Tolerance develops in spinal cord, but not in brain with chronic [Dmt1]DALDA treatment

Previously, we reported that H-2′,6′-dimethyltyrosine [Dmt1]-D-Arg-Phe-Lys-NH2 (DALDA), an analogue of the naturally occurring opioid peptide dermorphin, is a highly potent and selective mu receptor agonist with low cross-tolerance to morphine. In the present study, we investigated the effect of treating mice chronically with [Dmt1]DALDA. The AD50 of [Dmt1]DALDA (s.c.) increased eight-fold in animals given this drug chronically; in contrast, the AD50 increased two-fold in mice chronically treated with morphine. The AD50 of morphine (s.c.) in these [Dmt1]DALDA-treated animals was increased more than 120 times, while that of the more selective μ agonist [D-Ala2-MePhe4-Gly-ol5]enkephalin (DAMGO) given intrathecally was increased more than 240 times. However, the AD50 of DAMGO given intracerebroventricularly was essentially the same in animals treated chronically with [Dmt1]DALDA as in naive animals. The dose of naloxone required to precipitate withdrawal in [Dmt1]DALDA-treated animals was 20 times lower than that in morphine-tolerant animals. Using real-time quantitative PCR, we found that expression of the μ opioid receptor, δ opioid receptor, preproenkephalin and preprodynorphin genes was upregulated in the brain by [Dmt1]DALDA treatment. No significant changes in expression of opioid receptor or opioid peptide genes were detected in the spinal cord of [Dmt1]DALDA-treated mice, nor in the brain or spinal cord of morphine-treated mice. We conclude that a high degree of tolerance to [Dmt1]DALDA develops in the spinal cord but not brain, and cannot be accounted for by changes in expression of opioid receptors or opioid peptides in these tissues. British Journal of Pharmacology (2004) 143, 987–993. doi:10.1038/sj.bjp.0706007