Desensitization and neurohumor modulation: a model of drug dependence II

A theoretical model of drug tolerance and dependence is presented, based on the assumption that, besides their own function, some neurohumors may also modulate the output of other neurohumors. If the receptors of both neurohumors are rapidly desensitized and resensitized by their natural ligands, but slowly by drugs, prolonged exposure to drugs will necessarily lead to drug tolerance and dependence. This model proposes a function for co-transmitters and, applied to opioid and catecholamine neurohumors and drugs, it explains the presence of enkephalin in sympathetic neurons, the release of catecholamine neurohumors by opiates, the fact that signs of opiate abstinence are largely autonomic symptoms, the attenuation of the opiate abstinence syndrome by alpha2 agonists and its exacerbation by alpha2 antagonists, the analgesic action of excitement, and the increased toxicity of morphine in animals treated with 6-hydroxydopamine. The model also suggests possible interpretations for the late effects of large opiate doses, hyperalgesia caused by very small opiate doses, certain symptoms of autism, and sudden infant death syndrome.