Physical dependence and tolerance imply that adaptive changes have taken place in body tissues so that when the drug is abruptly withdrawn these adaptive changes are left unopposed, resulting generally in a rebound overactivity. The discovery that the CNS employs morphine-like substances (endomorphins, dynorphins) as neurotransmitters offers the explanation that exogenously administered opioid may suppress endogenous production of endorphins by a feedback mechanism. When administration of opioid is suddenly stopped there is an immediate deficiency of endogenous opioid, which thus causes the withdrawal syndrome.
Tolerance may result from a compensatory biochemical cell response to continued exposure to opioid. In short, both physical dependence and tolerance may follow the operation of homeostatic adaptation to continued high occupancy of opioid receptors. Changes of similar type may occur with GABA transmission, involving benzodiazepines.
Tolerance also results from metabolic changes (enzyme induction) and physiological/behavioural adaptation to drug effects, e.g. opioids. Physical dependence develops to a substantial degree with cerebral depressants, but is minor or absent with excitant drugs.
There is commonly cross-tolerance between drugs of similar, and sometimes even of dissimilar, chemical groups, e.g. alcohol and benzodiazepines.
There is danger in personal experimentation; as an American addict has succinctly put it, 'They all think they can take just one joy-pop but it's the first one that hooks you'.5
Unfortunately subjects cannot decide for themselves that their dependence will remain mild.
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