Peptide profile
Dermorphin
Ultra-potent frog-derived mu-opioid peptide · also known as Demorphin, H-Tyr-D-Ala-Phe-Gly-Tyr-Pro-Ser-NH2
Compare Dermorphin with other peptides →Summary
Dermorphin is a naturally occurring heptapeptide opioid first isolated from the skin secretions of South American phyllomedusa frogs. It binds with extraordinarily high selectivity and affinity to mu-opioid receptors, producing potent analgesic and sedative effects estimated to be 30–40 times more potent than morphine on a molar basis. Its unique structure incorporates a D-amino acid (D-Ala), which confers resistance to enzymatic degradation and prolongs its biological activity.
- Typical dose
- Not established for human use; animal research doses range from 1–10 mcg/kg
- Half-life
- ~30–60 minutes (longer than most endogenous opioids due to D-Ala residue)
- Route
- Subcutaneous, Intramuscular
- Cycle length
- Not established; research use only
Mechanism
How it works
Dermorphin acts as a highly selective, full agonist at mu-opioid receptors (MOR), activating Gi/Go protein signaling cascades that inhibit adenylyl cyclase, reduce cAMP levels, open inwardly rectifying K⁺ channels, and suppress voltage-gated Ca²⁺ channels, collectively hyperpolarizing neurons and suppressing nociceptive transmission. The presence of D-alanine at the second position renders it resistant to peptidase cleavage compared to endogenous opioid peptides, extending its half-life and potency. This receptor engagement in both spinal and supraspinal pain pathways accounts for its profound analgesic effect.
Reported in research
Benefits
- Extremely potent analgesia with high mu-opioid receptor selectivity (estimated 30–40× morphine potency)
- Prolonged duration of action due to D-amino acid conferring enzymatic resistance
- Research tool for studying mu-opioid receptor structure, function, and ligand design
- Potential investigational scaffold for developing novel analgesics with improved therapeutic profiles
Context, not a prescription
Dosing
- Typical range
- Not established for human use; animal research doses range from 1–10 mcg/kg (Subcutaneous, Intramuscular)
- Cycle length
- Not established; research use only
- Half-life
- ~30–60 minutes (longer than most endogenous opioids due to D-Ala residue)
Safety
Side effects & contraindications
Possible side effects
- Respiratory depression (dose-dependent, primary safety concern)
- Sedation and CNS depression
- Nausea and vomiting
- Constipation and GI motility suppression
- Physical dependence and tolerance with repeated administration
- Bradycardia and hypotension
- Pruritus (itching)
Contraindications
- Pre-existing respiratory compromise or severe COPD
- Concurrent use of CNS depressants, benzodiazepines, or other opioids
- History of opioid dependence or substance use disorder
- Pregnancy or breastfeeding
- Hepatic impairment (altered metabolism and clearance)
Research information, not medical advice. Always consult a licensed clinician before considering any peptide.
In depth
Full profile
What it does
Strong reduction in pain perception, sedation, muscle relaxation, and a sense of calm. At higher doses, slowed breathing and reduced heart rate.
How it works
Think of mu-opioid receptors like highly specific locks in your brain. Morphine is a key that fits but is a little rough around the edges, while dermorphin is a precision-cut master key that fits perfectly — and it's made of a tougher material so it doesn't wear out as quickly.
Once injected, dermorphin travels through the bloodstream and crosses into the brain where it binds pain receptors with high precision, producing strong pain relief and relaxation. It also slows breathing and gut movement, and with repeated use can cause the body to become dependent on it.
What to expect
Rapid onset within minutes of injection, with peak effects around 15–30 minutes depending on route and dose.
- Minutes 1–15: Rapid binding to mu-opioid receptors; pain relief and sedation begin quickly after injection
- Minutes 15–60: Peak analgesic and sedative effects; respiratory rate may be noticeably slowed
- Hours 1–4+: Effects gradually wear off; longer-lasting than morphine due to enzymatic resistance; repeated dosing risk of tolerance/dependence
Good to know
- This compound is for research purposes only and should never be self-administered
- If handling in a lab, always have naloxone (opioid reversal agent) immediately available
- Never combine with alcohol, benzodiazepines, or other CNS depressants
Staying safe
- Feeling very drowsy or sedated
- Slowed or shallow breathing
- Nausea or upset stomach
- Constipation
Avoid if you have:
- Anyone with breathing problems or lung disease
- Anyone with a history of opioid addiction
- Pregnant or breastfeeding individuals
- Anyone taking other sedatives, tranquilizers, or opioid medications
Mechanism of action
Dermorphin (H-Tyr-D-Ala-Phe-Gly-Tyr-Pro-Ser-NH2) is a heptapeptide full agonist with exceptional selectivity for the mu-opioid receptor (MOR, OPRM1), exhibiting Ki values in the subnanomolar range (~0.1–1 nM) and selectivity ratios exceeding 1000-fold over delta and kappa opioid receptors. Upon MOR engagement, it couples preferentially to Gi/Go proteins, leading to inhibition of adenylyl cyclase and downstream reduction in cAMP, activation of GIRK (G protein-coupled inwardly rectifying potassium) channels causing membrane hyperpolarization, and suppression of N-type and P/Q-type voltage-gated calcium channels, thereby reducing neurotransmitter release and neuronal excitability. The D-alanine at position 2 replaces the natural L-alanine, sterically hindering aminopeptidase and enkephalinase cleavage, extending plasma half-life significantly beyond endogenous enkephalins and providing a pharmacokinetic advantage for sustained receptor occupancy.
