title: Dynorphin A(6-12) analogs suppress thermal edema.
abstract: Dynorphin A (Dyn A) is a 17-residue opioid peptide derived from prodynorphin precursors found in mammalian tissues. Removal of Tyr1 from Dyn A produces a peptide that is more potent than Dyn A in attenuating the acute phase of the inflammatory response, as measured by inhibition of heat-induced edema in the anesthetized rat's paw (exposure to 58 degrees C water for 1 min). Dyn A(2-17), however, no longer interacts with opioid receptors. It was postulated that the non-opioid anti-inflammatory actions of Dyn A(2-17) may reside in Dyn A(6-12); that is, Arg-Arg-Ile-Arg-Pro-Lys-Leu. here we report on the activities of Dyn A(6-12) analogs modified by substitutions on the N terminus, by single N-methyl substitution and by single replacement of residues by alanine. The results indicated that the minimal sequence required for an anti-edema ED50 of <1.0 micromol/kg i.v. was anisoyl-Arg6-Arg7-Xaa8-Arg9-Pro10)-Xaa11-+ ++Xaa12-NH2. A prototype, p-anisoyl-[D-Leu12] Dyn A(6-12)-NH2, with an ED50 of 0.20 micromol/kg i.v. compared to an ED50 of 0.08 micromol/kg i.v. for Dyn A(2-17), was selected for further tests of biological activity. This analog, like Dyn A(2-17), lowered blood pressure in anesthetized rats. In a model of neurogenic inflammation, produced by antidromic stimulation of the vagus in the anesthetized rat, p-anisoyl-[D-Leu12] Dyn A(6-12)-NH2, 0.23 micromol/kg i.v., attenuated the negativity of tracheal tissue interstitial pressure (Pif), which normally develops after nerve stimulation. Modulation of interstitial pressure may be the mechanistic basis for the anti-edema properties of these Dyn A(6-12) analogs.
authors.affiliation: School of Public Health, University of California, Berkeley 94720, USA.
authors.forename: E T
authors.initials: ET
authors.lastname: Wei
authors.forename: H A
authors.initials: HA
authors.lastname: Thomas
authors.forename: E A
authors.initials: EA
authors.lastname: Gjerde
authors.forename: R K
authors.initials: RK
authors.lastname: Reed
authors.forename: S V
authors.initials: SV
authors.lastname: Burov
authors.forename: V I
authors.initials: VI
authors.lastname: Korolkov
authors.forename: O V
authors.initials: OV
authors.lastname: Glynskaya
authors.forename: M Y
authors.initials: MY
authors.lastname: Dorosh
authors.forename: G P
authors.initials: GP
authors.lastname: Vlasov
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000494:pharmacology*; D004399:Dynorphins / Q000737:chemistry / Q000494:pharmacology*; D004487:Edema / Q000188:drug therapy; D006614:Hindlimb / Q000473:pathology; D006358:Hot Temperature; D008297:Male; D010446:Peptide Fragments / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D010446:Peptide Fragments; C095267:dynorphin A (6-12); D004399:Dynorphins; C082245:dynorphin (2-17)