Brain Research, 380 (1986) 357-358 357 Elsevier BRE 21705 Chronic stress reduces the analgesic but not the stimulant effect of morphine in mice STEFANO PUGLISI-ALLEGRA 1, SIMONA CABIB 1and ALBERTO OLIVERIO 2 l lstituto di Psicobiologia e Psicofarmacologia, C. N.R. and -'Department of Genetics and Molecular Biology, Universitd di Roma, Rome (Italy) (Accepted April 22nd, 1986) Key words: chronic stress -- opioid tolerance -- analgesia -- locomotor activity -- mice After 10 daily 2-h sessions of immobilization stress, C57BL/6 mice show a reduced response to the analgesic effects of morphine. Chronic stress does not modify the stimulant effect of morphine on locomotor activity. These results are discussed in terms of the ef- fects of stress on different endorphinergic systems Evidence exists that the effects of drugs depend on the history of the organism. For instance, stress has been shown to modulate the effects of dopaminergic compounds in several experimental paradigms 2'3's. In the case of morphine effects, tolerance to opioid- induced analgesia has been found to develop after chronic exposure to some stressors l'4,s. However, morphine has many behavioral effects that seem to be modulated by different endogenous opioid sys- tems and that could be differently affected by a histo- ry of stressful experiences. The purpose of this research was the analysis of the effects of chronic immobilization stress on morphine- induced running and analgesia in the mouse. Male C57BL/6 mice (Charles River Lab., Calco, Como, Italy) aged 11-12 weeks and weighing 25-28 g at the beginning of the experiment were used. They were housed in groups of 6 in standard breeding cages (27 x 24 x 13 cm) and kept on a 12/12 h light/dark cycle with water and food ad libi- tum. Mice were stressed by immobilizing them for 2 h in a snug-fit plexiglass restraining apparatus once a day for 10 days 5 and control groups were handled daily. Twenty-four hours after the last stressful expe- rience, the animals were injected i.p. (10 ml/kg) with two doses of morphine hydrochloride (10 and 20 mg/kg) or with saline solution (NaC1 0.9%). Differ- ent groups of naive mice were tested either for pain sensitivity or for locomotor activity 30 min after in- jection and their response was compared with that of unstressed mice. All tests were performed during the second half of the light period, between 16.00 and 18.00 h. Pain thresholds were determined by the hot-plate method 7. The endpoint used was the licking of the fo- repaws or hindpaws. Locomotor activity was mea- sured by an automated apparatus consisting of 8 tog- gle-floor boxes 7, each divided into two 20 x 10 cm compartments connected by a 3 x 3 cm opening. For each mouse, the number of crossings from one com- partment to the other was recorded by means of a mi- croswitch connected to the tilting floor of the box. Locomotor activity was registered for 60 min. Results were analyzed by two-factor ANOVA, the factors being: treatment (3 levels: 0, 10, 20 mg/kg of morphine) and stress (2 levels: stressed, unstressed). Results are shown in Fig. 1. In this experiment, morphine was able to induce dose-dependent analge- sia and running. As for the analgesic effect, ANOVA showed both a treatment (F2,10 9 = 33.46, P < 0.001) and a stress main effect (Fl,109 = 8.77; P < 0.01). Concerning the effect of morphine on locomotor ac- tivity, ANOVA showed only a significant treatment main effect (F2,61 = 25.90; P < 0.001). Thus, chronic Correspondence: S. Puglisi-Allegra, Istituto di Psicobiologia e Psicofarmacologia, via Reno 1, 00198 Rome, Italy. 0006-8993/86/$03.50 © 1986 Elsevier Science Publishers B.V. (Biomedical Division)