Enkephalin analogs and physical dependence.

A novel method of drug delivery, the osmotic minipump, was used to measure the ability of morphine and eight enkephalin analogs to produce physical dependence. After 3 days of morphine or peptide infusions into the rat brain, the dependent state was established and revealed by naloxone challenge; escape behavior, shaking, tachycardia and an increased respiration rate provided objective evidence of withdrawal. The minipump method required only small amounts of test materials; 6 micrograms of morphine sulfate or 0.17 microgram of FK 33,824, the most potent enkephalin analog, infused for 3 days per rat, were sufficient to induce dependence in all animals tested at these dose levels. A positive rank correlation was obtained between the short-term activities of the eight enkephalin analogs in inhibiting a motor response to a noxious stimuli and the long-term activities of the enkephalin analogs in producing physical dependence.