Opioid Addiction as an Innate Immune Disorder
Scientific discovery is a wondrous thing. It is a linear progression from vacuum to vacuum tubes, from melting sand into glass to constructing silicon wafers and then on to images jumping out of computer screens. At various times, scientists have proclaimed that we are getting closer to wrapping up all the details.
There is a glaring exception to this idea of linear progression. In living systems, a new discovery sometimes just creates more confusion. When the opioid receptors were discovered, many thought we were getting close to solving the “pain problem”. But now we are at the point where opioids have emerged as a greater problem than “the pain”. My purpose here is to try to untangle this linear messiness and hopefully rescue Opioid Addiction from those who believe it to be a mental illness.[1]
Scalability
Living things are scalable. That means they are designed all the way down. What is visible to the naked eye looks nothing at all like what appears under a microscope. Even so, the disparate levels communicate seamlessly with one another, or so we believe.
Man-made objects are not scalable. Gazing into a Vincent van Gogh painting can create an emotion of “beautiful madness” inside us. Analyzing its paint pigments on the other hand yields up no such sense. Its madness simply does not exist at the pigment level. From whence cometh the beautiful madness then?
Interoception is your brains representation of all sensations from your internal organs and the hormones in your blood and your immune system. Your river of feelings might seem like it is flowing over you, but you are the river’s source. [2]
What Dr Lisa Feldman Barrett is saying is that the conscious mind is the recipient of sensations from within us. A sensation is more than just one of the five senses
Scalability is not just downward and tinier. It can scale upward into emotions and abstractions that imitate reality and also provide us with an escape from reality.
It is not unthinkable that a quantum physicist could make a discovery that applies to cellular biology.
There exists in living systems a symmetry on a deep level. For example, enzyme systems coexist with others that have opposite effects
Opioid receptors
Let us get specific and examine the metabolic minutiae of the endorphin system. It is unfortunate that the endorphin receptors got renamed to Opioid receptor. It hides and obscures their true nature. Opioid receptors (OR) are sub-micron in size and at least several thousand times larger than a molecule (> 10-10 meters). Animal design owes much to our plant ancestors. It is not pure accident that a plant can produce the opium molecule that fits nicely onto our endorphin receptors.
A central concept of opioid drugs is “tolerance”. Everything we used to know about tolerance was derived from observing humans and questioning them. Recently, studies on the submicron cellular level are telling a different story. Opioid induced hyperalgesia (OIH) is another example of a visible world concept. If one carefully interrogates an opioid addict, they usually express awareness of OIH on an emotional level. [3] Pain management doctors on the other hand mostly know it exists but do not sense it in their patients. In a cognitively dissonant way, they simply treat it by increasing dosing.
Toll receptors
Research indicates that a great deal is happening in addiction that goes well beyond opioid receptors. Toll receptors were first discovered forty years ago inside fruit flies. To everyone’s surprise, we also found them inside our brains. Ancient single celled creatures dealt with an existential question. When a molecule comes floating past, should it be eaten? If they ate the wrong thing it could kill them. They possessed an ancient Toll like receptors that would sniff out what floated past and determine if it could be eaten.
Clearly a correct diet is also vital to our survival. So what do the Toll like receptors (TLR4) in our brain think of opium? The short answer is that they do not like it. In an unfortunate subset of mice and humans, they even hate it and react violently to it. That reaction has a famous name, “withdrawal”. Heroin does not just sit down on the endorphin (opioid) receptor. Our TLR4’s also grab it and set off an alarm. The alarm consists of a storm of molecules called cytokines and has names like interleukins. [4].[5] [6] [7] The genetic basis of opioid addiction is determined by our innate immune system.
The classical concept of the brain is it is a bundle of nerves located in different rooms with names like Amygdala, Hippocampus, Cerebrum and Cerebellum. A realization is gradually emerging that there is a wireless brain in which messenger molecules (cytokines) quickly spread out like the packets on the internet. The prime initiators of these cytokines are a vast array of brain cells called Astrocytes. Astrocytes even outnumber our neurons. They come in different flavors. An important member of this family is the microglia. They are the brain police. They are part of our innate immune system and are constantly trying to protect us. Microglia have TLR4 receptors that are constantly sniffing around for molecules trying to sneak past the blood brain barrier. There are other receptors like Pattern Recognition Receptors (PRR) that also excel at seeing pieces of bacteria.
All these different and new pieces to the opioid story fall under the general name of the central immune system. Opioid addiction is a disease of Central Immune Signaling
Yes some people have an innate immune system that reacts strongly to opioids. Opioid addiction has more to do with peanut allergy than it does with mental illness. So instead of having to carry an Epipen like the peanut allergy people, opioid addicts should carry a Narcan syringe.
So now we come to a strange irony. The cure for withdrawal is the thing that triggers it in the first place. Please ponder on that. Heroin both causes withdrawal and also “cures” it. Addiction is a mental hamster wheel.
Opioid “tolerance” should instead be called intolerance. This raises an existential question. If our Innate Immune System (IIS) rejects them, why are we prescribing them? Their ability to create persistent changes in our psyche that leads to long standing maladaptive behavior called opioid addiction (OA) has created an urgency about elucidating the cellular biological basis of OA.
All opioids are not equal. Some like methadone and Buprenorphine cause less intolerance. Patients develop a dose ceiling for them unlike heroin of which most addicts can never get enough. The heroin high is largely a myth. Addicts consistently report that after the first week, the high disappears and is replaced by climbing out of a hole back to normal. “Chasing the dragon”, the mythical and ephemeral heroin high, is the road to opioid overdose and death.
