Drugs that modify opioid tolerance, physical dependence, and abstinence symptoms: preclinical and clinical studies

In summary, the effects of drugs affecting the MTD and abstinence syndrome in mice, rats, monkeys, and humans have been described. Although mu opioid antagonists block tolerance and dependence on morphine, they also antagonize the analgesic response to morphine and, therefore, may not be useful clinically in inhibiting the MTD process. On the other hand, delta-selective opioid antagonists do not modify morphine analgesia but block the MTD process and, therefore, may have therapeutic potential. Neuropeptides like TRH, MIF, and cyclo (Leu-Gly) appear to produce similar results although their mechanism of action may be quite different. Cyclo (Leu-Gly) produces its action on oral administration and, therefore, further studies are warranted with this peptide. The CCKB receptor antagonist enhances morphine analgesia and blocks tolerance to morphine but has no effect on the development of dependence on morphine. EAA antagonists like MK-801 block tolerance to the analgesic effect of morphine selectively but are quite toxic. Therefore, newer, less toxic agents like LY 274,614 need to be developed.