Study in vitro and in vivo of nociceptin/orphanin FQ(1–13)NH2 analogues substituting N-Me-Gly for Gly2 or Gly3

Abstract

In the present study, two analogues containing N-Me-Gly (Sarcosine, Sar) were synthesized to further investigate the structural-activity relationships of orphanin FQ/nociceptin (OFQ/NC, NC). The replacement of Gly 2 or Gly 3 with Sar increased the flexibility and decreased the hydrophobicity of the N-terminal tetrapeptide. The activity of the analogues was investigated in a series of assays in vivo and in vitro.[Sar 2 ]NC(1-13)NH 2 was found to (1) produce dose-dependent inhibition of the electrically induced contraction in MVD assay (pEC 50 = 6.14); (2) produce significant hyperalgesia effects in a dose-dependent manner when intracerebroventricularly (i.c.v.) injected in mice. The inhibitive effects of [Sar 2 ]NC(1-13)NH 2 in MVD assay could be significantly antagonized by [Nphe 1 ]NC(1-13)NH 2 , and partially antagonized by naloxone; the hyperalgesic effect of [Sar 2 ]NC(1-13)NH 2 could be significantly antagonized by naloxone, and partially antagonized by [Nphe 1 ]NC(1-13)NH 2 . On the contrary, [Sar 3 ]NC(1-13)NH 2 showed no effects in these assays. All the findings suggest that the flexibility of the peptide bond between Phe 1 and Gly 2 and between Gly 2 and Gly 3 play an important role in NC-OP 4 receptor interaction, and the hydrophobicity of the N-terminal tetrapeptide showed no significant effect on this interaction. The present work also helps to provide a novel method to elucidate structural and conformational requirements of the opioid peptide-receptor interaction.

Persistent Catechol-O-methyltransferase–dependent Pain Is Initiated by Peripheral β-Adrenergic Receptors

“…As previous preclinical and clinical studies have reported sex-specific differences in COMT-related phenotypes 79-83 and as males and females exhibit different COMT expression patterns, 84,85 we examined the contribution of peripheral adrenergic systems to COMT-dependent pain in both males and females. Counter to our expectation, male and female rats exhibited a comparable increase in mechanical and thermal pain following sustained systemic OR486 administration, which was blocked by suppressing peripheral adrenergic tone.…”

Catechol-O-methyltransferase inhibition alters pain and anxiety-related volitional behaviors through activation of β-adrenergic receptors in the rat

“…It is well-established that males and females differ with respect to COMT activity levels, with males exhibiting higher levels in brain (Chen et al, 2004) and peripheral tissues (Boudikova et al, 1990). A growing literature continues to demonstrate that the effects of COMT on nociception, cognition, and behavioral traits such as anxiety are sexually dimorphic, with the magnitude and direction of the effect being highly assay-dependent (Gogos et al, 1998, Harrison and Tunbridge, 2008, Papaleo et al, 2012, Belfer et al, 2013, Sannino et al, 2014, White et al, 2014).…”

Acupuncture Resolves Persistent Pain and Neuroinflammation in a Mouse Model of Chronic Overlapping Pain Conditions

“…As previous preclinical and clinical studies have reported sex differences in COMT-related phenotypes 5, 29, 36, 75, 105 and COMT expression patterns 7, 10 , we examined the effects of acupuncture in both males and females. We found that male and female mice in this study exhibited comparable increases in mechanical pain following sustained delivery of OR486.…”