Neuroscience of Opioid Abuse:

An overview of the neurological, biochemical and immunological effects of chronic opioid

abuse

By Cate LoCaste

Introduction

I chose to do my presentation on substance abuse because I didn't know as much about it as I do with other psychological diseases, and I learned in Psychopharmacology that there aren't really any effective methods of treatment for substance abuse. I hadn't been aware of that before, so I wanted to understand more about substance abuse and what makes it so difficult to treat. I also thought this topic would be good way to incorporate a lot of what I've learned in my graduate school courses.

Additionally, this topic interests me because I would like to work in a behavioral neuroscience lab eventually.

Courses I completed in my Master's program that influenced this project: Psychopharmacology, Principles of Neuroscience, Intro to Immunology, Physiology, Neuroscience of Learning, and Biochemistry.

Substance-Related Disorders

Substance-related disorders include abuse, dependence, intoxication and withdrawal. Dependence is a pattern of substance use that leads to significant impairment or

distress. It includes tolerance, abuse, withdrawal, overdosing on the substance, persistent use even with the knowledge of its harmful effects and expending a large amount of energy in order to obtain or continue the use of the substance

Abuse is demonstrated by a pattern of substance use that leads to problems at home, work or school, hazardous behavior, legal problems and continued use despite all of the problems it is causing

Intoxication is an acutely altered mental state caused by exposure to the drug. Withdrawal is characterized by significant impairment in functioning or impairment

in other important areas that is caused by cessation or reduction in use of the substance

Neuroscience of Substance Abuse

The structures of the brain involved in substance abuse are the ventral tegmental area (VTA), nucleus accumbens (NA), hippocampus, striatum, amygdala and the prefrontal cortex.

Dopamine is theorized to be the major neurotransmitter involved in substance abuse. The neurobiogical substrate of all addictive drugs is believed to involve the dopamine system of the nucleus accumbens in some way.

The mesolimbic dopamine system originates in the VTA and projects out to include the NA and prefrontal cortex, so it makes sense that these structures are involved in addiction.

Dopamine is synthesized from tyrosine in neurons.

Pathways and Structures Associated with Addiction

Neuroscience of Substance Abuse

Reinforcement plays a crucial role in substance abuse. Reinforcement is a consequence that strengthens the likelihood of a particular behavior occuring when preceded by a particular stimulus.

The degree of reinforcement depends on how quickly it takes for a drug to produce its effects. Drugs that produce an immediate high are more likely to be addictive.

Both negative and positive reinforcement are important for acquiring a drug addiction.

The pleasurable feelings achieved by taking a drug of abuse are positive reinforcers that motivate the person to repeat the drug taking behavior.

As stated previously, dopamine is associated with these feelings.

Negative reinforcers strengthen behaviors that stop aversive stimuli. The withdrawal symptoms caused by the cessation of drug-taking go away when the drug is taken again, thus making withdrawal a negative reinforcer, as withdrawal motivates the person to repeat the drug taking behavior.

The Opponent-Process Theory

The opponent-process theory is also considered to play a part in acquiring drug addiction.

It is a theory of motivation and emotion that considers opposite emotions as paired. When an emotion is elicited by a stimulus, it will then be suppressed by the opposite emotion, or opponent-process, in an attempt to return to homeostasis.

In the case of addiction, the high elicited by the drug is suppressed by the feelings of withdrawal and anxiety. With time, the opponent process of these aversive emotional states will grow to overshadow the high. Its growth will motivate the person to increase their amount of drug-taking behavior in order to achieve the same high as the first time they ever took the drug.

This then spirals into addiction and dependence as the opponent process grows to have serious negative physiological and psychological effects and more and more drug is needed to achieve a high.

Endogenous Opioids vs. Exogenous Opioids

Endogenous opioids are the endogenous neuropeptides that bind to opioid receptors. They are found widely in the brain.

They consist of enkephalins, endorphins dynorphins, endomorphins and nociceptin

Endogenous opioids are produced during stressful events. They function to mediate stress responses, including endocrine, ANS and behavioral responses.

Endogenous opioids have analgesic action in which they act to ameliorate the emotional component of pain without effecting the sensation of pain itself, further contributing to their impact on stress.

Opioids are a class of drugs that bind to opioid receptors. They include all drugs that produce morphine-like effects.

Opioids act to block pain perception and induce sleepiness. However, when abused, they can also induce euphoria, cause respiratory depression, become addictive, cause dependence and withdrawal.

Opioid drugs are considered to have a high abuse potential due to the powerful effects they can have on pain and pleasure sensations.

Morphine, heroin, hydrocodone, codeine and methadone are some of the most well-known opioid drugs.

