Recent publication: Xylazine is an agonist at kappa opioid receptors and exhibits sex-specific responses to opioid antagonism

[tryptakid]

My wife came across this recent publication indicating agonist activity of xylazine at kappa receptors, and also exploring sex differences.

One of the things that really jumps out to me is this:

Our findings carry important clinical and public health implications. Considering that xylazine is a full κOR agonist, we note two prominent historical and international examples of non-medical use of the κOR agonist pentazocine: the “Ts and Blues” (pentazocine and tripelennamine) outbreak in the midwestern United States from 1977 to 1981 [[77], [78], [79]], and pentazocine injection in Nigeria [80] and India [[81], [82], [83], [84]]. In both settings, characteristic skin lesions beyond the site of injection, eschar formation, and wound cratering were observed [[85], [86], [87], [88], [89], [90]], with morphological similarity [91] to reports involving xylazine from Puerto Rico [92], the Philadelphia area [9,93], and New Haven, Connecticut [94]. κOR distribution in human skin has led to its study as a therapeutic target [[95], [96], [97]], suggesting new directions for research into wound etiology.

It's worth a read - I had always assumed that the primary benefit to xylazine was the addition of a clonidine-like drug for potentiation, just as people mix clonidine with methadone or other agonists, but this study suggests that the story is much more complicated than that.

Edited to add:

Separately, withdrawal symptoms specific to pentazocine include heightened anxiety, agitation, and paranoia [98]; these are also cited by clinicians and people who use drugs to be distinguishing presentations of xylazine withdrawal, increasing the difficulty of initiating medication assisted therapy for opioid dependence [14,99,100]. Further investigations are needed to establish if similarities to skin ulcers and withdrawal are coincidental or may be mediated in part by κOR. It is also worth noting that pentazocine, akin to xylazine, also targets sigma receptors. In addition, existing human pharmaceutical κOR agonists (pentazocine, butorphanol, nalbuphine) could be investigated immediately to alleviate xylazine withdrawal, which is difficult to manage in clinical settings [7]. Dexmedetomidine, another α2-AR agonist approved for human use for other indications in the United States, could logically be considered a candidate medication to be investigated for its potential to manage xylazine withdrawal, although it would be considered off-label at the current time.

Thought I would share.

 

[Skorpio]

This is a really strong paper. Bryan Roth really has his fingers in a lot of pies.

The behavioral work indicates quite clearly that xylazine worsens withdrawal symptoms. They back this up by looking at c-fos (a transcription factor that is a marker of a recently fired neuron), in different anatomical regions, finding differences in activity at different brain regions (help me out @someguyontheinternet! My neuro-anatomy is fairly weak).

The pharmacology in this paper was extremely throurough, and used methods which complimented each other. Xylazine was screened against a host of kinases as well as more traditional receptors. One thing that interested me was this tidbit:

"Xylazine inhibits radioligand binding by 50 % or more at α2-ARs, as well as 5-HT7 serotonin receptor (5-HT7AR), kappa opioid receptor (κOR), sigma 1 receptor (σ1R), and sigma 2 receptors (σ2R) (Fig. S3)."

The sigma 1 receptor is like a tuning knob for other GPCRs, its agonism could very well contribute to the addictiveness of the combo.

The kappa opioid system is quite convoluted. Antagonists can either act as traditional competitive antagonists, or engage a MAPK pathway and generate free radicals, oxidizing the receptor into an "off" state. Nor-BNI acts through the second pathway, so it's effects should be more penetrant ( this type of antagonism isn't currently used in humans).

I also like the suggestion to use dexmedetomidine to treat withdrawal, followed by the disclaimer that this is not endorsing off-label use.

All in all, this is an extremely well executed paper from the McElligot lab, and on a super relevant subject.

 

[someguyontheinternet]

LC is the locus coeruleus which is the primary noradrenergic nucleus, it contains more NE producing neurons than anywhere else in the brain and projects basically everywhere

BSA is the basolateral amygdala which is a part of the amygdala involved in producing a fear/fight or flight response and memory of painful stimuli and takes sensory input from the primary auditory, temporal lobe (visual categories and colors), and the hippocampus as well as modulatory inputs from the LC, basal forebrain, and VTA

The CeA is the central nucleus of the amygdala and is involved in expression of fear conditioning, not totally sure what the specific role of the lateral part is

The DMS is the dorsal medial striatum which appears to be heavily involved in goal directed behavior and has been implicated in habituation and addiction, behaviors specifically rather than reward, as well as aversive behavior

