naltrindole and dermorphin

The dermorphin-derived peptide [Dmt(1)]DALDA (H-Dmt-D-Arg-Phe-Lys-NH(2)), labels mu-opioid receptors with high affinity and selectivity in receptor binding assays. In mouse, radiant heat tail-flick assay [Dmt(1)]DALDA produced profound spinal and supraspinal analgesia, being approximately 5000- and 100-fold more potent than morphine on a molar basis, respectively. When administered systemically, [Dmt(1)]DALDA was over 200-fold more potent than morphine. Pharmacologically, [Dmt(1)]DALDA was distinct from morphine. [Dmt(1)]DALDA displayed no cross-tolerance to morphine in the model used and it retained supraspinal analgesic activity in morphine-insensitive CXBK mice. Supraspinally, it also differed from morphine in its lack of sensitivity towards naloxonazine. Finally, in antisense mapping studies, [Dmt(1)]DALDA was insensitive to MOR-1 exon probes that reduced morphine analgesia, implying a distinct receptor mechanism of action. Thus, [Dmt(1)]DALDA is an interesting and extraordinarily potent, systemically active peptide analgesic, raising the possibility of novel approaches in the design of clinically useful drugs.

Topics: Analgesics; Animals; Drug Tolerance; Humans; Mice; Morphine; Naloxone; Naltrexone; Narcotic Antagonists; Oligodeoxyribonucleotides, Antisense; Oligopeptides; Opioid Peptides; Pain Measurement; Receptors, Opioid, mu; Time Factors

Studies were performed in conscious Sprague-Dawley rats to characterize the changes in renal excretory function produced by activation of delta opioid systems. The intravenous infusion of 50 microgram/kg/min, BW373U86 (BW), a nonpeptide delta opioid receptor agonist, produced a significant increase in urine flow rate and urinary sodium excretion. The infusion of BW at a dose of 30 microgram/kg/min produced diuresis without affecting urinary sodium excretion. In contrast, BW did not alter either renal excretory parameter at a dose of 10 microgram/kg/min. The renal responses produced by BW occurred without changes in heart rate or mean arterial blood pressure. The diuretic and natriuretic responses produced by the i.v. infusion of BW (50 microgram/kg/min) were prevented by pretreatment of animals with the selective delta opioid receptor antagonist, naltrindole (1 mg/kg, i.v.). When administered alone, naltrindole (1 mg/kg, i.v.) failed to change any systemic cardiovascular or renal excretory parameter. In other groups of animals, the peripheral administration of the delta opioid receptor agonist, SNC80, also evoked a profound diuretic and natriuretic response (naltrindole sensitive) similar to that produced by BW. In contrast to these findings, the diuretic and natriuretic response produced by BW infusion (30 or 50 microgram/kg/min, i.v.) was abolished in rats having undergone chronic bilateral renal denervation. Together, these results demonstrate that the peripheral administration of BW373U86 or SNC80 produce marked diuretic and natriuretic responses in conscious Sprague-Dawley rats via a delta opioid receptor pathway and that intact renal nerves are required for mediating these responses. Although endogenous delta opioid systems do not appear to exert a tonic influence under basal conditions, these findings suggest that delta opioid pathways may evoke significant changes in renal excretory function under conditions in which these systems are activated.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Benzamides; Denervation; Infusions, Intravenous; Kidney; Male; Naltrexone; Oligopeptides; Opioid Peptides; Piperazines; Rats; Rats, Sprague-Dawley; Receptors, Opioid, delta

We examined the in vitro and in vivo bioactivities of several families of peptidomimetic opioids including: constrained linear enkephalin (n = 12 analogs), dermorphin (n = 9 analogs) and morphiceptin (n = 17 analogs). The biological activities were assessed in vitro by examining the inhibitory effects of these agents on the electrically evoked contractions of the guinea pig ileum (GPI) and the mouse vas deferens (MVD) preparations. The in vivo bioactivities were determined from the antinociceptive activity of these agents on the 52.5 degrees C hot-plate test after spinal administration of rats with chronically placed spinal catheters. Examination of the effect of cyclization, incorporation of retro-inverso bonds and substitutions of D- or constrained amino acids reveals systematic changes in the activity of these agents. There was a significant correlation between the potency of these agents in the hot-plate bioassay and their activity in the GPI and, to a lesser extent, in the MVD tests. Examination of the ability of naltrindole (a delta selective antagonist) to reverse the drug action and the respective potency on the GPI and MVD, showed that a correlation exists with actions on the MVD, but not on the GPI, consistent with the likelihood that agents with high MVD/GPI ratios in vitro act at the mu sites, whereas those with low MVD/GPI ratios act at the delta receptor in the spinal cord. The close correlations between activity in the GPI and spinal cord suggest that the structural requirements for potency in the smooth muscle and in the spinal cord are essentially the same as those mu receptors that mediate nociceptive transmission.

Topics: Amino Acid Sequence; Analgesia; Analgesics, Opioid; Animals; Dose-Response Relationship, Drug; Endorphins; Enkephalins; Injections, Spinal; Male; Mice; Molecular Sequence Data; Muscle, Smooth; Naloxone; Naltrexone; Narcotic Antagonists; Nociceptors; Oligopeptides; Opioid Peptides; Rats; Rats, Sprague-Dawley; Receptors, Opioid, delta; Receptors, Opioid, mu; Spinal Cord; Structure-Activity Relationship; Vas Deferens