The effects of NG-nitro-L-arginine (L-NNA) and NG-monomethyl-L-arginine (L-NMMA), two potent inhibitors of nitric oxide synthase (NOS) on the development of tolerance to the analgesic action of [D-Ala2, Glu4] deltorphin II (deltorphin II), a delta 2-opioid receptor agonist, and morphine, a mu-opioid receptor agonist, were determined in mice. Male Swiss-Webster mice were rendered tolerant to deltorphin II by twice daily ICV injections of the drug for 4 days. Tolerance to morphine was induced by twice daily s.c. injections of the drug for 4 days. Multiple injections of deltorphin II (20 micrograms/mouse) or morphine (15 mg/kg) resulted in the development of tolerance to their analgesic action as evidenced by decreases in the response in comparison to mice injected with vehicle. Concurrent administration of L-NNA or L-NMMA (2,4, or 8 mg/kg, i.p.) had no effect on the development of tolerance to the analgesic action of deltorphin II. However, the same doses of L-NNA or L-NMMA inhibited the development of tolerance to the analgesic action of morphine. Acute treatment with L-NNA or L-NMMA did not modify deltorphin II- or morphine-induced analgesia in mice. It is concluded that NOS inhibition attenuates tolerance to the analgesic action of morphine but not to that of deltorphin II, a delta 2-opioid receptor agonist, in the mouse.