The BNST is the bed nucleus of the stria terminalis and is involved in stress responses within a circuit that stimulates the hypothalamic-pituitary-adrenal axis

Here's a paper on some of the circuitry

image uploader

Roles for the Dorsal Striatum in Aversive Behavior - PMC

The ability to identify and avoid environmental stimuli that signal danger is essential to survival. Our understanding of how the brain encodes aversive behaviors has been primarily focused on roles for the amygdala, hippocampus (HIPP), prefrontal ...

www.ncbi.nlm.nih.gov

 

[Skorpio]

LC is the locus coeruleus which is the primary noradrenergic nucleus, it contains more NE producing neurons than anywhere else in the brain and projects basically everywhere

BSA is the basolateral amygdala which is a part of the amygdala involved in producing a fear/fight or flight response and memory of painful stimuli and takes sensory input from the primary auditory, temporal lobe (visual categories and colors), and the hippocampus as well as modulatory inputs from the LC, basal forebrain, and VTA

The CeA is the central nucleus of the amygdala and is involved in expression of fear conditioning, not totally sure what the specific role of the lateral part is

The DMS is the dorsal medial striatum which appears to be heavily involved in goal directed behavior and has been implicated in habituation and addiction, behaviors specifically rather than reward, as well as aversive behavior

The BNST is the bed nucleus of the stria terminalis and is involved in stress responses within a circuit that stimulates the hypothalamic-pituitary-adrenal axis

Here's a paper on some of the circuitry

image uploader

Roles for the Dorsal Striatum in Aversive Behavior - PMC

The ability to identify and avoid environmental stimuli that signal danger is essential to survival. Our understanding of how the brain encodes aversive behaviors has been primarily focused on roles for the amygdala, hippocampus (HIPP), prefrontal ...

www.ncbi.nlm.nih.gov

Thanks for outlining the anatomy. My department has a neuro component, but all of those labs are pretty addiction focused, so my main passing knowledge is with striatal stuff. I am pretty unfamiliar with adrenergic anatomy.

 

[tryptakid]

@Skorpio and @someguyontheinternet - thanks so much for contributing this stuff. I'm starting to get a clearer understanding of some of these deeper neurological processes - I feel like I have a pretty good handle on surface level psychopharm and some understanding of the interplay between systems, but stuff like C-fos, GPCRs, and the role of sigma receptors are things that have been a little outside of my wheelhouse. This helps to clarify a lot.

Based on what @someguyontheinternet mentions, I'm thinking about how the dopamine reward pathway model of addiction is both overly simplistic but also not entirely inaccurate either. We're getting a point where we can see how these agents potentiate, leave markers of activity, and interface with different parts of the brain, and can conceivably predict and model what the development of addictive behaviors looks like pharmacologically, and how it can be paralleled by non-pharmacological mechanisms since we know the function that each of these pieces would typically serve.

What worries me a bit is the idea that xylazine seems to be such an ideal agent to further diminish the end users will to even try to stop using (when coupled with an opioid agonist)... how much did luck have with pairing these drugs together vs. was xylazine hand selected. Obviously, this is another step in understanding the activity that is taking place, but if you're the cartels or hostile state with interests in destabilizing the US, this combination of drugs is damn near ideal.

I work in addictions as a psychotherapist, and I'm honestly treating more people with alcohol and cannabis use disorders than opioid use disorder at this point. People using xylafent are barely engaging. Most of the people on buprenorphine have been on for ages. Further, because of the wounds that xylazine causes, people are becoming more and more avoidant of presenting for care at all. It's a fucking terrible situation and it makes me so grateful I stopped doing dope in 2008 - dodged bullet after bullet after bullet...

I am encouraged that there are identified agents that could be helpful in the treatment of xylafent dependent individuals. Hopefully it leads to some new protocols since OG buprenorphine protocol and methadone were designed to treat opioids we're barely even encountering anymore (heroin/oxy).

 

[Skorpio]

Not to be overly cynical, but I wouldn't be surprised if 5 years from now, people will be pining for the good days of "clean tranq".

The way things are going I wouldn't be too surprised if people find out VX nerve gas can enhance the "hit".

 

[Pickledlemons]

Not to be overly cynical, but I wouldn't be surprised if 5 years from now, people will be pining for the good days of "clean tranq".

The way things are going I wouldn't be too surprised if people find out VX nerve gas can enhance the "hit".

That does seem to be the pattern, yup.

 

[MedicinalUser247]

VX ? Better get the Atropine and Oxime out.