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Stress, pain and addiction affect the HPA, HPG, and HPT axis: part 1.

With the fast-moving life of today, one tends to find oneself always trying to cope with constant stressors. The fast evolution and constant change that characterizes this era of rapid technology has altered the fabric of our society. Everything and everyone has evolved abruptly, especially over the past 10 years or so. This hasty shift in technology, work conditions, family makeup, and expectations can easily create very steep imbalances, predisposing individuals to fall into what we call stress. Stress may be triggered by the slightest event, including family, friends, and peer pressure. Our society is inflamed; hence stress and pain are becoming fuel for the addiction epidemics.

The debilitating stress effects of pain have also significantly contributed to an indoctrinatory overprescription pattern of painkillers. In particular,. opioid prescription and abuse have increased in the last decades. Prescription of opioids for management of noncancer chronic pain is increasing over the years, providing the main source of opioid access. The long-term effects of opioids use on the metabolism, particularly the endocrine system, is one of the prime foci of recent research studies. Opioids act on the hypothalamic-pituitary-adrenal (HPA) axis; increased levels of prolactin and GH; and decreased oxytocin, testosterone, LH, and estradiol in humans. However, the effects of opioids on arginine vasopressin and ACTH are conflicting.

Stress, Reward System, and Dopaminergic Pathway

Stress can be defined as any stimulus that alters physiological and psychological homeostasis or equilibrium. The nature and effects of stress may vary that stimulate or suppress several molecular and/ or cellular signalling molecules. The stress response generally varies from one person to another due to distinctive coping styles. (1), (2) Acute and chronic stress may lead to physiological and psychological disorders, including predisposition to addiction. (3)

Humans respond to stress via the HPA axis, activation of corticotrophin-releasing factor outside the hypothalamus and activation of sympathetic nervous system via adrenaline or noradrenaline. (4-6)

Alcohol and stress can induce the hypothalamus to release corticotrophin-releasing hormone (CRH) that facilitates release of 3-endorphin. CRH is then transported to the anterior pituitary gland that synthesizes proopiomelanocortin (POMC), a key factor for stress hormones including ACTH and betalipotropin. ACTH is a potent stimulator of cortisol release. Other stress I nducers, including noradrenaline, serotonin, and GABA, regulate CRH release. Similar pathophysiological changes are observed in addicted individuals. (7-10) In stress conditions, sympathetic nerves contribute to adrenaline and noradrenaline release from the adrenal gland and cause stress. (11), (12)

Increased CRF production outside the hypothalamus stimulates the mesocorticolimbic dopaminergic system, which is dopamine dependent. This system includes nucleus accumbens, amygdala, hippocampus, and ventral tegmental area (VTA). In addictive individuals, the brain's reward pathway is primarily mediated by the mesocorticolimbic dopamine system. Apart from addiction, the limbic system and hypothalamus are involved in the stress response and stimulation of CRF activity. (13-15)

Dopamine Levels in Acute Stress and Chronic Stress

Preclinical and human clinical studies have demonstrated the influence of stress on dopamine synthesis or mesocorticolimbic dopaminergic activity. Radiological studies have demonstrated that amphetamine, alcohol, and other addictive drugs have triggered dopamine release. (16-18) The pathophysiological relationship between stress hormones, drug addiction, and mesocorticolimbic dopamine activity is well documented.

Pruessner and colleagues have confirmed that stress during early stages of life could promote dopamine release in the ventral striatum that causes psychosocial stress and addiction. (19) The study results were confirmed by Oswald et al., suggesting the links between stress-associated cortisol release, dopamine levels, and amphetamine. (20) Psychological studies have confirmed that cortisol is a key contributor for dopamine release in stressed individuals. (21) However, the levels of cortisol and dopamine vary in acute and chronic stress conditions.

In adrenalectomized experimental animals, the body's stress response via the HPA axis contributes to glucocorticoids and dopamine suppression in the nucleus accumbens. (22), (23) When the adrenal glucocorticoids were replaced with corticosterone injections, normal dopamine levels were restored. These studies have suggested the role of adrenals on dopamine release; acute stress could moderately affect the adrenals, and contributes to moderate dopamine increase. However, in chronic stress, it could be vice versa.

