Comment by Allen S. Levine (January 15, 2014)

The analgesic and euphoric properties of opioids have long been recognized and highly valued, however, investigation of the molecular basis of their actions and appreciation of the full extent of their subjective and behavioral effects have a much shorter history. The modern era began in 1973, when three groups reported discovery of specific opioid receptors in the brains of laboratory animals(1-3), ending an intense scientific race. These discoveries were based on highly specific radioactive ligands. A lesson to all of us is an anecdote of the eminent pharmacologist Avram Goldstein, who had postulated the presence of opioid receptors in the central nervous system in 1971(4). Goldstein said he actually had a suitable radioligand in his laboratory safe, but was distracted by other events and was not spending enough of his time in his laboratory to identify the receptors. The discovery of opiate receptors in the brain paved the way to the discovery of endogenous ligands for them(3,5,6).  Originally referred to as enkephalins or endorphins, these are now known as endogenous opioids and are widely distributed in the central nervous system.

The discovery of opioids and their receptors came at a propitious time for the study of the neurochemical control of eating, as demonstrated by a classic paper by Stephen G. Holtzman(7). Holtzman was interested in the actions of the drug naloxone, which was developed in the early 1960s and was famous for its ability to reverse the otherwise fatal effects of overdoses of heroin or other opiates when injected sufficiently early.  After the discovery of the opioid receptors, it became clear that naloxone is an opioid receptor antagonist, binding most avidly to the mu receptor. Holtzman found that in rats, naloxone markedly reduced the potency of the non-opioid psychomotor stimulant d-amphetamine to increase locomotor activity and avoidance responding, but did not affect d-amphetamine’s potency to stimulate eating. Naloxone alone, however, dose-dependently decreased food intake in rats that had been deprived of food for 48 h. This was unexpected because naloxone and other “narcotic” antagonists had not been reported to have agonist effects on their own(7). Another important result was that the effects of naloxone on amphetamine-induced behavior and on eating appeared to be different in rats and mice. Whereas 1 mg/kg naloxone reduced food intake in rats by ~50%, even 30 mg/kg naloxone failed to affect food intake in mice.

David R. Brown joined Stephen Holtzman’s group as a graduate student in 1978.  Holtzman recalled his naloxone finding and recommended that Brown start a project related to naloxone and ingestive behavior. Others had also found that naloxone could decrease food consumption in genetically obese rats and mice and decrease stress-induced feeding(8,9). On the other hand, opioid peptides had been reported to increase food intake.  Brown and Holtzman’s first study(10), which is posted here, evaluated the effects of naloxone on food and water intake in both rats and mice, at different levels of deprivation, at different times of the day and in both male and female animals - a series of new and critically important investigations. Lengthening the food deprivation period tended to diminish the effectiveness of naloxone, perhaps due to the change in the strength of hunger stimuli. They concluded that, because low doses of naloxone decreased intake, the drug might have been acting at specific tissue sites such as endorphin receptors. Brown and Holtzman went on to publish a series of papers on opioids and eating and drinking in the next few years, and a number of other investigators also soon took up various aspects of the problem of opioidergic control of ingestive behavior. As David Brown commented to me, Holtzman’s serendipitous finding in 1974 launched a number of careers in psychopharmacology.

Since that time, a host of studies has been done determining which opioid receptors are involved in ingestive behavior, which brain sites are important, how opioids interact with other neuroregulators, the types of diets and foods/macronutrients involved, etc. An important aspect of this work is the involvement of opioids in food reward and, most recently, the idea that some foods might be addictive.  For many years, opioids were said to increase consumption of high fat diets(11).  However, several laboratories - including my own - have stressed that it is not the specific nature of the diet, but rather the relative preference for it that is more important(12-14).  This issue is still a topic of interest and it appears that injection site, diet composition and palatability are important considerations in assessing the role of opioids in feeding.  Gene expression studies also suggest that deprivation of a rewarding diet can lead to changes in mRNA expression of opioids similar to those occurring with food deprivation -  thus leading one to think that reward deprivation, like energy deprivation, involves opioid circuitry(15).  

The involvement of opioids and their receptors in food and water intake, as well as the intake of palatable or rewarding diets, is now a well established component of ingestive science. A number of laboratories have dedicated their efforts directly or indirectly to opioid regulation of feeding in animals and humans(16-18). These studies were stimulated, in part, by the findings from Stephen Holtzman and his graduate student David Brown.

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