Systemically, dermorphin demonstrates rapid CNS penetration with supraspinal and spinal analgesic activity mediated through MOR populations in the periaqueductal gray (PAG), rostral ventromedial medulla (RVM), and dorsal horn laminae I/II. It modulates the HPA axis via opioidergic inhibition of CRH release and influences dopaminergic reward circuitry through disinhibition of VTA dopamine neurons. Cardiovascular effects include MOR-mediated bradycardia and vasodilation. Gastrointestinal effects (constipation, reduced motility) arise from peripheral MOR activation in the enteric nervous system. Tolerance develops via receptor desensitization (GRK-mediated phosphorylation and β-arrestin recruitment), receptor internalization, and compensatory upregulation of adenylyl cyclase.
Pharmacodynamics
Following subcutaneous or intramuscular administration in animal models, peak plasma concentrations are reached within 10–20 minutes. CNS penetration is rapid due to its relatively small size and moderate lipophilicity. Onset of analgesia in rodent hot-plate and tail-flick assays occurs within 5–15 minutes post-injection.
Dose-dependent increases in nociceptive thresholds (hot-plate latency increases of >200% at microgram doses in rodents), suppression of respiratory rate and tidal volume (dose-limiting toxicity), inhibition of GI transit, sedation quantified by open-field locomotor reduction, and modest hypothermia. Prolonged exposure induces measurable tolerance within 3–5 days of repeated dosing in rodent models.
Timeline
- Days 1–3: Initial MOR engagement produces maximal analgesic effects; GRK2/3-mediated phosphorylation of MOR begins; β-arrestin-2 recruitment initiates early desensitization within hours of first dose
- Days 3–7: Progressive receptor internalization and downregulation reduces analgesic potency; compensatory adenylyl cyclase superactivation begins (cAMP overshoot upon withdrawal); early physical dependence established
- Weeks 2+: Significant tolerance requiring dose escalation for equivalent analgesia; neuroadaptive changes in locus coeruleus (noradrenergic hyperactivity) and NAc dopamine signaling established; cessation produces withdrawal syndrome in animal models
Comparisons
- Dermorphin — effectiveness Very High, safety Caution, cost $, High (complexity) to use
- DAMGO ([D-Ala2,N-Me-Phe4,Gly-ol5]-enkephalin) — effectiveness Very High, safety Caution, cost $$$, High (complexity) to use
Adverse effects
Common:
- Dose-dependent respiratory depression via brainstem MOR activation (pre-Bötzinger complex suppression)
- Constipation through peripheral MOR agonism in myenteric plexus reducing acetylcholine release
- Sedation and psychomotor slowing due to cortical and subcortical MOR activation
- Nausea/vomiting via area postrema chemoreceptor trigger zone MOR stimulation
Rare:
- Severe apnea and fatal respiratory depression at supramaximal doses (animal LD50 data exist but human thresholds unknown)
- Seizure-like activity reported at very high doses in some rodent studies, potentially via excitatory interneuron disinhibition
Contraindications & risk mitigation
Contraindicated in:
- Individuals with COPD, sleep apnea, or any condition impairing respiratory drive
- Patients on MAO inhibitors (serotonergic/opioid interaction risk)
- Individuals with hepatic failure (reduced first-pass processing and metabolite clearance)
- Those with documented opioid use disorder or high MOR downregulation from prior opioid exposure
- Maintain naloxone (0.4–2 mg IV/IM) immediately available when conducting any animal or in vitro studies with dermorphin
- Titrate doses conservatively in animal studies given the 30–40× potency differential versus morphine
- Monitor respiratory parameters continuously in any in vivo administration context
- Never combine with GABA-A agonists (barbiturates, benzodiazepines) due to synergistic respiratory depression
Qué hace
Strong reduction in pain perception, sedation, muscle relaxation, and a sense of calm. At higher doses, slowed breathing and reduced heart rate.
