Mary Ann Marrazzi

An auto‐addiction opioid model of chronic anorexia nervosa

The phenomenology of chronic anorexia nervosa is compared with that of addictive states. A model is proposed in which brain opioids mediate the elation, neuroendocrine changes, and down-regulation of metabolism that occur in adaptation to dieting. The physiology of opioids is reviewed, and clinical and animal data are marshalled to support an auto-addictive model. Opiate blockade together with therapeutic approaches used in the addictions may prove helpful in this stubborn disorder.

Endogenous codeine and morphine in anorexia and bulimia nervosa

The endogenous plasma alkaloids codeine and morphine were shown to be elevated in patients with anorexia nervosa and bulimia nervosa compared to control subjects. The role of these opioids in the pathophysiology of these eating disorders is discussed in relation to an auto-addiction opioid model. This model proposes that endogenous opioids are released during an initial period of dieting and reinforce a state of starvation dependence [1,2].

Atypical endogenous opioid systems in mice in relation to an auto-addiction opioid model of anorexia nervosa

We have proposed that the atypical opioid system in the mouse may be representative of that in the anorexia nervosa patient and may account for a biological predisposition to the disorder. This is in the context of our auto-addiction model of anorexia nervosa in which endogenous opioids play a critical role in its etiology. Morphine activation of the endogenous opioid systems increases food intake and causes sedation in most species, including normal humans and rats. In contrast in BALB/C mice, morphine causes anorexia and hyperactivity, which we suggest may be true in the anorexia nervosa patient. A variety of atypical opioid systems have been demonstrated in different mouse strains, based on other responses. The present study examines these strains with reference to the responses relevant to our anorexia nervosa model. Three patterns are described--anorexia with hyperactivity (BALB/C and C57BL/6J mice), anorexia without hyperactivity (DBA/J mice), and a biphasic curve with hyperphagia at low doses and anorexia and hyperactivity at higher doses (CF-1 mice). Only female mice were used. These atypical opioid systems may reflect a spectrum of biological predispositions to the disorder. These strain differences may also provide useful correlations of the genetic determinants of various opiate responses and provide useful comparisons in characterizing the essential features responsible for the atypical responses.

High-Dose Naltrexone and Liver Function Safety

Studies have found naltrexone useful in the treatment of diseases other than opiate addiction in which endogenous opioids presumably play a role, such as alcoholism and eating disorders. Some of these studies involve high doses (100-200 mg bid). Because investigational studies with high doses (300 mg/day) reported clinically significant increases in liver enzyme levels, the authors measured a spectrum of liver function parameters in response to high doses of naltrexone in a double-blind, crossover trial (100 mg bid) followed by an open-label period (200 mg bid). They observed no adverse clinical or laboratory changes in liver function in association with high-dose naltrexone therapy in eating disorders.

Atypical responses to morphine in mice: A possible relationship to anorexia nervosa?

According to our previously proposed auto-addiction hypothesis of chronic anorexia nervosa, patients become addicted to an initial period of dieting through endogenous opioid mediated mechanisms. Morphine causes hyperactivity and anorexia in the mouse, symptoms of anorexia nervosa but responses opposite to those of most species including rats and normal human subjects. This suggests that the atypical opioid systems in the mouse may resemble those of the chronic anorexia nervosa patient in contrast to those of most species including the normal human. Characterization of this atypical opioid system may be useful in understanding the pathophysiology of anorexia nervosa.

Male/female comparison of morphine effect on food intake—relation to anorexia nervosa

We have proposed that endogenous opioids play a critical role in the etiology of anorexia nervosa by mediating an auto-addiction. A biological predisposition may result from an atypical endogenous opioid system. Morphine activation of the system increases food intake in most species, including normal humans and rats, but decreases food intake in mice. The atypical opioid system in mice may be representative of that in anorexia nervosa patients, causing the biological predisposition. Anorexia nervosa is 10 times more prevalent in females than males. In the context of this auto-addiction opioid model, it was interesting to determine if the effects of morphine on food intake were markedly different between the two sexes. Full dose-response curves were done of the effects of morphine on food intake in males and females in both rats and mice, representing the typical and atypical responses, respectively. Differences between the sexes were not found to explain the marked prevalence of anorexia nervosa for females. The marked preference is probably at some other step.