Endogenous Peptide Precursors

Endogenous opioids are synthesized in the soma of neurons from propeptide or pre-propeptide precursors.

The protein precursors are then packaged into vesicles where they will be further broken down into short strands of amino acids.

The vesicles travel down the axon to be released. There is typically no re-uptake of neuropeptide transmitters as they are usually completely degraded.

Opioid Receptors

There are three major types of opioid receptors in the brain: mu, delta and kappa Mu receptors bind the enkephalins and beta-endorphins. They are mostly found in

the periacqueductal gray and the dorsal horn of the spinal cord. They are sensitive to morphine and other alkaloid substances. Mu receptors are responsible for the euphoric effects elicited by opioids. They are also mostly responsible for the analgesia induced by opioids.

Delta receptors bind the enkephalins. They are mostly found in the basal ganglia of humans, however, their location varies between species.

Kappa receptors bind the dynorphins. They have great analgesic potential, however, their side effects are unpleasant. Kappa receptors are responsible for the dysphoric feelings, hallucinations and nausea caused by opioids. They are being investigated as a mechanism of addiction control. Kappa receptors are mostly expressed in the claustrum.

Mechanism by which Opioids become Drugs of Abuse

Animals will bar-press to have morphine injected into their VTA or their nucleus accumbens, and this effect is blocked if naltrexone is also injected into these regions, indicating that there are opioid receptors concentrated in the VTA and nucleus accumbens that are contributing to the positive reinforcement caused by opioids.

Opioid binding in these regions sends a signal for more dopamine to be released, and the augmented dopamine-dependent neurotransmission further activates the reward pathways, resulting in euphoria. This rush takes about a minute to begin and lasts up to a few minutes. As mentioned before, a fast onset of action increases the likelihood of abuse.

Exogenous opioids binding to opioid receptors results in overall inhibition of the CNS, in addition to analgesia from both physical and emotional pains. These effects can last for hours after the initial high ends.

In addition to agonizing opioid receptors, opioids activate Toll-like receptor 4 (TLR4). TLR4 and its MyD88-dependent signaling pathway appear to contribute to drug reinforcement.

Mechanism by which Opioids become Drugs of Abuse

TLR4 is an innate immune pattern-recognition receptor. A study in which TLR4/MD2 was blocked by naloxone in rats resulted in suppression of opioid-induced conditioned place preference. Also, mice with MyD88-TLR4-dependent signaling knocked out yielded the same suppression.

The naloxone rats showed reduced self-administration of opioid. Importantly, naloxone rats had significantly decreased morphine-induced increases in dopamine concentration in the nucleus accumbens, a major region for drug reinforcement. This data indicates that opioid action at TLR4/MD2 affects the mesolimbic dopamine system in addition to the opioid action at opioid receptors, which helps provide more information on how opioids act to change reward behaviors.

These are just some examples of the mechanisms by which opioids act to increase drug reinforcement, thus increasing their abuse potential. There are many other mechanisms, including ones that are dopamine-independent.

Mechanism by which Opioids become Drugs of Abuse

Allodynia (increased pain sensitivity) occurs for several days after the first exposure to heroin. This hyperalgesia is progressive, and it is a withdrawal symptom that is associated with tolerance to the drug.

Tolerance and the worsening withdrawal symptoms, including increases in pain, anxiety, dysphoria and irritability result in the need to continuously increase drug-taking activity to overcome the combined effects of tolerance and withdrawal and obtain a high.

Upon cessation, relapse is difficult to avoid. One reason for this is that the cues associated with drug-taking increase with time and become inescapable. Another reason is that the severity of the withdrawal symptoms has increased with drug-taking activity, making it extremely difficult for a person to hold out until the symptoms pass. Lastly, the body grows dependent on the exogenous opioid with chronic, long-term abuse, so it needs it in order to continue to function. Because of this, complete cessation of the drug can result in death.

24-Hour Response to Heroin

Short Term Physiological Effects of Exogenous Opioid Abuse

Exogenous opioids acts on mu receptors to reduce the brain's responsiveness to changes in carbon dioxide concentrations and hypoxia, which is a deficiency in the amount of oxygen getting to all body tissues. When too much opioid is taken, like in an overdose, this action results in respiratory depression, which can lead to death if not quickly treated.

Their ability to inhibit the CNS also results in hypotension (abnormally low blood pressure), slowed heart rate due to inhibition of baroreceptor reflexes and vasodilation of cutaneous blood vessels, which causes flushing.

