Vol. 297, Issue 1, 364-371, April 2001

Antinociceptive and Respiratory Effects of Intrathecal H-Tyr-D-Arg-Phe-Lys-NH₂ (DALDA) and [Dmt¹]DALDA

Megumi Shimoyama, Naohito Shimoyama, Guo-Min Zhao, Peter W. Schiller and Hazel H. Szeto

Department of Physiology, Chiba University School of Medicine, Chuo-ku, Chiba-shi, Chiba-ken, Japan (M.S.); Department of Pain and Palliative Care, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan (N.S.); Department of Pharmacology, Cornell University Medical College, New York, New York (G.M.Z., H.H.S.); and Laboratory of Chemical Biology and Peptide Research, Clinical Research Institute of Montreal, Montreal, Quebec, Canada (P.W.S.)

DALDA (H-Tyr-D-Arg-Phe-Lys-NH₂) and [Dmt¹]DALDA (H-Dmt-D-Arg-Phe-Lys-NH₂) (Dmt = 2',6'-dimethyltyrosine) are potent and highly selective µ-opioid agonists (K_i/K_i^µ > 10,000 and K_i/K_i^µ > 100). Both peptides carry a 3+ charge at physiological pH. Their antinociceptive and respiratory effects were compared with morphine (MOR) after intrathecal administration in rats. Both DALDA and [Dmt¹]DALDA produced dose-dependent and naloxone-reversible antinociceptive effects with relative potencies of 14 and 3000× that of MOR. The antinociceptive potency of [Dmt¹]DALDA far exceeded its affinity and potency at the µ-opioid receptor and may be explained by its ability to inhibit norepinephrine (NE) uptake in spinal cord synaptosomes. The antinociceptive response to [Dmt¹]DALDA was significantly attenuated by the ₂-adrenergic antagonist yohimbine. Thus, [Dmt¹]DALDA may be regarded as a drug with dual actions, and its antinociceptive potency is better described by both its affinity and potency at µ-opioid receptors, and its potency at inhibiting NE uptake. The analgesic duration of an equipotent dose of MOR, DALDA, and [Dmt¹]DALDA was 3, 7, and 13 h, respectively, and the long duration may be due to the hydrophilic nature of these peptide analogs. Respiratory effects were determined using whole body plethysmography at 3 and 30× the antinociceptive ED₅₀. A significant depression in minute ventilation was observed with the higher dose of morphine and both doses of DALDA, but not with either dose of [Dmt¹]DALDA. Because of its high antinociceptive potency, long duration of action, and low propensity to induce respiratory depression, [Dmt¹]DALDA is of interest as a drug candidate for intrathecal analgesia.