The “endorphin high” achieved by exercise is the absolute most a heroin addict can hope for. It is what brings them back to normal and allows them to show up for work each day.
Chirality
Chirality is the property of handedness. For some unknown reason, most humans are right handed and for another unknown reason living things produce only left handed amino acids. In 1848 at the age of 25, Louis Pasteur discovered molecular chirality.[8] How then does one tell if a tool (like a monkey wrench) is left or right handed? If the tool is symmetrical in any of its three planes, then it is not chiral (handed). Look at some tools and find their symmetrical plane. In biochemistry, a left and right enantiomer is one of the two stereoisomers of a molecule.
In 1963 a drug called Thalidomide was introduced as a treatment for the morning sickness of pregnancy. The Thalidomide was a racemic mix. Racemic means that it was a mix of both left and right handed molecules. The left handed version caused an epidemic of birth defects while the right handed version cured morning sickness. This ignited extensive research by the Pharma industry.[9] Unfortunately, even pure enantiomers when introduced in vivo can undergo rapid racemization.[10]
Methadone is a racemic mix with an extensive history as a treatment for opioid addiction. Enantiomeric methadone has become a subject of research.[11] It has been known since 1988 that opioid receptors have a mix of stereo selective and non-stereoselective sites. [12] [13] Left handed methadone protects against heroin while the right handed kind does not. Buprenorphine is a pure stereoisomer. That is why smaller doses of it are required.
Addiction the sixth sense.
I once had a shot of IV Morphine prior to a surgical procedure. It made the air thick and I felt myself falling back into me. Three hours later, I vomited. If that is what heroin is like, I would ask for a refund. Vicodin takes away pain but the pain comes back worse (opioid induced hyperalgesia).
Some say, “with the first shot of heroin you are hooked”. I do not believe that for a second.
After interviewing hundreds of heroin addicts in depth, I find them all to be unique and similar to one another. Almost none drink alcohol, almost all smoke cigarettes. What does that mean. The extant literature ignores these signs.
The genome (genetic code) is sensate. Our cells are covered with receptors that talk back to and advise the genome. It listens and reacts. We can sense molecules.
A fundamental message in Medicine is that people are highly diverse. Addiction is also diverse. The opioid receptor lets the genome sense the Metabolic Symphony Orchestra.
Heroin is invisible to the five senses. It enters stealthily and embraces a receptor that is a direct line to our genetic code. It triggers a cascade of feelings and emotions inside our conscious mind. It has as much to do with the five senses as a Picasso painting has to do with a paintbrush. Addiction is a sixth sense that ignites and expands us and then steals away like a shifty politician,
“Sometimes I wait for it, quiet like a beggar waiting for the bus the exhausted air a window to frame my watching, and it comes to me like a crazy corner of the eye conjuring, strutting like a thief in drag.
I glimpse the odd indescribable loveliness of happiness like seeing Icarus tumble from the sky wings dripping wax as casually as sweat beading away from a body in the desert. A molten pool to gather broken bones in after his inevitable descent.”
Brita Finlayson 2006
Douglas R. Finlayson MD August 2020
[1] Maha Elsayed, Pierre Magistretti: A new Outlook on Mental Illness: Glial involvement beyond the Glue.
Front Cell Neurosci 2015; 9:468
[2] Lisa Feldman Barrett PhD: How Emotions Are Made. Houghton Mifflin, Harcourt 2017
[3] Personal observations through interviews with opioid addicted patients.
[4] Mark R. Hutchinson, Yehuda Shavit, Peter Grace, Kenner Rice, Steven Maier, Linda Watkins (2011)
Exploring the neuroimmunopharmacology of Opioids: Review of mechanisms of Central Immune Signaling.
Pharmacological Reviews 63:772-810 2011.
[5] Milligan ED, et al (2000) Thermal hyperalgesia and mechanical allodynia producedby intrathecal administration of the human immunodeficiency virus-1 (HIV-1)envelope glycoprotein, gp120. Brain Res 861:105–116.
[6] Milligan ED and Watkins LR (2009) Pathological and protective roles of glia in chronic pain. Nat Rev Neurosci 10:23–36.
[7] Watkins LR, Hutchinson MR, Milligan ED, and Maier SF (2007b) “Listening” and“talking” to neurons: implications of immune activation for pain control and increasing the efficacy of opioids. Brain Res Rev 56:148–169.
[8] Hegstrom R., Kondeuti K.: The Handedness of the Universe. Scientific American January 1990
[9] Eriksson T. et al.: Clinical Pharmacoloogy of Thalidomide. Eur J. Clin Pharmacology. 2001 Aug;57(5):365-76 PMID 11599564
[10] Jacques V et al.: Differentiation of antiinflammatory and antitumorigenic properties of stabilized enantiomers of thalidomide analogs. Proc Natl Acad Sci 2015 Mar PMID 25775521
[11] Moryl N. et al.: A phase I study of D-Methadone in patient with chronic pain. J. opioid management 2016 Jan 12(1) 47-55 PMID 26908303
[12] Shibinga NE, Goldstein A.: Opioid peptides and opioid receptors in cells of the immune system. Annu rev Immunol 1988. 6:219-249.
[13] Guo-xi Xie, Goldstein Avram et al.: Chimeric opioid peptides: Tools for identifying opioid receptors types. Proc Natl. Acad Sci. Apr 1990. Vol 87 pp 3180-3184