Additionally, they cause release of histamine that results in itching. Opioids act on the enteric nervous system, which is contained by the GI tract. The

constipation and diarrhea associated with opioids appear to be caused by direct effects on ENS function, through the inhibition of enteric neuronal activity in both the small intestine and the colon. This inhibition prevents peristaltic smooth muscle contraction, which further inhibits movement of water and electrolytes, causing constipation.

Long Term Effects of Opioid Abuse on the Brain

A study using brain proton magnetic resonance imaging compared long term opioid abusers to normal people. Their findings showed that long term abuse of opioids produces significant changes in neural viability and concentrations of metabolites in the anterior cingulate gyrus, dorsolateral prefrontal cortex and orbitofrontal cortex.

Specifically, the concentrations of N-acetylaspartate, glutamate, choline-containing metabolites, creatine and phosphocreatine are much lower in the opioid abusers.

N-acetylaspartate is a marker of neuronal integrity, and it is believed to be involved in brain fluid balance and providing acetate for myelin synthesis.

Glutamate is an excitatory neurotransmitter. A significant lack of glutamate correlated with greater abuse and worse prognosis.

The decrease in choline-containing metabolites is associated with poorer working memory, along with worse global cognition and visuospatial functioning.

The lack of creatine and phosphocreatine was related to higher impulsivity.

Exogenous Opioids and Immunosuppression

Chronic opioid administration has an inhibitory effect on both humoral and cellular immune responses through inhibition of cytokine and phagocytic activity, as well as suppression of natural killer cells in innate immunity.

In cellular immunity, there are helper T cells, cytotoxic T cells and regulatory T cells. TC cells recognize antigen, and kill pathogenic cells or mutated cells. TH cells help orchestrate many different immune responses depending on what is needed. TReg cells suppress the actions of other T cells to reign in the immune response or prevent T cells from acting on something they shouldn't.

Humoral immunity is derived from B cell responses. B cells develop into plasma cells that produce antibodies against anitgens. B cells can also bind and present antigens to T cells.

NK cells are a part of innate immunity. Innate immunity does not require prior exposure to antigen to be activated, meaning that it can act immediately on invaders. NK cells are considered to important for tumor surveillance. They kill cells that lack strong inhibitory signals.

Exogenous Opioids and Immunosuppression

There are opioid receptors outside of the CNS that opioids can bind to and generate analgesia during states of inflammation.

There is evidence that immune cells can express opioid receptors, and that this mechanism allows opioids to modulate immune responses. This is one way that endogenous opioids can work to augment the immune response. Exogenous opioids have an opposite, inhibitory effect. This is important because it was originally believed that heroin addicts were at increased risk of infection because of dirty needles or impure heroin..

Cytokines are the principle mediators of immune responses, and opioids share many characteristics with them. Like cytokines, opioids can function to produce immune cells, carry signals and communicate with other cells and work to alter production and function of all immunocytes. Their ability to modulate chemokines, a class of cytokines that recruits white blood cells to sites of infection, has been recently shown to facilitate encephalopathy, which is an AIDS-defining condition and is associated with infection of HIV.

Immunological Effects of Opioids

Opioid Abuse and Cell-Mediated Immunity

Mitogen-induced proliferation of T cells is suppressed by systemic injection of morphine. Because injection of morphine into the anterior hypothalamus decreases lymphocyte proliferation by 50% but does not induce analgesia, it is suspected that there is a supraspinal mechanism for mediating immunosuppression that is separate from adrenal activation and analgesia. When N-methylmorphine, which can't cross the BBB, is introduced systemically, the reduction in lymphocyte production is not seen, further supporting the belief that it is due to central supraspinal receptors.

IL-2, a signaling cytokine that promotes differentiation of T cells into effector T cells, regulatory T cells and memory T cells, is also inhibited by morphine. This contributes to the overall decrease in T cell activity.

During withdrawal, morphine exposure enhances infection of T cells and peripheral blood lymphocytes by HIV.

Morphine also appears to have the ability to influence T cell development by preventing them from reaching the DP stage through a yet unknown mechanism.

Exogenous Opioids and Humoral Immunity

Agonism of kappa opioid receptors results in pronounced suppression of humoral immunity. However, μ opioid receptors appear to still be involved at a lesser extent as this effect decreases when mu receptors are antagonized in addition to the kappa receptors.

The mechanism for humoral immunity suppression is less well-understood. It is believed that glucocorticoids are involved, and that the mechanism is indirect.

Exogenous opioid injection also appears to increase apoptosis of macrophages and B cells. This result is associated with an increase in transcription of cathepsin-B, which is an enzyme that promotes cell death. This effect is inhibited by naloxone, indicating that the receptors involved are the μ and κ of the CNS.

