Long‐lasting antinociceptive effects of a novel dynorphin analogue, Tyr‐D‐Ala‐Phe‐Leu‐Arg ψ (CH₂NH) Arg‐NH₂, in mice

Abstract

1 Tyr-D-Ala-Phe-Leu-Arg c (CH 2 NH) Arg-NH 2 (SK-9709) is a dynorphin derivative in which the peptide bond was replaced with a c (CH 2 NH) bond. In the present study, the antinociceptive eects of SK-9709 were determined in an acetic acid-induced writhing test and a hot-plate test. , s.c.). The eects of SK-9709 (s.c.) were also reversed by the selective mopioid receptor antagonist b-funaltrexamine (4.7 nmol per mouse, i.c.v.), and k-opioid receptor antagonist nor-binaltorphimine (4.9 nmol per mouse, i.t.). 4 In the hot-plate test, the antinociceptive eect of SK-9709 (s.c., i.c.v. and i.t.) was also dosedependent with the maximal peak eect at 120, 15 and 15 min similarly to the acetic acid-induced writhing test. The antinociceptive eects were dose-dependent and ED 50 values (range of 95% con®dence limits) after s.c., i.c.v. and i.t. injection were 39.1 (5.4 ± 283.0) mmol kg 71 , 6.5 (4.0 ± 10.7) and 7.4 (5.0 ± 11.0) nmol per mouse, respectively. 5 These ®ndings indicated that systemically administered SK-9709 produced long-lasting antinociceptive eects and these eects were mediated by both supra-spinal m-and spinal k-opioid receptors.

Reinstatement of cocaine place-conditioning prevented by the peptide kappa-opioid receptor antagonist arodyn

“…While the present study has utilized i.c.v. administration of arodyn, a number of studies have shown that dynorphin A analogs can cross the blood-brain barrier and remain active after systemic administration (Yu et al, 1997;Butelman et al, 1999;Hiramatsu et al, 2001;Brugos et al, 2004). In recent work, arodyn has been shown to cross a model of the blood-brain barrier (Chappa, Fang, Aldrich and Lunte, manuscript in preparation).…”

Dynorphin a Analogs for the Treatment of Chronic Neuropathic Pain

“…Another analog that was designed for an increase in stability was, SK-9709 (H-Tyr-DAla-Phe-Leu-ArgΨ(CH 2 NH)-Arg-NH 2 ), in which the peptide bond was replaced by a Ψ (CH 2 NH) bond. SK-9709 showed antinociceptive effects in the acetic acid induced writhing test after subcutaneous, intracerebroventricular and intrathecal injections and was able to cross the BBB [51]. Although E-2078 and SK-9709 both appear to be promising, selective and stable KOR agonists, they were found to be effective in inflammatory pain models, the formalin test and acetic acid-induced writhing test.…”

“…0.63 [15,51] Dyn A-(1-11)NH 2 H-Y-G-G-F-L-R-R-I-R-P-K-NH 2 1/17/44 1.1 ± 0.3 [40] [DAla 3 ] DynA-(1-11) NH 2 H-Y-G-a-F-L-R-R-I-R-P-K-NH 2 1/350/1300 8.1 ± 2.3 [40] [DPro] DynA-(1-11)…”

The Involvement of µ-Opioid Receptors in the Central Nervous System in the Worsening of Allergic Airway Inflammation by Psychological Stress in Mice

“…In experiments with opioid receptor antagonists (fig. 1b), β-funaltrexamine (β-FNA; (a MOR antagonist; Tocris, Bristol, UK), naltrindole (a δ-opioid receptor antagonist; Sigma), nor-binaltorphimine (nor-BNI; a ĸ-opioid receptor antagonist; Sigma) and naloxone methiodide (a nonselective opioid receptor antagonist; Sigma) were intraperitoneally or intracerebroventricularly administered 1 h before each period of stress at the dose indicated [29,30,31] to the stressed and nonstressed mice. These mice were then exposed to OVA on day 37 (second challenge).…”