dynorphins and Anorexia

This review summarizes recent work that focuses on the role of endogenous opioids (EOs) and opiate receptors in the control of food intake. Although the anorexic effect of opiate antagonists are now well accepted, the exact EO, site(s), and mechanism(s) of action remain to be established. However, accumulating evidence suggests that dynorphin, an endogenous ligand for kappa-type opiate receptors, is an important regulator (stimulant) of appetite. The roles of other EOs, such as beta-endorphin, are less clear. EOs appear to be involved in maintaining normal feeding behavior and are likely responsible for the overconsumption of fat in genetically obese and stressed subjects. Opiate antagonists block overconsumption of palatable foods, thus offering a promising approach to weight reduction for some overweight individuals. Anorexias may follow from a deficiency of kappa-type opioid activity, and surprisingly, can also result from excess opioid activity. Indeed, opiate antagonists of the mu type (naloxone) can enhance eating and weight gain in certain anorexic conditions. Therefore, it appears that excess opioid agonist activity may result in hyperphagia or anorexia (depending on the opiate receptor type). Finally, opiate antagonists may help normalize both types of pathological feeding states.

Topics: Animals; Anorexia; Appetite Regulation; beta-Endorphin; Dynorphins; Endorphins; Feeding and Eating Disorders; Food Preferences; Humans; Models, Biological; Narcotic Antagonists; Receptors, Opioid; Stress, Physiological

Rats implanted with the Walker-256 (W-256) tumor exhibit marked anorexia that is most apparent at night. In this model, the hypothalamic kappa opioid system was examined for deficits that might contribute to this tumor-induced anorexia. In anorexic tumor-bearing rats (TBR), nocturnal levels of ir-DYN-8 were significantly reduced in the hypothalamus, but ir-DYN-17 levels were not. Accumulation of 3H-etorphine or 3H-ethylketocyclazocine, a putative ligand for the kappa receptor subtype, was not increased in the hypothalamus of the TBR, as might have been expected if there were less endogenous dynorphin to occupy the opioid receptors in this region. In vitro binding assays with 3H-ethylketocyclazocine indicated that dynorphin depletion in the TBR was not sufficient to increase the numbers of kappa opioid receptors in the hypothalamus. Also, the sensitivity of kappa opioid receptors involved in feeding was not altered in the TBR as indicated by an intact feeding response to ketocyclazocine. In summary, the marginal deficits of hypothalamic dynorphin in W-256 tumor-bearing rats that coincide with the phase of tumor-induced anorexia may contribute to the reduction in food intake.

Topics: Animals; Anorexia; Carcinoma 256, Walker; Circadian Rhythm; Cyclazocine; Dynorphins; Eating; Ethylketocyclazocine; Feeding and Eating Disorders; Hypothalamus; Male; Rats; Rats, Inbred Strains; Receptors, Opioid; Receptors, Opioid, kappa

Rats bearing the Walker-256 (W-256) tumor display an anorexic profile which resembles that of normal animals forced to drink 2% NaCl [2,24], a regimen which depletes neurohypophyseal dynorphin-A (DYN) [3,9]. As expected, the naloxone reversible feeding induced by 2-deoxy-D-glucose (2-DG) was attenuated (36%) in the W-256 tumor bearing rats (TBR). Interestingly, immunoreactive (ir) levels of dynorphin-A 1-17 (DYN-17) and its postulated breakdown product, dynorphin-A 1-18 (DYN-8), were also reduced in the neurohypophysis of W-256 TBR by 42 and 50%, respectively. However, ir-DYN levels were not reduced in TBR in those brain regions which are probably involved in the regulation of appetite (e.g., hypothalamus). 2-DG itself did not consistently affect ir-DYN levels in any tissue for either controls or TBR. The ratio of DYN-8 to DYN-17 did not change in response to any treatment, including the depletion of both peptides from the NIL of TBR. In summary, the present data do not support DYN depletion as being a factor which contributes to the anorexia of the W-256 TBR.

Topics: Animals; Anorexia; Brain Chemistry; Carcinoma 256, Walker; Dynorphins; Feeding and Eating Disorders; Male; Peptide Fragments; Pituitary Gland, Posterior; Rats; Rats, Inbred Strains

Anorexia is a major symptom of zinc deficiency, but the mechanism(s) for this anorexia are poorly defined. Recent studies have suggested an integral role for endogenous opiate peptides in appetite regulation. Dynorphin, a leucine-enkephalin containing opiate peptide, is a potent inducer of spontaneous feeding. In this study we showed that zinc deficient animals were relatively resistant to dynorphin-induced feeding. Measurement of dynorphin levels using a highly sensitive radioimmunoassay showed that zinc deficient animals had lower levels of dynorphin in the hypothalamus than did ad lib fed animals, with weight restricted animals having intermediate values. [3H]-naloxone binding was significantly increased to isolated brain membranes from zinc deficient animals using 1 nM unlabeled naloxone when compared to ad lib fed controls with the weight restricted animals again having intermediate values. These data suggest that abnormalities in endogenous opiate regulation of appetite may well play a role in the anorexia of zinc deficiency. The effects of zinc deficiency on endogenous opiate action appear to include alterations in receptor affinity, a post-receptor defect and alterations in the synthesis and/or release of dynorphin.

Topics: Animals; Anorexia; Brain; Dynorphins; Eating; Endorphins; Feeding and Eating Disorders; Humans; Hypothalamus; Male; Naloxone; Peptide Fragments; Radioimmunoassay; Rats; Rats, Inbred Strains; Zinc