dermorphin and tyrosyl-arginyl-phenylalanyl-sarcosine

The binding of Tyr-D-Arg(2)-Phe-sarcosine(Sar)(4) (TAPS), a proposed mu-opioid receptor-selective tetrapeptide analog of dermorphin to opioid receptors, was studied using selective binding assays for subtypes of mu-, delta- and kappa-opioid receptors. Subtype specific mu-opioid receptor binding was further characterized in the presence of sodium and guanosine nucleotides and the activity of TAPS in isolated guinea pig ileum was compared to other mu-opioid receptor-selective ligands. Further, the antinociceptive properties of TAPS following intrathecal (i.t.) administration in rats, as a model of spinal antinociception, were evaluated. The K(i)-values for TAPS at the mu(1)- and mu(2)-opioid receptor sites were 0.4 and 1.3 nM, respectively, suggesting high affinity binding to mu-opioid receptor binding sites with an increased selectivity to mu(1)-opioid receptor sites. The attenuated reduction of TAPS binding at the mu(2)-opioid receptor subtype in the presence of the stable guanosintriphosphate analog 5'-guanylylimidodiphosphate and sodium suggests a potential partial antagonist mode of action at this site.

Topics: Analgesics; Animals; Binding, Competitive; Catalepsy; Dose-Response Relationship, Drug; Electric Stimulation; Guinea Pigs; Ileum; In Vitro Techniques; Injections, Spinal; Male; Muscle Contraction; Naloxone; Nociceptors; Oligopeptides; Opioid Peptides; Pulmonary Ventilation; Radioligand Assay; Rats; Rats, Sprague-Dawley; Receptors, Opioid; Time Factors

Tyr-D-Arg2-Phe-sarcosine4 (TAPS), a mu-selective tetrapeptide analog of dermorphin, induced sustained antinociception and stimulated ventilatory minute volume (MV) at the doses of 3 to 100 pmol i.c.v. The doses of 30 and 100 pmol i.c.v. induced catalepsy. The effect of TAPS on MV was in negative correlation with the dose and the maximal response was achieved by the lowest (3 pmol) dose (+63 +/- 23%, P < .05). Morphine, an agonist at both mu 1 and mu 2 sites, at a dose of 150 nmol i.c.v. (equianalgesic to 100 pmol of TAPS decreased the MV by 30%, due to a decrease in ventilatory tidal volume. The antinociceptive effect of TAPS was antagonized by naloxone and the mu 1 receptor antagonist, naloxonazine. Naloxonazine also attenuated the catalepsy produced by 100 pmol of TAPS i.c.v. and the respiratory stimulation produced by 3 pmol of TAPS i.c.v. Pretreatment with 30 pmol of TAPS antagonized the respiratory depression induced by the mu opioid agonist dermorphin (changes in MV after dermorphin alone at 1 or 3 nmol were -22 +/- 10% and -60 +/- 9% and, after pretreatment with TAPS, +44 +/- 11% and -18 +/- 5%, respectively). After combined pretreatment with naloxonazine and TAPS, 1 nmol of dermorphin had no significant effect on ventilation. In contrast, pretreatment with a low respiratory stimulant dose (10 pmol i.c.v.) of dermorphin did not modify the effect of 1 nmol of dermorphin. In conclusion, the antinociceptive, cataleptic and respiratory stimulant effects of TAPS appear to be a related to its agonist action at the mu 1 opioid receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Amino Acid Sequence; Analgesics; Animals; Catalepsy; Dose-Response Relationship, Drug; Male; Molecular Sequence Data; Naloxone; Oligopeptides; Opioid Peptides; Rats; Rats, Sprague-Dawley; Receptors, Opioid, mu; Respiration