Desensitization and coupled receptors: a model of drug dependence

It is assumed that certain drug receptors are so coupled with certain physiological receptors that stimulation of either receptor increases the sensitivity of the other. If the drug receptor suffers tolerance (i.e. slow desensitization) and if insensitivity of the drug receptor also makes the physiological receptor insensitive, then tolerance must be responsible for a physiological deficiency. This may be remedied by increased drug administration which will raise the sensitivity of the remaining physiological receptors so that a normal or near-normal physiological situation is achieved. Thus the organism is not only tolerant to the drug but also dependent on it. If such theoretical considerations apply to opiate receptors (as drug receptors) and to catecholamine receptors (as physiological receptors), then the theory predicts that acute morphine administration increases the sensitivity of dopamine receptors, that sympathetic stimulation decreases pain sensitivity, that opioid tolerance provokes increased catecholamine activity, that alpha-receptor stimulants attenuate and alpha-receptor antagonists exacerbate morphine abstinence, and that catecholaminergic inhibition results in increased morphine toxicity. All of these predictions have been verified experimentally.