An experiment in which B cells from mice that had been abruptly taken off of morphine were added to normal cells resulted in immunosuppression and inhibition of proliferation of immune cells in response to antigens. This suggests that B cells mediate the severe immunosuppression following cessation of morphine.

Exogenous Opioids and NK cells

Binding of opioid receptors by morphine in the CNS suppresses NK cell activity. This was shown in an experiment in which morphine was administered to rats which resulted in a significant decrease in cytolytic activity by NK cells. This effect went away if the rats were also treated with naltrexone, a competitive antagonist of morphine.

Another experiment provided evidence that the suppression of NK cells required the activation of D1 dopamine receptors in the nucleus accumbens, and that antagonizing the NPY Y1 receptor prevents conditioned suppression of NK cells. The NPY Y1 receptor is the receptor for a sympathetic transmitter called neuropeptide Y. The SNS was mentioned in a previous slide as playing a role in morphine induced modulation of the immune response. NPY has been shown to inhibit both splenic and central NK cell activity. Under physiological conditions, there is evidence that NPY alone modulates NK cell activity on a dose-dependent basis. The mechanism is not yet understood, but it seems like NPY uses a distinct mechanism to modulate NK cell activity than the catecholamines also released by the SNS.

Treatment Medications

Opioid abuse is treated with medications like naloxone, naltrexone, methadone, buprenorphine, benzodiazepines, clonidine and LAAM depending on the stage of use.

Naloxone works as an antagonist with the greatest affinity for mu receptors in the CNS, competing with the opioid for binding. It prevents the effects of opioids including respiratory depression, sedation and hypotension. It can also reverse the dysphoric effects. Intravenous injection gives an onset of action of about two minutes.

Naltrexone is a competitive antagonist at mu, kappa, and delta receptors in the CNS. It competitively binds to them and blocks the effects of opioids, including respiratory depression, miosis, euphoria, and drug craving. The major metabolite of naltrexone, 6-β-naltrexol, is also an antagonist and is believed to contribute to the antagonistic activity of the drug.

Medication Descriptions

Treatment Medications cont.

Benzodiazepines are GABA agonists used to treat anxiety. Methadone is a synthetic opiate that acts slowly and has a long half-life, preventing it

from producing a euphoric state while also suppressing withdrawal and reducing craving for other opioids, like heroin.

Buprenorphine is a partial opioid receptor agonist. This property is why it produces less of a high, has less physical dependence and a more mild withdrawal. It is used to suppress withdrawal, block the action of other opioids and decrease cravings for other opioid drugs.

LAAM is a synthetic opioid. It works similarly to methadone as it has a long duration of action. It is considered a last resort for patients who don't respond to methadone or buprenorphine as it has life-threatening side-effects.

Clonidine slows heart beat and lowers blood pressure, relieving some of the withdrawal symptoms associated with opioids.

How Treatment Works

Treatment varies depending on the stage of use. The stages are acute intoxication, overdose, withdrawal and abstinence maintenance.

Acute intoxication is treated with naloxone to block the effects of the opioid taken by competitively binding to opioid receptors. Respiratory support is given if needed as respiratory depression is usually the cause of death in opioid misuse.

Overdose is also treated with intranasal or intravenous naloxone as it has a short onset of action, so it can quickly begin blocking the opioid effects. There are at-home naloxone treatment kits available as treatment is often not sought for overdoses.

Withdrawal is treated with methadone, buprenorphine, clonidine and benzodiazepines. Methadone and buprenorphine help to reduce cravings while clonidine and the benzodiazepines ease the withdrawal symptoms of anxiety, fast heart rate, restlessness and insomnia.

Treatment cont.

Abstinence maintenance is treated with methadone, LAAM, buprenorphine or naltrexone. The major goal is to prevent relapse.

The use of methadone or buprenorphine will help to ease withdrawal and cravings as it is a full opioid receptor agonist. Treatment with methadone may last a few months to a lifetime. The affinity of opioid receptors for buprenorphine is much greater than their affinity for other opioids, so buprenorphine will also act to block the effects of other opioids if they are taken. Additionally, its partial agonist qualities cause its effects to plateau at a certain dosage, giving it a much lower risk of abuse or addiction.

Naltrexone will block the effect of the drug if it is used, so addiction won't be reinstated automatically.

LAAM is a last resort for patients who do not respond to buprenorphine, naltrexone or methadone. It does not require daily doses like methadone and is normally given 2-3 times a week. It causes ventricular rhythm disorders.

