Dermorphin 5mg

▎Dermorphin Structure

▎Dermorphin Research

What is the research background of Dermorphin?

Exploration of Bioactive Substances: Since the 1970s, scientists have been dedicated to finding substances with special physiological activities from living organisms. People have gradually realized that during the long process of evolution, animals will produce various unique biomolecules to adapt to the environment and maintain life activities, and these molecules may have important medicinal values.

The Particularity of Amphibian Skin: The skin of amphibians has multiple functions, such as respiration, protection, and secretion. The skin glands of amphibians can secrete a large number of bioactive substances, which play an important role in defending against natural enemies and adapting to the environment. The skin secretions of many amphibians contain rich peptide substances, which have diverse structures and various biological activities, attracting the attention of many scientists.

The Discovery of Dermorphin: In 1981, Italian scientists first isolated Dermorphin from the skin secretions of the South American tree frog (Phyllomedusa sauvagii). Through the analysis of the components of the skin secretions of the tree frog and the detection of biological activities, it was found that Dermorphin in it had a potent analgesic effect and a high affinity for opioid receptors. This discovery opened up a new research direction in the field of pain treatment.

What is the mechanism of action of Dermorphin?

1. Binding to Opioid Receptors

Dermorphin is a potent opioid-like peptide that can selectively bind to μ-opioid receptors. This binding activates the receptors, resulting in a series of physiological effects^{[1, 2]}. For example, in animal experiments, it has shown a powerful analgesic effect^{[1, 2]}. Its analgesic effect may be achieved by inhibiting the transmission of pain signals. When pain signals are transmitted to neurons, it will cause the excitation and firing of neurons. After Dermorphin binds to the μ-opioid receptor, it can inhibit the excitation of neurons, thereby reducing the transmission of pain signals.

2. Effects on the Nervous System

Effects at the Spinal Cord Level

In human studies, it has been found that intravenous infusion of dermorphin can induce a significant and persistent increase in the nociceptive flexor reflex threshold in healthy volunteers^[2]. This indicates that dermorphin can inhibit the transmission of nociceptive signals at the spinal cord level. This effect is also obvious in subjects with complete chronic spinal cord injury, further confirming that dermorphin mainly plays a role in inhibiting nociceptive transmission at the spinal cord level.

Naloxone can partially reverse (about 50%) the inhibitory effect of dermorphin on the nociceptive spinal reflex. This may mean that dermorphin interacts with different populations of spinal opioid receptors to produce an analgesic effect^[2].

Effects on the Central Nervous System

Intracerebroventricular administration of DM produces a long-lasting antinociceptive activity^[1]. This indicates that dermorphin can exert an analgesic effect by acting on the central nervous system. However, the specific mechanism of action of dermorphin in the central nervous system is not yet fully understood.

In rabbit experiments, after intravenous injection of dermorphin, the rabbits' behavior showed a significant increase in the time of remaining quiet and immobile, and a decrease in voluntary activities, but it had no effect on the pattern and frequency of the hippocampal electroencephalogram^[3]. This suggests that dermorphin may have an impact on certain specific behaviors and areas of the nervous system.

3. Effects on the Gastrointestinal Tract

Dermorphin has an effect on the intestinal propulsion in rats. Compared with morphine, intracerebroventricular injection of dermorphin inhibits intestinal propulsion just like morphine, and its activity is 143 times that of morphine^[4]. The antagonistic effect of naloxone on dermorphin is less effective than that on morphine. Intracerebroventricular administration of quaternized naloxone can antagonize the effect of intracerebroventricular dermorphin on the intestine, while intraperitoneal injection is only effective at a dose of 8mg/kg. Dermorphin administered intraperitoneally is completely ineffective at the maximum effective dose (0.56 micrograms per rat). Increasing the dose of intraperitoneal injection of dermorphin (from 12 to 6400 micrograms per kilogram) has an inhibitory effect on intestinal propulsion that is independent of the dose, but never exceeds 50%. Only a high dose of naloxone (30mg/kg, intraperitoneal injection) can antagonize the effect of this intraperitoneal injection. This indicates that the effect of dermorphin on the intestine may involve both central and peripheral components.

4. Effects on Muscles

Dermorphin action was studied on cross-section strip of frog stomach muscle by a mechanographic recorder^[5]. The research results show that dermorphin (10 (-5)-10 (-8) M) can block the action of acetylcholine, spontaneous activity, and muscle contraction caused by direct electrical stimulation. All these effects are difficult to reverse. If dermorphin is injected into the incubation medium during the K (+) depolarization (KCl - 100mM) of the muscle, it cannot block the spontaneous and induced activities. Therefore, dermorphin has a voltage-dependent effect and may act on the voltage-dependent Ca (2+) channels of the muscle cell membrane.

