Dermorphin

Dermorphin is a potent synthetic peptide derived from frog skin that may relieve pain far more effectively than morphine. It binds to mu-opioid receptors in the nervous system, helping to reduce pain perception and increase pain tolerance. Dermorphin is a heptapeptide (Tyr-D-Ala-Phe-Gly-Tyr-Pro-Ser-NH2) from Phyllomedusa sauvagii skin secretion. It is ~30–40× more potent than morphine in animal models and shows high mu-opioid receptor selectivity. D-amino acids confer resistance to enzymatic breakdown, prolonging action.

- Study novel alternatives to traditional opioids for pain relief

- Research treatments for chronic or neuropathic pain

Mechanism of Action

How this peptide works in the body

Mu-Opioid Receptor Agonism: ● Dermorphin binds with extremely high affinity to mu-opioid receptors (MORs), a class of G-protein-coupled receptors located throughout the brain, spinal cord, and peripheral nervous system. Upon binding, Dermorphin activates Gi/o proteins that inhibit adenylate cyclase, thereby reducing cyclic AMP (cAMP) production. This results in decreased PKA activity and reduced phosphorylation of ion channels involved in nociceptive signaling. Inhibition of Neurotransmitter Release: ● Through Gβγ-mediated inhibition of voltage-gated calcium channels (VGCCs), Dermorphin suppresses presynaptic calcium influx. This limits the release of pain-related neurotransmitters such as glutamate, substance P, and CGRP (calcitonin gene-related peptide), effectively reducing signal transmission within nociceptive pathways. Hyperpolarization of Neuronal Membranes: ● Dermorphin also promotes the opening of G-protein-coupled inwardly rectifying potassium (GIRK) channels, causing potassium efflux. This hyperpolarizes the membrane potential of postsynaptic neurons in the dorsal horn of the spinal cord, making them less responsive to pain signals. Stimulation of Endogenous Dynorphin Release: ● Some Dermorphin analogs trigger the release of dynorphins, endogenous opioid peptides that act on kappa-opioid receptors (KOR). KOR activation may modulate pain perception and help mitigate side effects commonly associated with chronic mu-opioid receptor stimulation, such as tolerance and dependence. Enzymatic Stability via D-Amino Acids: ● Dermorphin's structure includes D-Ala at position 2, conferring resistance to enzymatic degradation by peptidases. This increases its metabolic stability, leading to prolonged half-life and enhanced bioavailability compared to standard opioid peptides.