Tolerance and cross-tolerance to the antinociceptive effects of [d-Arg2]-dermorphin tetrapeptide analogue and morphine

Abstract Rats were given repeated subcutaneous injections of [ d -Arg 2 , Sar 4 ]-dermorphin (1–4) [DAS-DER (1–4)] and/or morphine over a period of 4 or 7 days. Antinociception was determined at 90 min for DAS-DER (1–4) and 30 min for morphine after each morning injection (9:00 a.m.), using the tail-flick and digit pinching tests in rats. Subcutaneous administration of DAS-DER (1–4) and morphine produced the development of antinociceptive tolerance, respectively. A marked tolerance to DAS-DER (1–4) and morphine was seen in rats made tolerant to morphine. However, administration of morphine produced no significant decrement in the antinociceptive activity in rats made tolerant to DAS-DER (1–4). These results suggest that the site of action of DAS-DER (1–4) may be more limited than that of morphine in the nociceptive pathways, for lack of its antinociceptive efficacy in morphine-tolerant rats.