Alcohol and Opioid Peptides: Neuropharmacological Rationale for Physical Craving of Alcohol

Abstract

Abstract

Until recently alcoholism was regarded as an incurable psychological problem. During the last decade a chain of research has led to important hypotheses about the etiology of the physical craving of alcohol. Recent discoveries indicate that the brain has receptor sites for naturally occurring opiatelike substances (endorphins, enkephalins, and dynor-phins) which are produced by the nervous system. Opiates such as morphine or heroin and some of the metabolic products of alcohol (tetrahydroisoquinolines) can also attach themselves to these receptors. It has been further discovered that the physiological craving for alcohol may be the result of a deficiency of the naturally occurring opiatelike substances as well as other neurochemical deficits (i.e., dopaminergic, GABAergic, and serotonergic). These neurochemical deficits can occur genetically or as a result of long-term heavy drinking.

SUMMARY

Scrutiny of available data reveals the following salient points: (1) Ethanol and opiates have a common biochemical mechanism of action; (2) the metabolic condensation by-products of ethanol, tetrahydroisoquinolines, link ethanol and opiate actions by virtue of interaction at multiple opioid receptor sites in the brain; (3) inbred mice showing a prediction toward alcohol preference exhibit significant differences of brain opiate peptides (endorphins and enkephalins) relative to mice showing an aversion to alcohol. Stress induces significant brain reductions of endogenous opioid peptides and induces copious alcohol consumption. Long-term ethanol ingestion remarkably reduces animal brain endorphins and enkephalins. Similarly, cerebrospinal fluid endorphin levels are reduced in human alcoholics, as are plasma enkephalin levels [40].

Both acute and chronic treatment with D-phenylalanine and hydrocin-namic acid, known carboxypeptidase A (enkephalinase) inhibitors, significantly attenuate both forced and volitional ethanol intake, in mice with a genetic predisposition to prefer alcohol. These animals are known to have innate brain enkephalin deficiencies. Since these agents, through their enkephalinase inhibitory activity, raise brain enkephalin levels, we propose that excessive alcohol intake can be regulated by alteration of endogenous brain opioid peptadergic functionality and interaction with other neuroaminergic pathways.