Cómo funciona
Think of mu-opioid receptors like highly specific locks in your brain. Morphine is a key that fits but is a little rough around the edges, while dermorphin is a precision-cut master key that fits perfectly — and it's made of a tougher material so it doesn't wear out as quickly.
Once injected, dermorphin travels through the bloodstream and crosses into the brain where it binds pain receptors with high precision, producing strong pain relief and relaxation. It also slows breathing and gut movement, and with repeated use can cause the body to become dependent on it.
Qué esperar
Rapid onset within minutes of injection, with peak effects around 15–30 minutes depending on route and dose.
- Minutes 1–15: Rapid binding to mu-opioid receptors; pain relief and sedation begin quickly after injection
- Minutes 15–60: Peak analgesic and sedative effects; respiratory rate may be noticeably slowed
- Hours 1–4+: Effects gradually wear off; longer-lasting than morphine due to enzymatic resistance; repeated dosing risk of tolerance/dependence
Bueno saber
- This compound is for research purposes only and should never be self-administered
- If handling in a lab, always have naloxone (opioid reversal agent) immediately available
- Never combine with alcohol, benzodiazepines, or other CNS depressants
Manteniéndose seguro
- Feeling very drowsy or sedated
- Slowed or shallow breathing
- Nausea or upset stomach
- Constipation
Evitar si tienes:
- Anyone with breathing problems or lung disease
- Anyone with a history of opioid addiction
- Pregnant or breastfeeding individuals
- Anyone taking other sedatives, tranquilizers, or opioid medications
Mecanismo de acción
Dermorphin (H-Tyr-D-Ala-Phe-Gly-Tyr-Pro-Ser-NH2) is a heptapeptide full agonist with exceptional selectivity for the mu-opioid receptor (MOR, OPRM1), exhibiting Ki values in the subnanomolar range (~0.1–1 nM) and selectivity ratios exceeding 1000-fold over delta and kappa opioid receptors. Upon MOR engagement, it couples preferentially to Gi/Go proteins, leading to inhibition of adenylyl cyclase and downstream reduction in cAMP, activation of GIRK (G protein-coupled inwardly rectifying potassium) channels causing membrane hyperpolarization, and suppression of N-type and P/Q-type voltage-gated calcium channels, thereby reducing neurotransmitter release and neuronal excitability. The D-alanine at position 2 replaces the natural L-alanine, sterically hindering aminopeptidase and enkephalinase cleavage, extending plasma half-life significantly beyond endogenous enkephalins and providing a pharmacokinetic advantage for sustained receptor occupancy.
Systemically, dermorphin demonstrates rapid CNS penetration with supraspinal and spinal analgesic activity mediated through MOR populations in the periaqueductal gray (PAG), rostral ventromedial medulla (RVM), and dorsal horn laminae I/II. It modulates the HPA axis via opioidergic inhibition of CRH release and influences dopaminergic reward circuitry through disinhibition of VTA dopamine neurons. Cardiovascular effects include MOR-mediated bradycardia and vasodilation. Gastrointestinal effects (constipation, reduced motility) arise from peripheral MOR activation in the enteric nervous system. Tolerance develops via receptor desensitization (GRK-mediated phosphorylation and β-arrestin recruitment), receptor internalization, and compensatory upregulation of adenylyl cyclase.
Farmacodinamia
Following subcutaneous or intramuscular administration in animal models, peak plasma concentrations are reached within 10–20 minutes. CNS penetration is rapid due to its relatively small size and moderate lipophilicity. Onset of analgesia in rodent hot-plate and tail-flick assays occurs within 5–15 minutes post-injection.
Dose-dependent increases in nociceptive thresholds (hot-plate latency increases of >200% at microgram doses in rodents), suppression of respiratory rate and tidal volume (dose-limiting toxicity), inhibition of GI transit, sedation quantified by open-field locomotor reduction, and modest hypothermia. Prolonged exposure induces measurable tolerance within 3–5 days of repeated dosing in rodent models.