In acute stress, the expression and activity of dopamine is comparatively less than in chronically stressed individuals. The negative effects in the former are generally reversible and moderate. However, in chronically stressed individuals, the altered dopamine levels lead to hormonal, psychological, and behavioral dysregulation that increases the predisposition to addiction.

Dopamine Receptor Levels in Acute and Chronic Stress

The effects of dopamine on stress conditions depend on the expression of dopaminergic receptors. Humans exhibit genetic variability in the expression of dopaminergic receptors such as D2 and/or D3 receptors, dopamine turnover in response to stress-related stimuli.

Experimental studies have suggested that the effects of acute or chronic stress on the mesolimbic system and behavioral patterns are influenced by epigenetic patterns. Acute stressors induce 3,4-dihydroxy phenylacetic accumulation in the brain with significant reduction in dopamine levels. (24)

In experimental animals, repeated or prolonged stress could lead to hyposensitivity of D2 presynaptic receptors. Continuous exposure to restraint stress leads to decrease in D2 receptor density with normal levels of Dl receptor density in the nucleus accumbens. The direct relationship between the dopamine receptors and stress conditions is also confirmed by electric foot-shock tests. In experimental animals, activation of D1 and D2 receptors are vital for attenuation of fear, motor suppression, and so on.

Prenatal stress could alter the response to stress and expression of dopamine agonist/antagonist receptors. In prenatal stressed experimental animals, a significant increase in D2 receptor binding in the nucleus accumbens was observed. Significant decreases in D3 receptor binding in the core nucleus accumbens and shell were also observed. (25) In some individuals, chronic stress could decrease the density of D2 receptors but not the affinity.

Dopamine Uptake in Acute and Chronic Stress

Several research studies have suggested that removal of dopamine in chronic stressed animals is an adaptive mechanism of mesoprefrontal cortex. Increased D1 receptor stimulation during stress allows the posterior cortical and subcortical structures to regulate behaviors. Stress could alter the mesoprefrontal dopamine fibers and affect biochemical responsiveness of the dopamine subcortical innervations.

In experimental animals, repeated stress reduced basal locomotor activity and utilization of dopamine in the brain. The effects could be reversed by acute administration of D1 or D2 receptor antagonists.

In prolonged, mild stress conditions, dopamine uptake levels are affected, leading to altered behaviors. (26-28)

Moderate uptake of dopamine is important for normal behaviors, and excessive dopamine activity or impaired uptake leads to altered spatial working memory functions. This condition is common in acutely and chronically stressed individuals. However, the uptake of dopamine differs in both stress conditions.

Dopamine Metabolism in Acute and Chronic Stress

Repeated or prolonged stress has negligible effects on dopamine and serotonin metabolism. This may be due to adaptive mechanisms of the higher centers via the stress response mechanisms. However, acute stress conditions could decrease the hypothalamic epinephrine levels and return to normal within few hours.

Dopamine metabolism is affected due to hypothalamic adrenaline concentration and turnover in response to acute and chronic stress. Impaired adrenaline and noradrenalin turnover affects dopamine metabolism and causes behavioral changes, including predisposition to addiction. (29), (30)

As with stressed individuals, decreased dopaminergic functions are reported in cocaine addicts. This could be due to reduced D2 receptor availability or expression, or impaired dopamine metabolism in cingulate gyri, frontal lobes, and orbitofrontal cortex.

