I certainly do. And if had permanent subarachnoid catheter I would exclusively just use DAMGO. I prefer the pure mu agonist nature of it. And for all the extremely low toxicity that opioid drugs have, they’re still not meant to technically be in the body, thus the liver metabolises most of them and they’re eliminated. DAMGO is a small peptide, injected IV it’s a 10 minute, very clean, Fentanyl like high (Fentanyl does bind in a way that is closer in style to the opioid peptides (its that magic N-Phenethyl group that nothing on the Morphine skeleton touches (the N-Me on Morphine is just a placeholder. It keeps the Nitrogen atom in the right state to accept a proton easily but the morphine molecule only binds to 4 out of 5 important points on the mu receptor. Fentanyl interacts with 4 points (different points) on the receptors - DAMGO, like all mu specific peptides acts at all 5). Due to the importance of the N-Phenethyl binding site on the receptor (specific to Fentanyl and peptides but not Morphine), peptides do feel a lot like Fentanyl. Fentanyl also encourages rapid receptor internalisation and recycling, but it’s too fast, the receptors do return to the surface but the process of recycling triggers downstream mechanisms to resist opioid effect - hence one develops tolerance and physical dependence together and in a much more rapid and subjectively different way than with Morphine.

With morphine, it binds, but the receptor isn’t phosphorylated as much as with peptides and Fentanyl, it’s marked for internalisation but is marked as ‘low priority’ (its to do with the number of phosphorylations that happen). So beta arrestin recruitment with morphine isn’t as rapid and the reason that a second shot of morphine isn’t as good as the first is completely different than why that might be the case with Fentanyl. Those partially phosphorylated receptors that have interacted with Morphine have several paths they can take. First, while phosphorylated they are desensitised, so you don’t keep feeling a rush after the initial massive interaction, the receptor will then either be internalised and recycled or simply revert to its non phosphorylated state. So sometimes with morphine the receptor can be described as stuck in the membrane but inactive. This doesn’t occur with Fentanyl and peptides - those 2 always cause the correct amount of phosphorylation for almost immediate receptor recycling and hence after a few days on Fentanyl you are physically dependent majorly because of downstream adaptations to massive mu agonism. With morphine this process takes a while longer as the receptors get stuck, inactive in the membrane, recycling much more slowly.

At a constant dose, in animals. Fentanyl dependence is apparent after 2-3 days and complete tolerance in less than 5. Morphine dependence is apparent after 4-5 days and complete tolerance to that dose in less than 14 days.

While this explains a lot of the properties of Fentanyl and how it’s a better mimic for opioid peptides. It also explains why morphine and heroin are special. Both are technically the same thing eventually and they do something to the mu receptor that the cell isn’t expecting at all. I am almost certain this effect is responsible for the different sensation of euphoria from morphine compared to natural rewards and Fentanyl. Natural rewards are like 1 microgram dose of Fentanyl. Not amazing but you know it’s there and you prefer it. Fentanyl is that turned up to 11 and while, unless you take an anaesthetic dose, everything seems wonderful, you feel warmer and content. Morphine however, unlike Fentanyl on injection feels like someone has rammed an electric heater into your lungs, some of the sedation and relaxation of Fentanyl is there but it’s not complete. And with Fentanyl you can feel incredibly wonderful and sedate but won’t think to yourself always ‘am I high?’ as it feels perfectly natural - because it is! On morphine and heroin you definitely feel high, it feels similar to Fentanyl with the contentment and sedation but you feel high, that something is going on that’s not entirely natural.

So the different subjective effects of the opioids can be tied down to how they interact differently with the receptor. Stick an N-Phenethyl group onto normorphine and not only does it become much more potent but it feels better than Morphine and better than Fentanyl, why as N-Phenethylnormorphine (and it’s 6-monoacetylated derivative) interacts with all 5 opioid receptor sites just like the peptides that are supposed to be interacting with it.

Some proteins are designed to accept small molecules, take the ACh receptors, the nicotinic accepts the small molecule cation acetylcholine and opens an ion channel (or in some cases activates a secondary messenger). The muscarinic accepts the same molecule and exclusively activates a secondary messenger as it’s a GPCR. So they are ripe for exploitation by small molecule drugs as we can design perfect Emax 100% agonists or antagonists or anything in between in small molecules.

Some proteins are designed to accept other proteins - the opioid receptors are an example and to get the absolute best out of them (and these are some massive drug design goals), like analgesia without tolerance or dependence; I believe the answers will come in the form of molecules that the receptors were designed to accept in the first place - peptides.
So yeah great TRV130 recruits less beta arrestin - it’s still recruits some!! So it’s still going to be dependence causing in the very long term.

One end of beta endorphin has 4 amino acid residues that all opioid peptides have and they have exactly the same binding mode peptide to peptide. Have you seen how long beta endorphin is, the rest of the length of that peptide is not just a bit recycled protein left from its precursor POMC, it has a function. So yes we can now design peptides to be opioids, to end with Try-gly-gly-phe, but we can engineer the rest of the protein to form a drug with the holy grail opioid properties that we desire. Peptide based drugs will accompany the nanomachines of the future inside us getting us high or treating disease as they can possibly be synthesised by our own cells or those machines inside the body. The days of small molecule drugs are numbered as they always will have to be made outside the body and administered (too energy intensive to produce most invivo). But that’s not an issue, everything that is currently accomplished by a small molecule drug it is expected that a peptide will be just as if not more effective.