Cronología
- Days 1–3: Initial MOR engagement produces maximal analgesic effects; GRK2/3-mediated phosphorylation of MOR begins; β-arrestin-2 recruitment initiates early desensitization within hours of first dose
- Days 3–7: Progressive receptor internalization and downregulation reduces analgesic potency; compensatory adenylyl cyclase superactivation begins (cAMP overshoot upon withdrawal); early physical dependence established
- Weeks 2+: Significant tolerance requiring dose escalation for equivalent analgesia; neuroadaptive changes in locus coeruleus (noradrenergic hyperactivity) and NAc dopamine signaling established; cessation produces withdrawal syndrome in animal models
Comparaciones
- Dermorphin — efectividad Very High, seguridad Caution, costo $, High (complexity) de usar
- DAMGO ([D-Ala2,N-Me-Phe4,Gly-ol5]-enkephalin) — efectividad Very High, seguridad Caution, costo $$$, High (complexity) de usar
Efectos adversos
Comunes:
- Dose-dependent respiratory depression via brainstem MOR activation (pre-Bötzinger complex suppression)
- Constipation through peripheral MOR agonism in myenteric plexus reducing acetylcholine release
- Sedation and psychomotor slowing due to cortical and subcortical MOR activation
- Nausea/vomiting via area postrema chemoreceptor trigger zone MOR stimulation
Raros:
- Severe apnea and fatal respiratory depression at supramaximal doses (animal LD50 data exist but human thresholds unknown)
- Seizure-like activity reported at very high doses in some rodent studies, potentially via excitatory interneuron disinhibition
Contraindicaciones y mitigación de riesgos
Contraindicado en:
- Individuals with COPD, sleep apnea, or any condition impairing respiratory drive
- Patients on MAO inhibitors (serotonergic/opioid interaction risk)
- Individuals with hepatic failure (reduced first-pass processing and metabolite clearance)
- Those with documented opioid use disorder or high MOR downregulation from prior opioid exposure
- Maintain naloxone (0.4–2 mg IV/IM) immediately available when conducting any animal or in vitro studies with dermorphin
- Titrate doses conservatively in animal studies given the 30–40× potency differential versus morphine
- Monitor respiratory parameters continuously in any in vivo administration context
- Never combine with GABA-A agonists (barbiturates, benzodiazepines) due to synergistic respiratory depression
Reference data
Specifications
- Molecular formula
- C₄₀H₅₁N₇O₁₀
- Molecular weight
- 801.88 g/mol
- Half-life
- ~30–60 minutes (longer than most endogenous opioids due to D-Ala residue)
- Route
- Subcutaneous, Intramuscular
- Cycle length
- Not established; research use only
- Storage
- Store lyophilized powder at -20°C, protected from light and moisture. Once reconstituted, store at 4°C and use within 48–72 hours. Avoid repeated freeze-thaw cycles.
- Legal status
- Not approved for human use by the FDA or EMA. Classified as a research chemical in most jurisdictions. Use in competitive horse racing is banned (USEF, FEI). Scheduling may apply under controlled substance analogs laws in various countries.
FAQ
Common questions
How does dermorphin's receptor selectivity compare to DAMGO and morphine?
Dermorphin exhibits Ki ~0.1–0.5 nM at MOR with selectivity ratios >500:1 versus DOR and KOR, comparable to DAMGO (the synthetic reference mu-selective agonist). Morphine has moderate MOR selectivity (~1–5 nM Ki) with some KOR activity. Dermorphin's natural origin and D-amino acid conformation make it a pharmacologically important tool compound for dissecting MOR-specific signaling, particularly in studying biased agonism (G-protein vs. β-arrestin pathways).
What is the significance of the D-alanine residue in dermorphin's structure?
The D-Ala at position 2 is critical for both receptor selectivity and metabolic stability. L-amino acid peptidases cannot efficiently hydrolyze peptide bonds involving D-amino acids, dramatically slowing enzymatic degradation. This structural feature also optimally positions the pharmacophore (Tyr-D-Ala-Phe) for mu-receptor binding, a design principle widely adopted in synthetic opioid peptide research (e.g., DAMGO, DPDPE analogs).
Has dermorphin been detected in doping cases?
Yes. Dermorphin gained notoriety in 2012 when it was detected in multiple horse racing doping cases in the United States ('frog juice' doping scandal). The FEI and USEF explicitly ban dermorphin, and sensitive LC-MS/MS methods have been validated for its detection in equine urine and plasma.
What is the evidence level?
This compound is classified as Animal data. Most data comes from preclinical animal studies. Human clinical trial evidence is limited or absent.
Research
Research & sources
Current evidence for Dermorphin is rated as Animal data. Research is based primarily on animal models.
- 1. Dermorphin and deltorphins: extraordinary peptides from frog skin (1992) — Erspamer V, Peptides Journal
- 2. The opioid peptides of the skin of Phyllomedusa sauvagei (1981) — Montecucchi PC et al., International Journal of Peptide and Protein Research 17(3):316-321
- 3. Structure-activity relationships of dermorphin analogs (2000) — Lazarus LH et al., Pharmacological Reviews
- 4. Detection of dermorphin in equine plasma and urine by LC-MS/MS (2013) — Stanley SD et al., Drug Testing and Analysis
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