Antinociceptive and respiratory effects of intrathecal H-Tyr-D-Arg-Phe-Lys-NH2 (DALDA) and [Dmt(1)]DALDA

DALDA (H-Tyr-D-Arg-Phe-Lys-NH2) and [Dmt(1)]DALDA (H-Dmt-D-Arg-Phe-Lys-NH2) (Dmt = 2', 6'-dimethyltyrosine) are potent and highly selective mu -opioid agonists (K-i(delta)/K-i(mu) >10,000 and K-i(k)/K-i(mu) > 100). Both pepti des carry a 3+ charge at physiological pH. Their antinociceptive and respir atory effects were compared with morphine (MOR) after intrathecal administr ation in rats. Both DALDA and [Dmt(1)]DALDA produced dose-dependent and nal oxone-reversible antinociceptive effects with relative potencies of 14 and 3000x that of MOR. The antinociceptive potency of [Dmt(1)]DALDA far exceede d its affinity and potency at the mu -opioid receptor and may be explained by its ability to inhibit norepinephrine (NE) uptake in spinal cord synapto somes. The antinociceptive response to [Dmt(1)]DALDA was significantly atte nuated by the alpha (2)-adrenergic antagonist yohimbine. Thus, [Dmt(1)]DALD A may be regarded as a drug with dual actions, and its antinociceptive pote ncy is better described by both its affinity and potency at mu -opioid rece ptors, and its potency at inhibiting NE uptake. The analgesic duration of a n equipotent dose of MOR, DALDA, and [Dmt(1)]DALDA was 3, 7, and 13 h, resp ectively, and the long duration may be due to the hydrophilic nature of the se peptide analogs. Respiratory effects were determined using whole body pl ethysmography at 3 and 30x the antinociceptive ED50. A significant depressi on in minute ventilation was observed with the higher dose of morphine and both doses of DALDA, but not with either dose of [Dmt(1)]DALDA. Because of its high antinociceptive potency, long duration of action, and low propensi ty to induce respiratory depression, [Dmt(1)]DALDA is of interest as a drug candidate for intrathecal analgesia.