European Journal of Pharmacology, 76 ( 1981) 235-239 235 Elsevier/North-Holland Biomedical Press POSSIBLE REGULATORY ROLE OF DYNORPHIN-(I-13) ON NARCOTIC-INDUCED CHANGES IN NALOXONE EFFICACY F. CANKAT TULUNAY, MIN-FENG JEN, JAW-KANG CHANG *, HORACE H. LOH and NANCY M. LEE Departments of Psychiatry and Pharmacology, University of California Medical Center, San Francisco, California 94143, and * Peninsula Laboratories, San Carlos, California, U.S.A. Received 24 June 1981, revised MS received 16 September 1981, accepted 22 September 1981 F.C. TULUNAY, M.F. JEN, J.K. CHANG, H.H. LOH and N.M. LEE, Possible regulato O' role ofdynorphin-(1-13) on narcotic-induced changes in naloxone efficacy, European J. Pharmacol. 76 (1981) 235-239. Pretreatment of mice with a single injection of morphine, fl-endorphin, Leu-enkephalin,FK33824 or [D-Ala2-D-LeuS]enkephalin, for 3 h increased the ability of naloxone to antagonize the analgesic effects of morphine. However, dynorphin-(1-13) can only antagonize morphine, fl-endorphin or Leu-enkephalin induced increased naloxone efficacy but not FK33824 or [D-Ala2-D - Leu2 ]enkephalin. Dynorphin itself can also increase naloxone efficacywhen treated alone. However,this effect can be prevented when animals are pretreated with dynorphin and naloxone together. Dynorphin-( 1 - 13) Morphine fl-Endorphin Enkephalins Naloxone Analgesia 1. Introduction 2. Materials and methods In previous studies (Friedman et al., 1981; Tulunay et al., 1981), we demonstrated that dy- norphin-(1-13), although itself is not analgesic, can modify the analgesic activity of morphine or fl- endorphin. In naive animals, dynorphin's effect is inhibitory, but in tolerant animals, the effect is to potentiate. Although dynorphin contains Leu- enkephalin at its N-terminus, the peptide seems to be effective in modifying the analgesic activities of morphine or fl-endorphin only and not those of enkephalin analogs. Tulunay and Takemori (1974a) reported that pretreatment of mice with narcotic agonists in- duced a substantial increase in naloxone efficacy whereas pretreatment with narcotic antagonists or non-narcotic drugs did not, suggesting that the increased efficacy of naloxone might be a sensitive indicator of the development of tolerance. In this study, we report the effect of dynorphin-(1-13) on naloxone efficacy in animals pretreated with morphine or opioid peptides, further characteriz- ing the role of dynorphin in opiate analgesia. 2.1. Animals Male Simonsen ICR mice (Gilroy, CA) weigh- ing between 20-25 g~were used in all experiments. They were housed for at least one day prior to experimentation and used within 5 days. Each mouse was used only once. 2.2. Analgesic assay Analgesia was measured by the tail-flick method of D'Amour and Smith (1941) as modified by Tulunay and Takemori (1974a). For EDs0 de- terminations, the animals' responses were made quantal by establishing an endpoint which repre- sented a significant increase in reaction time. The endpoint was an increase in the reaction time of an individual animal of greater than 3 standard deviation (S.D.) of the control mean reaction time for all animals used in the assay. The usual control mean reaction time was 3.1-+ 0.05 sec. Nonre- sponding animals were removed from the heat 0014-2999/81/0000-0000/$02.75 © 1981 Elsevier/North-Holland Biomedical Press