Treatment of Opioid Abuse with Acupuncture

Acupuncture is being increasingly used in treatment of addiction as it is believed that is has the potential to aid in relief of the psychological symptoms associated with dependence and addiction. However, there is no agreement in the literature on its efficacy, and much of the research regarding it has not been conducted uniformly enough for the results to be valid.

Acupuncture has been determined to have use returning biochemical balance in the central nervous system and recovery of homeostasis.

There is some evidence to suggest that electroacupuncture is beneficial as an adjunctive treatment in alleviating withdrawal symptoms in heroin addicts.

In a study comparing patients treated with just methadone to patients treated with methadone and acupuncture, no significant differences were found in coping mechanisms adopted during treatment.

In another study, acupuncture in addition to methadone treatment was shown to improve sleep latency.

Overdose Deaths from Prescription Opioids

Summary and Conclusion

Chronic abuse of exogenous opioids has long-term consequences for the neuronal and hormonal systems that are not completely resolved after cessation. There is evidence of destruction of white matter in the brain believed to be caused by opioid abuse, which would cause problems for decision-making, impulse-control and planning. The physical dependence created by opioids produces withdrawal symptoms upon cessation that may result in death. The treatment options for addiction to opioids are not ideal, and relapse is highly likely without further support.

Abuse of opioid pain medications as well as abuse of heroin is increasing. The number of young people using heroin in the United States has doubled since 2008. This is thought to be due to prescription opioids becoming harder to obtain.

It is important to study the effects of chronic opioid abuse for many reasons. One is that gaining knowledge about the mechanisms by which exogenous opioids work may help to improve treatment options. Additionally, it allows us to be able to provide the population with better information on the long term effects of opioid abuse and hopefully prevent them from engaging in drug-taking activities.

References

Opiate tolerance to daily heroin administration: an apparent phenomenon associated with enhanced pain sensitivity. JP Laulin et al.

Opioid therapy and immunosuppression: a review. Vallejo J et al.

Role of endogenous opioid system in the regulation of the stress response. Guy Dolet et al.

Intensive Care Unit-acquired Infection as a Side Effect of Sedation. Saad Nseir et al.

A Possible Mechanism Underlying the Effectiveness of Acupuncture in the Treatment of Drug Addiction. Chae Ha Yang et al.

Hedonic Homeostatic Dysregulation as a Driver of Drug-Seeking Behavior. George F Koob.

National Institute on Drug Abuse (NIH)

Opioid Abuse Treatment & Management. Adrien Preda et al.

The National Alliance of Advocates for Buprenorphine Treatment

Www.drugbank.ca for buprenorphine, morphine, heroin, naloxone, clonidine and naltrexone

A Possible Mechanism Underlying the Effectiveness of Acupuncture in the Treatment of Drug Addiction. Chae Ha Yang et al.

References

Efficacy of Acupuncture for Psychological Symptoms Associated with Opioid Addiction: A Systematic Review and Meta-Analysis. Zhang Boyuan et al.

Clinical Efficacy of Acupuncture as an Adjunct to Methadone Treatment Services for Heroin Addicts: A Randomized Controlled Trial. Yuan-Yu Chan et al.

Immunotherapeutics. Peter J. Delves.

Neuropeptide Y Y1 receptors mediate morphine-induced reductions of natural killer cell activity. Timothy B. Sauren.

Opioids, opioid receptors, and the immune response. Lois McCarthy et al.

Morphine suppresses primary humoral immune responses by a predominantly indirect mechanism. SB Pruett et al.

Effect of Opiates, Anesthetic Techniques, and Other Perioperative Factors on Surgical Cancer Patients. Alan David Kaye et al.

Splenic macrophages and B cells mediate immunosuppression following abrupt withdrawal from morphine. RT Rahim et al.

References

Frontal Metabolite Concentration Deficits in Opiate Dependence Relate to Substance Use, Cognition, and Self-Regulation. DE Murray et al.

Opioid activation of Toll-Like receptor 4 contributes to drug reinforcement. MR Hutchinson et al.

Overlapping Mechanisms of Stress-Induced Relapse to Opioid Use Disorder and Chronic Pain: Clinical Implications. Udi E. Ghitza

Methadone Maintenance Treatment Versus Methadone Maintenance Treatment Plus Auricular Acupuncture: Impacts on Patient Satisfaction and Coping Mechanism. Pei Lin Lua et al.

Morphine Suppresses Primary Humoral Immune Responses by aPredominantly Indirect Mechanism. SB Pruett et al.

Opioidergic effects on enteric and sensory nerves in the lower GI tract: basic mechanisms and clinical implications. Patrick A Hughes et al.

Current State of Opioid Therapy and Abuse. Laxmaiah Manchikanti et al.