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

DALDA (H-Tyr-D-Arg-Phe-Lys-NH2) and [Dmt ]DALDA (H-DmtD-Arg-Phe-Lys-NH2) (Dmt 5 29,69-dimethyltyrosine) are potent and highly selective m-opioid agonists (Ki d/Ki m . 10,000 and Ki k/Ki m . 100). Both peptides carry a 31 charge at physiological pH. Their antinociceptive and respiratory effects were compared with morphine (MOR) after intrathecal administration in rats. Both DALDA and [Dmt]DALDA produced dose-dependent and naloxone-reversible antinociceptive effects with relative potencies of 14 and 30003 that of MOR. The antinociceptive potency of [Dmt]DALDA far exceeded its affinity and potency at the m-opioid receptor and may be explained by its ability to inhibit norepinephrine (NE) uptake in spinal cord synaptosomes. The antinociceptive response to [Dmt]DALDA was significantly attenuated by the a2-adrenergic antagonist yohimbine. Thus, [Dmt]DALDA may be regarded as a drug with dual actions, and its antinociceptive potency is better described by both its affinity and potency at m-opioid receptors, and its potency at inhibiting NE uptake. The analgesic duration of an equipotent dose of MOR, DALDA, and [Dmt]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 303 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 [Dmt]DALDA. Because of its high antinociceptive potency, long duration of action, and low propensity to induce respiratory depression, [Dmt]DALDA is of interest as a drug candidate for intrathecal analgesia. The intrathecal administration of opioids is a useful technique in pain management. It is used in the management of postoperative pain, cancer pain, and pain associated with labor and delivery. Presently, the most often-used intrathecal opioids include morphine, fentanyl, and sufentanil. Following distribution within the cerebrospinal fluid (CSF), the opioids penetrate through the pia mater and into the spinal cord where they act on opioid receptors in the superficial laminae of the dorsal horn. Lipid solubility is the major determinant of the rate of onset of opioid action: the more lipid soluble the opioid, the more rapid the onset of action. Thus, sufentanil has a much more rapid onset of action than fentanyl or morphine. However, the physicochemical properties of opioids not only determine their rate of absorption but also their clearance from CSF into the vascular system and their distribution within the CSF (Payne and Inturrisi, 1985; Moulin et al., 1986; Hansdottir et al., 1991). The increased lipid solubility results in increased systemic absorption, which limits the duration of analgesia. Although morphine has a longer duration of action than fentanyl, it is still too short-acting for many purposes and repeat dosing or intrathecal infusion is often required. In addition, the slow clearance of hydrophilic drugs from CSF allows for rostral spread of the opioid to medullary respiratory centers, thereby resulting in respiratory depression. Although respiratory depression is less of a problem with the more lipophilic drugs, delayed respiratory depression is the most dangerous side effect after intrathecal morphine (Cousins and Mather,