THE DEVELOPMENT OF TOLERANCE IN RATS TO SOME NEW SYNTHETIC ANALGESICS

¹ Department of Pharmacology, University of Michigan, Ann Arbor, Michigan, and Biology Division, Sterling-Winthrop Research Institute, Rensselaer, New York

1. We have demonstrated the development of tolerance in rats to the analgesic action of morphine and several new analgesic drugs by measuring the degree of analgesia to a standard radiant thermal stimulus.

2. At the end of 6 weeks of daily subcutaneous administration of morphine (10 mgm. per kgm. per day), WIN 642-4, (2 mgm. per kgm. per day), WIN 1539 (3 mgm. per kgm. per day), and WIN 1161-2 (3 mgm. per kgm. per day), the analgesic response was less than 50 per cent of the initial value. The response of WIN 1783-2 (3 mgm. per kgm. per day) at the same time was about 80 per cent of normal.

3. After discontinuance of the drugs, rats treated with WIN 1539 and WIN 1161-2 showed the least amount of recovery from the tolerance. With the other compounds, responses of about 90 per cent of normal were obtained at 3 weeks after withdrawal.

4. There was a change in the character of the side-effects from depression to excitation following drug injection during the development of tolerance.

5. After withdrawal, the only symptom observed was hyperexcitability which reached its maximum in about 48 hours.

6. The daily administration of these compounds caused a decreased rate of growth which was probably due to a decrease in food consumption.

7. Of the compounds tested, l-isomethadone showed the least tendency to develop tolerance and to induce the addiction syndrome, as it is seen in rats.