George K.W. Yim

Opioid modulation of appetite

The discovery of opiate receptors and endogenous opioid peptides within the central nervous system has resulted in a number of speculations concerning the physiological significance of these peptides. In the present article, we review the evidence suggesting a primary role for some of the opioid peptides as regulators of ingestive behavior. In particular, we elaborate a hypothesis in which we suggest that in some species opioid peptides may play a role as a tonic inducer of ingestive behaviors, held in check by a variety of neuropeptides and monoamines. This review explores in detail the role of the opioid peptides as major mediators of the reward system and as a link between reward and feeding behaviors. Finally, a teleological role for opioid peptides in species preservation, which may explain the discrepancies in the role of the opioid peptides in feeding behavior in different species is proposed. It is suggested that the feeding profile of the animal provides important clues as to whether or not the animal has an opiate-sensitive feeding system. We stress that interactions with ingested nutrients and the milieu interieur provide an important means by which animals modulate the opiate-entrained feeding drives.

Naloxone reduction of stress-related feeding

Abstract The effects of the narcotic antagonist, naloxone, on various types of stress- related feeding in rats were examined. Tail pinch-induced eating of a palatable substance, and 3 hr daytime rat chow intake following acute 2-deoxy-D-glucose (2-DG, 400 mg/kg) administration or 24 hr food deprivation were significantly decreased by low doses (1 mg/kg) of naloxone. Night time food intake was likewise decreased by naloxone (4 mg/kg). In contrast, hyperphagia induced by insulin (10 U/kg) was not decreased by naloxone (0.06–16 mg/kg). These findings suggest that narcotic antagonists should be considered as possible anorexics selective for stress-induced eating, and that endogenous opiates may prove to be another significant factor involved in the control of food intake.

Stereochemical effects of 3,4-methylenedioxymethamphetamine (MDMA) and related amphetamine derivatives on inhibition of uptake of [3H]monoamines into synaptosomes from different regions of rat brain

3,4-Methylenedioxymethamphetamine (MDMA) is a recently popularized recreational drug, although some have advocated its psychotherapeutic potential. Since the pharmacology of MDMA is largely uncharacterized, the stereochemical profiles of MDMA and some of its homologs were derived on inhibition of synaptosomal uptake of [3H]monoamines and compared to those of amphetamine and the hallucinogenic phenylisopropylamine 2,5-dimethoxy-4-methylamphetamine (DOM). In contrast to the 5-fold stereoselectivity observed with amphetamine, only the S-(+) enantiomer of MDMA and 3,4-methylenedioxyamphetamine (MDA) inhibited [3H]dopamine uptake into striatal synaptosomes. Neither stereoisomer of the alpha-ethyl homolog of MDMA, N-methyl-1-(1,3-benzodioxol-5-yl)-2-butanamine (MBDB), inhibited [3H]dopamine uptake. The two stereoisomers of amphetamine and the MDMA-related compounds were equipotent in inhibiting [3H]norepinephrine uptake into hypothalamic synaptosomes. Both stereoisomers of MDMA, MDA and MBDB were potent inhibitors of [3H]serotonin uptake into hippocampal synaptosomes, but only S-(+)-amphetamine produced an appreciable inhibition of [3H]serotonin uptake. Neither stereoisomer of DOM inhibited synaptosomal uptake of any [3H]monoamine. These results suggest that MDMA and its homologs may be more closely related to amphetamine rather than to DOM in their biochemical mode of action. The pronounced effects of the methylenedioxy-substituted compounds on [3H]serotonin and [3H]norepinephrine uptake implicate these neurotransmitters in the pharmacological effects of these drugs.

Distribution and metabolism of barbital-14C in tolerant and nontolerant rats

Abstract Tolerance to barbital, as evidenced by a significant decrease in sleeping time, was induced in rats by chronic barbital administration. In an effort to elucidate the mechanism of tolerance, barbital- 14 C distribution and metabolism were compared between tolerant and nontolerant rats. Levels of radioactivity in brain, plasma, and urine did not significantly differ between the two groups. This indicated that tolerance to barbital cannot be ascribed to decreased drug absorption, to increased excretion of the drug, or to a decreased permeability of the blood-brain barrier. Tolerant rats metabolize barbital in a manner qualitatively similar to that of nontolerant rats, as indicated by the recovery of the same three barbital metabolites from urine of either tolerant or control animals. The quantity of barbital metabolites excreted by the tolerant rats was not significantly higher than control values.

Relationship between plasma concentrations of immunoreactive beta-endorphin and food intake in rats☆

Periods of increased food intake in male rats were characterized by significant elevations in the plasma concentrations of immunoreactive beta-endorphin (beta-ep). Administration of 2-deoxy-D-glucose (400 mg/kg) produced rapid and concurrent increases in both food intake and plasma beta-ep. Administration of insulin (10 units/kg) produced large delayed increases in food intake but only modest delayed increases in plasma beta-ep. Spontaneous nocturnal feeding was associated with increased plasma beta-ep. Increases in daytime food intake in rats subjected to 24 hr of food deprivation were also characterized by elevated plasma beta-ep. In all cases examined, those feeding behaviors in male rats which were subject to inhibition by naloxone were characterized by elevated concentration of plasma beta-ep.

