By R Carter
One of the results of the opiate crisis has been increased NIH funding of research into addiction and the search for pain relief mechanisms which are non-addictive. I’ve read articles that have advocated Frontal Lobotomy for chronic pain relief, the use of Tetrodotoxin, a toxin from the Blue-ringed octopus which is lethal, being 45 times more potent that cyanide, Ketamine infusions which actually look to have some promise, as well as dozens of other ideas, each having a noteworthy avenue for research even if they represent a long shot at best.
I put more of my faith for research in genetics, epigenetics and the biomolecular pathways between our blueprint for life and its effects on our brain and behavior. Somewhere in the 20,000 plus proteins produced by our genetic blueprint and their impact on our neurons and neural pathways, is an answer for how we can harness those systems we are born with, to attenuate the negative effects of addiction which is what those suffering from opiate hysteria desperately want.
The science here gets deep very fast, so in this article I’m skipping over as much of that science using the KISS principle as best I can. I don’t propose to understand all of it myself, but having a medical background, there’s a general understanding I can use to dumb it down for myself and others.
|The Science Simplified|
Delta FosB, represented by “∆FosB”, is an acronym for a specific gene in the family of genes known as FOS, occurring on the 19th chromosome in the human genome. Proteins created by ∆FosB react with proteins created by another gene segment from the JUN family of genes, i.e. c-Jun and JunD forming what is known as a Transcription factor (TF). The TF is part of our epigenetic system, (epi) meaning, above, so epigenetics is a layer of protein synthesization which occurs not on the genes but just above them, using proteins created by other genes.
The function of TFs is to regulate—turn on and off—genes in order to make sure that they are expressed in the right cell at the right time and in the right amount throughout the life of the cell and the organism. One of the amazing things about our genetic makeup is that these epigenetic processes occur in multiple locations across our genome, making our genome highly redundant to failure. But this built in failsafe mechanism is also a problem when it comes to targeting specific proteins involved with disease processes and errors in metabolism. Turning something on or off in one location sometimes has little or no effect as an epigenetic process on another gene segment simply activates and nullifies the changes made in the target location.
For this reason researcher often look for a single protein in a chain of protein creation events which can interrupt a disease process and in doing so, effect a change beneficial for the body. ∆FosB is one of those proteins, having the potential of derailing the behavioral effects of addiction.
|Reward Circuitry of the Brain|
The Nucleus Accumbens (NAc) pronounced, new-clee-us a-cum-bens, is an area of the brain signified in Figure 1 by the red dot and occurs in both hemispheres of the brain. It’s the center of the reward system but that reward system occupies a larger structure known as the Ventral Striatum as shown as the pink area in Figure 2.
Connections from the NAc and up through the Ventral Striatum, connect the reward system to the rest of the brain. Connections number in the billions, affecting every aspect of human perception as seen in the tractography image in Figure 3.
The Ventral Striatum plays a central regulatory role in reward behaviors, the numerous connection throughout the rest of the brain indicate how powerful that reward system is, having a major impact on all functions of human perception including smell, sight, sound, touch, taste, along with higher functions such as memory, planning, anticipation and motivation.
As the reward system is repeatedly activated by any number of experiences, ΔFosB accumulates in cells of the Ventral Striatum and act as behavioral modifiers, a sort of long term memory which enhances anticipation of repeating the experiences. ΔFosB can accumulate to significant levels in as little as ten days which many believe is the link between the psychic addictions seen in addictive behavior. ΔFosB doesn’t just accumulate from drug addiction, but also accumulates following many behaviors postulating a link between those pleasurable processes and addiction, these are known as process addictions. Some are known such as over eating, gambling, risk taking and sex. In fact the initial identification of ΔFosB in this area of the brain was found during animal studies of sexual behavior. Subsequent studies have made reliable links to the accumulation of ΔFosB between drug addiction and what are otherwise normal behaviors such as sex.
|The Role of ΔFosB|
ΔFosB has been identified as playing a central, crucial (necessary and sufficient) role in the development and maintenance of addiction. ΔFosB overexpression (i.e., an abnormally and excessively high level of ΔFosB) triggers the development of addiction-related neuroplasticity throughout the reward system and produces behavioral characteristics of an addiction. The ΔFosB variant differs from the full length FosB and other proteins produced by FOS genes, in its capacity to produce these effects and appears to be the single most significant link between addictive behavior and epigenetic changes which occur in neurons of the brain. For this reason it has been labeled as the switch that turns addictive behavior on and off.
