Pharmacological Data on Dermorphins, a New Class of Potent Opioid Peptides From Amphibian Skin

Abstract

1 Dermorphin and Hyp';-dermorphin are the first representatives of a new class of potent opioid peptides occurring in amphibian skin. They present the unique feature of having a D-Ala residue incorporated in the peptide molecule. 2 Dermorphin displayed a potent depressive action on electrically stimulated contractions of the guinea-pig ileum and mouse vas deferens preparations. Dermorphin was respectively 57,294, 18 and 39 times more potent than Met-enkephalin, Leu-enkephalin, f8-endorphin, and morphine on the guinea-pig ileum opiate receptors. On the vas deferens receptors, dermorphin was about as potent as the enkephalins and 40 times more potent than morphine. Naloxone was a powerful antagonist to dermorphin in both preparations. 3 Dermorphin produced potent and long-lasting analgesia in mice by intravenous injection, and in rats by intracerebroventricular injection, the ED9() being here of the order of 13-23 pmol/rat. Morphine was 752 and 2170 times less potent, depending on the analgesia test used. At high intracerebroventricular doses analgesia was accompanied by catalepsy. 4 Intracerebroventricular infusion of dermorphin induced development of tolerance and precipitation of withdrawal symptoms upon administration of naloxone. Both tolerance and physical dependence were consistently less marked with dermorphin than with morphine. 5

Tolerance develops in spinal cord, but not in brain with chronic [Dmt1]DALDA treatment

“…These limitations have spurred the search for opioids that may retain morphine's analgesic potency but have low tolerance. In previous studies (Schiller et al, 2000;Riba et al, 2002a), we have defined some of the pharmacological characteristics of H-2 0 ,6 0 -dimethyltyrosine [Dmt 1 ]-D-ArgPhe-Lys-NH 2 (DALDA), an analogue of the naturally occurring opioid peptide dermorphin (Broccardo et al, 1981).…”

Antinociception and physical dependence produced by [D‐Arg2] dermorphin tetrapeptide analogues and morphine in rats

“…The antinociceptive effect of dermorphin was completely antagonized by pretreatment with naloxone. In addition, tolerance and physical dependence were consistently less marked with dermorphin than with morphine (Broccardo et al, 1981).…”

“…It has been proposed that the N-terminal tetrapeptide amide (H-Tyr-D-Ala-Phe-Gly-NH2) is the minimal fragment required for opioid activity, and D-Ala in position 2 in the peptide chain of dermorphin is of crucial importance for opioid activity (Broccardo et al, 1981;De Castiglione et al, 1981;Salvadori et al, 1982b). However, it has been found experimentally that this dermorphin tetrapeptide amide fragment is rather less potent than the parent heptapeptide amide (Broccardo et al, 1981;Salvadori et al, 1982a). The antinociceptive effect of dermorphin was completely antagonized by pretreatment with naloxone.…”

“…Dermorphin (H-Tyr-D-Ala-Phe-Gly-Tyr-Pro-Ser-NH2), is a heptapeptide amide that was isolated (Erspamer & Melchiorri, 1980) and identified (Montecucchi et al, 1981) in the skin of a South American frog, and found to produce potent and long-lasting antinociceptive activity (Broccardo et al, 1981;Feuerstein & Faden, 1983;Gullner & Kelly, 1983). The antinociceptive effect of dermorphin is known to be more powerful than that of I Author for correspondence.…”

Site-specific overexpression of corticotropin-releasing hormone (CRH) in the mouse brain – modelling central CRH system hyperactivity

“…There is a high degree of homology between rat, mouse and human CRH genes (Herman et al, 1992) (Seasholtz et al, 1988) (Vamvakopoulos et al, 1990). Other CRH-like peptides were soon discovered in the urophyses of teleost fish (Catostomus commersoni) ) (Ichikawa et al, 1982) and skin of the tree frog (Phyllomedusa sauvegei) (Montecucchi and Henschen, 1981) (Broccardo et al, 1981). These peptides are known as urotensin I and sauvagine respectively, and exhibit ACTH releasing activity from pituitary with equal efficacy to human or rat CRH.…”