5. Relationship between Molecular Structure and Mechanism of Action

Molecular mechanical simulations have been carried out on dermorphin (Pattabiraman N, 1986). The research shows that the D-Ala2 at the N-terminus and the L-Pro6 residue at the C-terminus in the dermorphin sequence suggest the possible existence of a β-turn. From a stereochemical perspective, there may be three types (II', III', and V') of β-turns at the N-terminus of the peptide, and two types (I and III) of β-turns at the C-terminus. In the molecular mechanics calculations, six folded conformations and one extended conformation were considered to evaluate the relative stability of dermorphin. Among them, three folded conformations have lower energy and have the following general characteristics: similar energy, three hydrogen bonds, a semi-rigid β-sheet fragment, and a favorable Tyr1-Tyr5 interaction. The existence of the β-sheet structure may play a role in the selective interaction between dermorphin and the μ-receptor.

What are the applications of Dermorphin?

Used for Postoperative Pain Management: A randomized, placebo-controlled study in 1985 showed that Dermorphin administered via the intrathecal route was significantly more effective than placebo and the reference compound morphine in postoperative pain management^{[6, 7]}. This indicates that Dermorphin may have great potential in relieving postoperative pain. For postoperative patients, effective pain management can not only improve the comfort of patients but also help patients recover and return to normal life.

Application in Palliative Care: Considering its excellent analgesic effect, Dermorphin has also been suggested for use in the palliative care of advanced patients^{[6, 7]}. In palliative care, relieving the pain of patients is a crucial goal, and Dermorphin, with its powerful analgesic effect and relatively low risk of side effects, provides a possible option for relieving the pain of advanced patients.

Inhibitory Effect on Spinal Pain: Studies have shown that Dermorphin can inhibit the transmission of nociception in the spinal cord. In healthy volunteers, intravenous infusion of 0.16mg/kg of Dermorphin can significantly and persistently increase the threshold of the nociceptive flexor reflex^[8]. Similar effects were also observed in subjects with complete chronic spinal cord injury, indicating that Dermorphin mainly acts at the spinal cord level to inhibit the transmission of pain. This inhibitory effect on spinal pain provides new hope for the treatment of patients suffering from spinal cord-related pain diseases.

In conclusion, Dermorphin is a potent opioid-like peptide that can bind to μ-opioid receptors, showing a significant analgesic effect and inhibiting the transmission of nociceptive signals in the spinal cord. It has potential applications in postoperative pain management, palliative care, etc., bringing new ideas for pain treatment.

About The Author

The above-mentioned materials are all researched, edited and compiled by Cocer Peptides.

Scientific Journal Author

Giuliano Fontani is a researcher associated with the University of Siena, Italy, focusing on neurosciences and physiology. He has studied the effects of dermorphin, a naturally occurring peptide, on behavior and hippocampal electrical activity in rabbits, contributing to the understanding of opioid receptor function. His work also explores the relationship between brain activity and behavior, with publications in journals like Life Sciences. Giuliano Fontani is listed in the reference of citation [3].

▎Relevant Citations

[1]    Mizusawa K. Dermorphin[M]//2021:107-109.DOI:10.1016/b978-0-12-820649-2.00027-9.

[2]    Sandrini G, Degli Uberti E C, Salvadori S, et al. Dermorphin inhibits spinal nociceptive flexion reflex in humans[J]. Brain Research, 1986,371(2):364-367.DOI:10.1016/0006-8993(86)90376-8.

[3]    Fontani G, Vergnani L, Salvadori S, et al. Effect of dermorphin on behavior and hippocampal electrical activity in rabbits[J]. Life Sciences, 1993,52(3):323-328.DOI:10.1016/0024-3205(93)90224-q.

[4]    Parolaro D, Sala M, Crema G, et al. Central and peripheral components of dermorphin's effect on rat intestinal  propulsion in comparison to morphine[J]. Peptides, 1983,4(1):55-58.DOI:10.1016/0196-9781(83)90165-1.

[5]    Babskaia N E. The potential-dependent action of the opioid peptide dermorphin[J]. Biull Eksp Biol Med, 1992,114(11):502-504. https://pubmed.ncbi.nlm.nih.gov/1363279/.

[6]    Hesselink J M K, Schatman M E. Rediscovery of old drugs: the forgotten case of dermorphin for postoperative pain  and palliation[J]. Journal of Pain Research, 2018,11:2991-2995.DOI:10.2147/JPR.S186082.

[7]    Keppel Hesselink J, Schatman M. Journal of Pain Research, 2018,11:2991.DOI:10.2147/JPR.S186082.

[8]    Pattabiraman N, Sorensen K R, Langridge R, et al. Molecular mechanics studies of dermorphin[J]. Biochemical and Biophysical Research Communications, 1986,140(1):342-349.DOI:10.1016/0006-291x(86)91096-x.

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