The process which produces ΔFosB starts in the synaptic cleft of neurons where either a normal process or a chemical substance floods the synaptic cleft with dopamine repeatedly over a period of time as short as ten days. In the postsynaptic neuron multiple chemical pathways lead to increased levels of CREB (cAMP response element-binding protein) a transcription protein which turns on epigenetic processes which produce ΔFosB, see Figure 4 below.
ΔFosB is an important mediator of the long-term brain plasticity aka epigenetics, induced by chronic exposure to several types of psychoactive stimuli, including drugs of abuse, stress, and electroconvulsive seizures. A distinct feature of ΔFosB is that once induced, it persists in brain for relatively long periods of time in the absence of further stimulation. The half-life of ΔFosB is unknown. Studies done to date indicate that ΔFosB lasts for up to two months once the stimulus which caused it’s production have been withdrawn. This would explain the cravings experienced by addicts, which last up to six months following absence of the stimulus of choice. Because of the area where ΔFosB accumulates, in the reward circuitry of the brain with neuronal connection throughout the rest of the brain, addicted individuals report triggering effects from a number of different stimuli. These include tastes, sights, sounds, touch, or specific processes related to what’s been called the rituals of addiction, those activities which precede the act which floods the brain and reward system with dopamine.
Repeated stress has also been identified as a factor which causes the accumulation of ΔFosB in the brain, albeit not from dopamine but from Glucocorticoids produced while under stress. It’s postulated then that long term stress primes the brain, making it more susceptible to addiction. When the individual chooses to alleviate that stress with a pleasurable process or chemical substance, the brain is already primed for the addictive biomolecular processes which lead to addiction. Making the individual more susceptible to repeating that same process again and again. This may explain the rapid and high addiction rates seen in certain high stress professions.
One of the promising outcomes of research in this area is the identification of drugs or treatments that oppose the action or reduce the expression of ΔFosB.
Current medical reviews of research involving lab animals have identified a drug class – class I histone deacetylase inhibitors (HDAC) and G9a – that indirectly inhibits the function and further increases in NAc ΔFosB. These reviews and the subsequent preliminary evidence which used oral administration or abdominal administration of the sodium salt of butyric acid or other class I HDAC inhibitors for an extended period, indicate that these drugs have efficacy in reducing addictive behavior in lab animals that have developed addictions to ethanol, psychostimulants (i.e., amphetamine and cocaine), nicotine, and opiates; however, as of August 2015, few clinical trials involving human addicts and any HDAC class I inhibitors have been conducted to test for treatment efficacy in humans or identify an optimal dosing regimen.
|What the Future May Hold|
Epigenetic research is a new field in genetic research which has come about in the last 10-15 years. More graduates planning careers in genetics are choosing fields related to epigenetics than traditional genetic professions.
The promise of epigenetics are the discoveries of biomolecular processes which turn on or turn off parts of the human genome which have traditionally been considered as inactive or dormant, this represent as much as 70% of the human genome. Technologies such as CRISPR, a gene splicing technology, hold out the promise that gene modification may lead to discoveries about epigenetic processes which have remained hidden up until now. These epigenetic processes are what gives the human brain its ability to adapt to environmental elements (neuroplasticity), so much so that links have already been established which show that through epigenetic proteins, hereditary traits have been passed onto offspring while in utero, leading to the discovery of how resistance to some types of diseases and environmental stresses such as famine, are handed down from one generation to the next.
The ability to pass these epigenetic proteins across the placental barrier, essentially turning on epigenetic processes in a developing fetus, has been theorized as a contributing factor to the inheritance of addictive behaviors, causes for obesity and depression as well as resistance to some types of diseases.
The ability to identify key proteins such as ΔFosB and their down regulators HDAC and G9a, hold the promise that proteins can be identified through epigenetic research which will turned on or attenuate the effects of ΔFosB; speeding up the process whereby addiction treatments can reverse the damage caused to the nervous systems of those addicted to processes or substances.
They may even lead to methods of stimulating the production of naturally occurring Endorphins which can moderate pain naturally without the effects of addiction.
Delta FosB is a protein created by the FOS genes on chromosome 19 of the human genome. Delta FosB has been identified as the single most important link in addictive behaviors and has thus been labeled the switch that turns addictive behavior on and off. What’s important for chronic pain patients taking opiates to understand, is that this protein is created regardless of any other psychosocial factors. Understanding its role holds the promise of pain relief without the reinforcing behaviors of addiction.