Dopamine dysmetabolism could lead to loss of control with compulsive reinforcement that predispose to addictive behaviors. (31)

Dopamine Factors and Predisposition to Addiction

Significant neurobiological links between stress, dopamine factors, reward pathways, and risk of addiction are well documented. The reinforcing properties of habit-causing drugs are associated with the activation of the mesolimbic dopaminergic pathways such as prefrontal cortex, ventral striatum and ventral tegmental area. (32), (33) Apart from stress mechanisms, the dopamine pathway is also associated with reward processing, adaptation, and learning. (34)

The role of dopamine factors in drug reward mechanisms is reported in opioid and alcohol abusers. This is due to activation of mesolimbic dopamine systems with drug cravings and euphoria. (35-38)

Experimental animal studies have suggested that stress exposure with increased glucocorticoid release could increase dopamine release in the nucleus accumbens. (39) Suppression of glucocorticoids could reduce extracellular levels of dopamine in resting and during response to stress and addictive substances. (40)

Chronic elevation of glucocorticoids inhibits dopamine synthesis and turnover in the nucleus accumbens. This mechanism suggests that alterations in the HPA and glucocorticoid levels could affect dopamine transmission. Drug abuse, stress, and increased levels of CRF and/or glucocorticoids could increase glutamic acid activity in the ventral tegmental area. This leads to enhanced activity of dopaminergic neuron. (41)

Human brain imaging studies have further shown that stress-induced cortisol elevation is associated with dopamine accumulation in the ventral striatum. Some evidence also reveals that amphetamine-induced increases in cortisol are associated with both dopamine binding in the ventral striatum and ratings of amphetamine-induced euphoria. (42)

Drug abuse and stress activate the mesolimbic pathways, which results in synaptic adaptations in the ventral tegmental area of dopamine neurons with adaptive morphological changes in the medial prefrontal cortex areas. (43) The ventral striatum is a main regulator of behavioral response, stress, and mesolimbic dopamine pathways. (44) Mesolimbic dopamine pathways are linked with rewarding, stress adaptation and goal-directed behaviours. These pathways are also important for emotion control, stress processing, decision making and impulse control. Altered status leads to impaired stress processing, impulse control, and predisposition to addiction. (45)

Opioid abuse can impair secretion of pituitary hormones and cause hypogonadism and menstrual disorders. (46) The negative interaction between addiction and the hypothalamic-pituitary-gonadal (HPG) axis is well studied.

Effects of Addiction of Endocrine Pathology

Effects on HPA, Pituitary, and Sex Hormones

It is documented that prolonged elevation of glucocorticoid level is associated with persistent, chronic pain or stress disorders. Furthermore, in certain individuals, the administration of opioids for pain leads to negative effects on the HPA axis. Moreover, chronic opioid use and or abuse leads to decreased glucocorticoid response to acute activation of the hypothalamus-pituitary-adrenal axis, leading to adrenal insufficiency. It is worth noting that opioids exert direct stimulatory effects on adrenal glucocorticoid secretion via [mu]- and K-receptors. (47), (48)

The influential role of opioids on the hypothalamic-pituitary-gonadal HPG axis was studied extensively. A dose-dependent response was observed between morphine and LH release in experimental animals. (49), (50)

Opioids can effectively inhibit hypothalamic GnRH secretion and suppress LH levels in humans. (51) Chronic morphine abuse is related to inhibition of GnRH secretion in humans.52 Li and Pelletier reported that morphine can reduce the biosynthesis of GnRH by downregulation of GnRH mRNA levels. (53) Opioids can regulate biosynthesis of gonadal sex steroidal hormones, the end products of the HPA axis via the feedback inhibition process. In experimental castrated-animal studies, estradiol-or testosterone-induced LH decrease was reversed by naloxone adm in istration. (54)

Chronic morphine abuse has no direct effect on serum LH levels. However, it can increase the hypothalamus sensitivity to the testosterone-related negative feedback mechanism. In females, prolonged opioid abuse leads to estradiol--surge induced LH hypersecretion and increases estradiol-mediated negative feedback mechanisms. Thus, it is clear that morphine can amplify positive and negative feedback on gonadotropin release. (55), (56)

