Diacetyldihydromorphine (Improved Diamorphine/Heroin analog)

[Neuroprotection]

Here’s an interesting review which discusses negative feedback against reward.

Introduction: Addiction and Brain Reward and Anti-Reward Pathways

Addictive drugs have in common that they are voluntarily self-administered by laboratory animals (usually avidly) and that they enhance the functioning of the reward circuitry of the brain (producing the “high” that the drug-user seeks). ...

www.ncbi.nlm.nih.gov

 

[Neuroprotection]

Kappa antagonists have rather differing effects based on their preference for beta arrrestin or g-protein pathways (and the biased signaling for kappa receptors gets weird).

NorBNI tends to be a really popular antagonist (wild structure, a dimer of morphinans) that seems to block one arm of signaling. JDTiC is a different antagonist that gets called irreversible, but rather than alkylating the receptors, it fucks with c-jun kinase and has effects that way that last in the timescale of weeks.

These antagonists have pretty different effects on stress and DA signaling and generally complicate reading research about the kappa receptor (and of course performing that research).

That’s interesting. However, I thought the issues with different signalling pathways can be resolved/minimised by administering larger doses of any Kappa antagonist over a longer period of time. many studies I’ve come across investigating the effects of kappa Opioid antagonists on behaviour Will take account of biased agonism and off target affects as possible complicating factors. they sometimes address this by using two different antagonists from completely different chemical classes, compare other studies where other antagonists have been used, Use receptor knockout animals etc. of course these methods aren’t perfect, but they do go a long way.

 

[Neuroprotection]

I was thinking more along the lines of where the kappa receptors are, what neurons in which circuits have kappa inputs rather than dynorphin signaling outputs. I think most (or all?) kappa receptors are presynaptic and modulate vesicle release through GIRK mediated hyperpolarization so they could be on a variety of types of neurons that release different transmitters but where they are in which circuits is the important part for determining the impact on behavior

There are negative feedback systems all throughout biology at what seems to me to be every level of intracellular cell signaling and throughout the brain and other organs. Feedback systems to maintain homeostasis are some of the biggest drivers of signaling and change

Sorry, my understanding of brain circuitry is very poor. if I remember correctly, Kappa opioid Receptors are found in many different brain regions, including the prefrontal cortex, nucleus accumbens in both shell and core, as well as in the hippocampus. I think they are mainly found presynaptically as you said where they suppress neurotransmitter release. interestingly, despite their very widespread distribution and the multiple neurotransmitters they regulate, The most dramatic affect on behaviour seems to be their ability to suppress dopamine release and hence brain reward. less well understood, is The mechanism behind their ability to induce psychosis like behaviour when strongly activated. Kappa receptor. function is thought to be enhanced during drug withdrawal where they contribute to negative mood states like anxiety, despair/depression and anhedonia. such effects can probably be attributed to Kappa opioid Receptors in the nucleus accumbens and amygdala. however, cognitive impairment including working memory dysfunction which often occurs in drug withdrawal, might also be mediated by Kappa opioid receptors. here is the study, it took me ages to find it but I’m really glad I did because it’s so interesting.

Release of endogenous dynorphin opioids in the prefrontal cortex disrupts cognition

Following repeated opioid use, some dependent individuals experience persistent cognitive deficits that contribute to relapse of drug-taking behaviors, and one component of this response may be mediated by the endogenous dynorphin/kappa opioid system in neocortex. In mice, we find that acute...

www.biorxiv.org

 

[Skorpio]

That’s interesting. However, I thought the issues with different signalling pathways can be resolved/minimised by administering larger doses of any Kappa antagonist over a longer period of time. many studies I’ve come across investigating the effects of kappa Opioid antagonists on behaviour Will take account of biased agonism and off target affects as possible complicating factors. they sometimes address this by using two different antagonists from completely different chemical classes, compare other studies where other antagonists have been used, Use receptor knockout animals etc. of course these methods aren’t perfect, but they do go a long way.

Kappa opioid bias is weird, with the p38 mapk arm driving a periredoxin toIncreasing the dose of a biased ligand is only feasable if the unwanted effects dont produce toxicity or other adverse effects to limit dosing. Kappa opioid bias is weird, with the p38 mapk arm driving a periredoxin to produce reactive oxygen species whixh modify proteins. This has a longer time course than phorphorylation, and seems fairly unique to that receptor.

Yoh are on point with the facts that knockout animals are the best way to study signaling bias.