TOLERANCE TO THE LENTICULAR EFFECTS OF OPIATES

¹ Departments of Anesthesiology and Medicine, New York Medical College, New York, New York

Opiates, when injected in large doses, induce transient lenticular opacities in mice. In this study it was found that a single previous dose of levorphanol established long-term resistance or tolerance to the lenticular effects of a second dose. However, high concentrations of epinephrine instilled in the eyes of tolerant mice were able to restore the normal lenticular response to parenteral levorphanol. The epinephrine concentrations required for an ED5O response correlated with the size of the first dose of levorphanol. Morphine or methadone, when substituted for the first dose of levorphanol, produced a cross-tolerance to the second dose of levorphanol as measured in terms of an epinephrine concentration. When larger doses of levorphanol were given, short-term tolerance also was observed. This effect developed within 30 min and persisted for up to 8 hr. Lenticular tolerance was found to develop in mice previously treated with reserpine, suggesting that this phenomenon probably does not require adrenergic mediation. Levallorphan was able to prevent the development of long-term tolerance when given in a large dose relative to the dose of levorphanol. The antibiotics actinomycin or puromycin also blocked long-term tolerance development, although neither of these inhibitors of protein synthesis prevented the appearance of short-term tolerance. Evidently, long-term lenticular tolerance to opiates is a complex phenomenon involving a decreased sensitivity to instilled epinephrine that may be related to the formation of an inhibitory protein.