TY - JOUR T1 - Antinociceptive and Respiratory Effects of Intrathecal H-Tyr-<span class="sc">d</span>-Arg-Phe-Lys-NH<sub>2</sub> (DALDA) and [Dmt<sup>1</sup>]DALDA JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 364 LP - 371 VL - 297 IS - 1 AU - Megumi Shimoyama AU - Naohito Shimoyama AU - Guo-Min Zhao AU - Peter W. Schiller AU - Hazel H. Szeto Y1 - 2001/04/01 UR - http://jpet.aspetjournals.org/content/297/1/364.abstract N2 - 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 (Kiδ/Kiμ&gt; 10,000 andKiκ/Kiμ&gt; 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 α2-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. The American Society for Pharmacology and Experimental Therapeutics ER -