Opioids, including exogenous and endogenous, can influence the increase and decrease of gonadal steroid hormones. Opioid peptides can cause decrease in LH pulse frequency. (57) In female experimental animals, central opioid neuron-mediated tonic inhibition of LH levels significantly affected the luteal phase. This leads to reduced LH surge and associated amenorrhea or oligomenorrhea.58 Effects on opioids on the HPG axis can reduce the LH levels in humans. (59), (60) The negative effects of opioids on the HPG axis depend on the circulatory levels of sex steroids during the menstrual cycle. (60) The adverse events of opioids on the HPG axis vary with age and increase during the pubertal stage. (62) During early and middle puberty, the negative feedback mechanism of estradiol on the HPG axis is independent of opioid receptor pathways. (63) In humans, chronic opioid administration leads to reduced LH levels; however, the serum FSH levels remain normal. Studies have confirmed that opioids can affect LH release only in the presence of sex steroids. This is due to negative feedback inhibition of hypothalamus GnRH secretion. (64) It is now clear that sex steroidal hormones are essential for modulation of opioid sensitivity in the HPG axis.

Effects of Opioids on Arginine-Vasopressin

Effects of Narcotics on Oxytocin

Opioids selectively inhibit oxytocin secretion in humans. Prolonged morphine abuse could affect biosynthesis and release of oxytocin. Opioids suppress oxytocin regulation by directly acting at the pituitary and hypothalamic regions with key involvement of both K- and [mu]-receptors.

Effects of Addictive Drugs on the Pathophysiology of Thyroid Hormones

In humans, administration of morphine could significantly increase the TSH levels among normal and hypothyroid individuals. (65) The TSH-stimulatory effects of morphine were confirmed by several other studies. (660 When compared with normal individuals and cigarette smokers, decreased levels of TSH were observed among opium users. The underlying pathophysiological mechanism could be stress conditions. (67)

Opioids stimulate TSH secretion in humans due to interaction with endogenous enkephalins. The hypothalamus is the key site for opioid action on the hypothalamus-pituitary-thyroid (HPT) axis. K-receptors are the primary binding sites involved in the opioid action on TSH.

Roles of Addictive Substances on Sex Hormonal Disorders +

Administration of morphine reduces LH secretion as a result of decreased concentrations of sex steroidal hormones. Opioids significantly impair female menstrual cycle by suppression of progesterone, LH, estradiol and FSH levels. (68) Irregular menstrual cycle with amenorrhea is a prominent symptom of hypogonadism in women.

Opioids cause decreased synthesis of adrenal androgen production and androgen-dependent loss of libido. Controlled clinical trials have suggested that prolonged use of heroin could affect sexual desire and performance in men.

In heroin- and methadone-addicted men, decreased levels of testosterone were reported. About 89% of male hypogonadism is associated with oral opioid abuse. Oral opiates can significantly reduce FSH, LH, estradiol, and dihydrotestosterone among men. (69), (70) With addition of hypogonadism and loss of libido, opiates can cause symptoms of depression. (71), (72) Depression with sexual--dysfunction related stress is a key risk for addictive behaviors that can drive the individuals towards habit-forming drugs such alcohol, morphine, marijuana, and heroin.

This review article clearly indicates how complex is the stress, pain, addiction, and neuroendocrine interplay. Therefore a more comprehensive wholesome understanding of this stress, survival, and reward symphony is a must for us to effectively address and cure this disease of pain, stress, and addiction imbalance. I therefore propose an integrative addiction educational forum led by the experts in natural addiction therapy.

Notes

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Dalai Akoury, MD, is the founder of AWAREmed Health and Wellness Resource Center and the director of the Wellness U program. Dr. Akoury is board certified in anti-aging, functional, and regenerative medicine, as well as having accumulated more than 20 years of experience in emergency medicine and pediatrics, and a master's degree in public health. Dr. Akoury has also served fellowships in pediatric hematology/oncology and performed research in leukemia and the effects of smoking. This lifetime of experience, along with a unique sensitivity, genuine compassion, and driving passion to inspire health in everyone, has prepared "Dr. Dolly" to be in this place at this time. About developing her dream, AWAREmed and Wellness U, Dr. Akoury says, "My mission is to ignite the spark of health deep within everyone, and to allow this sparkle of wellness to shine through everyone's eyes, becoming one with the universe, and aligning body, mind, and spirit."
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