally in mammalian tissue, but DADLE's two D-amino acid substitutions are laboratory modifications and the peptide is produced by chemical synthesis. Reviews discussing DADLE in nervous-system disease treat it as a pharmacological tool compound rather than an endogenous signalling molecule (PMID 29032758).
What kinds of studies have used DADLE?▾
Published work is preclinical. Researchers reported effects in ex vivo brain slices under ischemia/reperfusion (PMID 22943142), in rat models of cerebral ischemic injury (PMID 33667516), in normothermic ex vivo liver perfusion (PMID 31071481) and in cirrhotic rats undergoing hepatic ischemia-reperfusion (PMID 35599785). None of these were human trials.
Why is DADLE associated with hibernation?▾
The association dates to research on opioid-like activity found in hibernating animals, which led to DADLE being described as a candidate hibernation-inducing factor. A review of hibernation-based approaches examined such strategies in hemorrhagic shock models (PMID 29283978), and an older study reported protective effects of a hibernation-inducer on hepatocytes during hypothermic preservation (PMID 17909722).
Which receptor does DADLE act on?▾
DADLE is characterised as a delta opioid receptor agonist, in contrast to mu-preferring clinical opioids. Studies reported that delta receptor activation attenuated lipopolysaccharide-induced myocardial injury through autophagy regulation (PMID 28647372) and that delta receptor activation in the anterior cingulate cortex alleviated affective pain in rats (PMID 35569643).
Is there human safety data on DADLE?▾
The verified studies summarised here are animal, tissue-slice, perfused-organ and cell experiments focused on injury endpoints, and they did not report human safety outcomes. Reviews describe delta opioid receptor biology as multifaceted across nervous-system conditions without establishing a clinical tolerability profile (PMID 29032758). Questions about safety belong with a licensed physician.
Why do researchers study delivery systems for DADLE?▾
Peptides are broken down quickly and cross biological barriers poorly, which limits how much reaches target tissue. One study reported that chitosan nanoparticles worked as efficient carriers for delivering biodegradable drugs to neuronal cells (PMID 24357163). Other work reported that the delta opioid peptide targeted brain microvascular endothelial cells and reduced apoptosis (PMID 36678674).
Track it. Calculate it. Actually understand it.
References
This page summarises published research for education — it is not medical advice, and nothing here is a recommendation to use, purchase, or dose any substance. Study parameters described are what researchers reported, not instructions. Consult a qualified clinician before any health decision.