Comparison of insulin hypoglycemia-induced and fluoroacetate-induced convulsions in gold thioglucose lesioned mice

Abstract In addition to its well known effects in producing hyperphagia, resulting in obesity, and histological damage focused relatively selectively in the ventromedial hypothalamic area, systemically administered gold thioglucose (GTG) also increased the sensitivity to insulin hypoglycemic convulsions. The change was in the convulsive response to equal hypoglycemia, rather than in the degree of hypoglycemia in response to insulin. The effect suggests that a relatively discrete control center is involved in adjusting brain function to metabolic alterations, in this case hypoglycemia. These results compare the effects of GTG lesions on insulin hypoglycemic- and fluoroacetate-induced convulsions. Gold thioglucose lesions did not alter the sensitivity to another metabolic convulsant, fluoroacetate, which blocks the Krebs cycle by blocking the conversion of citrate to isocitrate. Thus, although related in both cases to a shortage of available cellular fuel, the metabolic convulsions induced by insulin hypoglycemia and by fluoroacetate must be qualitatively different. Moreover, operation of the glucose sensing and regulatory mechanism lesioned by gold thioglucose, i.e. the ”gold thioglucose lesioned glucostat“, did not appear to require the Krebs cycle as blocked by fluoroacetate.

The Neurobiology of Anorexia Nervosa: An Auto-Addiction?

Anorexia nervosa (AN) is a disorder in which patients refuse to eat, as a result of a morbid fear of obesity. They believe themselves to be “fat and ugly” despite severe emaciation and an appearance shocking to others. They lose weight through caloric restriction, ritualistic exercising, and abuse of laxatives and diuretics. Some patients become involved in bulimic binging and purging cycles in which they transiently lose control of disciplined dieting but avoid weight gain through vomiting. A related eating disorder is bulimia in which the binge-purge cycle occurs without caloric restriction and normal body weight is maintained. The incidence of eating disorders is highest between the ages of 15 and 30 years and is 10–20 times greater in females than males (1). In women, amenorrhea also occurs. The prevalence is highest in middle class Caucasian families. The patients are typically perfectionist and model children until the onset of the disorder which may be triggered by a spectrum of psychosocial stressors. Prevalence of the disorder has been reported as high as 1 in 200 adolescent girls in British schools (2) and the rate is rising. It can be a lethal disorder. A mortality rate of close to 20% was found in two populations of AN patients over approximately a 20-year period (3,4). Suicide is a prominent factor in mortality.

Effects of U50,488, a selective kappa agonist, on atypical mouse opiate systems

We have proposed that endogenous opioids play a critical role in the etiology of anorexia nervosa, mediating an auto-addiction, and that atypical opioid systems in mice may be representative of those in anorexia nervosa patients, in contrast to normal humans and rats. A biological predisposition to eating disorders may result from these atypical opioid systems. Definition of these systems as atypical is based on their responses to morphine, which are preferential for the mu receptor subtype. Three patterns have been described in four strains of mice: anorexia with hyperactivity (BALB/C and C57BL/J), anorexia without hyperactivity (DBA/J), and a biphasic curve (CF-1). The latter showed anorexia and hyperactivity at high doses but increased food intake without a change in motor activity at low doses. These patterns contrast to the increase in food intake and sedation in typical species, including rats and normal humans. In the present study, U50,488, a selective kappa agonist, increases food intake in all four mouse strains, as previously reported in rats. Thus, these two agonists have opposite effects on the atypical mouse systems, but similar effects on the typical rat system. The typical and atypical opioid systems respond oppositely to morphine but similarly to U50,488.

Effects of bipiperidyl mustard (BPM) lesions on insulin hypoglycemic convulsions

Systemic gold thioglucose (GTG) is well known to produce hyperphagia, resulting in obesity, and histological damage focused relatively selectively in the ventromedial hypothalamus (VMH). Although structurally very different, bipiperidyl mustard (BPM) produces apparently similar effects. However, a proposed mechanism for concentration and hence localization of GTG toxicity depends on its structural similarity to glucose, binding it to glucoreceptors and focusing the cytotoxicity of the gold thio-portion. We recently showed that GTG treatment also produces an early decrease and a later increase in sensitivity to insulin hypoglycemic convulsions. We report here that BPM also produces a similar biphasic change in sensitivity to insulin hypoglucemic convulsions. For both, the differences are in the brains convulsive response to hypoglycemia, rather than in the degree of hypoglycemia in response to insulin. Thus, GTG and BPM cytotoxic lesions appear similar in this regard as well. BPM is another way of producing a relatively discrete brain lesion which alters the brains functional adjustment to hypoglycemia. The significance of this control center and its relationship to the control(s) of feeding and systemic metabolism are discussed.