Stimulation of food intake following opiate agonists in rats but not hamsters.

The proposed μ and ϰ opiate receptor agonists morphine and ketocyclazocine, as well as meperidine, were compared for their ability to stimulate feeding and drinking by male rats and hamsters that were not deprived of food or water. Morphine (8.0 mg/kg) and ketocyclazocine (0.5–4.0 mg/kg), but not meperidine (0.5–64.0 mg/kg), increased 3-h food intake by rats. By 6 h the hyperphagic responses were less pronounced. However, 6-h water intake was increased by all three agonists. In contrast to rats, hamsters failed to increased food or water intake over an 8-h period following morphine (6.25–800 mg/kg), ketocyclazocine (0.25–16.0 mg/kg), or meperidine (1.0–128 mg/kg) administration. Thus, ϰ or μ opiate receptors may mediate the observed hyperphagic effect of opiate agonists on rat food intake. In addition, these results are consistent with our earlier suggestion that hamsters lack an opiate-sensitive feeding system.

Pharmacological modulation of edema mediated by prostaglandin, serotonin and histamine

Previous studies demonstrated that the formamidine pesticide chlordimeform (CDM) reversibly inhibited prostaglandin biosynthesis and prevented the late (PG-mediated) phase of carrageenin-induced hind paw edema. This study emphasizes antagonism by CDM of the early (5HT and histamine-mediated) phase of carrageenin edema. CDM and cyproheptadine both antagonized paw edema induced by albumin (5HT and histamine-mediated) and by the direct injection of 5HT and histamine, whereas aspirin and the PG antagonist, SC-19220, were ineffective. As expected, cyproheptadine selectively reduced the early phase, whereas aspirin and SC-19220 selectively reduced the late phase of carrageenin-induced edema. These results are thus consistent with earlier studies demonstrating PG mediation of the late phase of carrageenin edema, and 5HT and histamine mediation of albumin edema and the early phase of carrageenin edema. In addition, they indicate that CDM possesses multiple acute anti-inflammatory, actions not exhibited by aspirin, by SC-19220 or by cyproheptadine alone.

Prostaglandin synthesis inhibited by formamidine pesticides

Abstract The formamidine pesticides, chlordimeform and amitraz, were shown to have both antipyretic and anti-inflammatory activity when given intraperitoneally to rats at 5 to 80 mg per kg. They reduced yeast-induced fever in rats with potencies intermediate between those of indomethacin and aspirin, and antagonized the carageenin-induced swelling of the hind paw. In both these actions, chlordimeform was more potent than amitraz. Both formamidines also inhibited the synthesis of prostaglandin E 2 from arachidonic acid by bovine seminal vesicle microsomes. At an arachidonic acid concentration of 0.4 μM, the I 50 values for chlordimeform and amitraz were 34 and 880 μM respectively, compared to 0.4 μM and 790 μM for indomethacin and aspirin. These aspirin-like actions may provide a clue to some of the physiological effects of the formamidines, which represent a new and unsual group of prostaglandin synthetase inhibitors.

Actions of GABA, picrotoxin and bicuculline on adrenal medulla

Abstract GABA releases catecholamines from isolated perfused bovine adrenal glands. The secretory response is dependent on calcium and independent of acetylcholine. Tachyphylaxis to the releasing effect is observed. Picrotoxin inhibits the effect of acetylcholine and the effect of low but not high concentrations of GABA. Bicuculline, another reported GABA antagonist, blocks the effect of all concentrations of GABA but not the effect of acetylcholine. Bicuculline is therefore a more specific GABA blocker in adrenal medulla than picrotoxin. These findings suggest the existence of GABA receptors in adrenal medulla which may be analogous in some respects to those reported in autonomic ganglia.

Blockade of N-methyl-d-aspartate receptors prevents cyanide-induced neuronal injury in primary hippocampal cultures

Cyanide-induced alterations of cytosolic calcium levels and cytotoxicity were examined in primary cultures of rat hippocampus. Cytosolic free Ca2+ ([Ca2+]i) levels were measured in hippocampal neurons using the fluorescent probe, fura 2. A concentration-dependent rise in [Ca2+]i occurred rapidly following exposure of cells to 0.5-10 mM NaCN. In normal medium (1.3 mM Ca2+), 2 mM NaCN produced an increase in [Ca2+]i (172 +/- 27% of control), 45 sec following exposure. Ca2+ elevation produced by NaCN was blocked by removal of Ca2+ from the external medium or by pretreatment with the N-methyl-D-aspartate (NMDA) receptor antagonist, 2-amino-5-phosphonovalerate (APV). The cytotoxicity of cyanide, assessed by measuring the efflux of lactate dehydrogenase, was blocked by APV. These results indicate that in hippocampal neurons, cytosolic Ca2+ accumulation induced by cyanide originates from the extracellular compartment and the NMDA receptor ionophore is a significant route for Ca2+ entry. It is proposed that excitotoxic mechanisms may contribute to altered neuronal homeostasis and injury associated with cyanide.