Nociceptin Inhibits Uterine Contractions in Term-Pregnant Rats by Signaling Through Multiple Pathways1

Abstract

The actions of the endogenous peptide nociceptin (PNOC; previously abbreviated as N/OFQ) on the myometrium have not been investigated previously. Our aim was to study the presence and functional role of PNOC in the modulation of uterine contractility in pregnant rats at term. The presence of PNOC and its receptors (OPRL1; previously called NOP) in the uterus were detected by radioimmunoassay and radioligand-binding experiments. The PNOC-stimulated G protein activation was assessed by a [(35)S]GTPgammaS-binding technique. The effects of PNOC in uterine rings precontracted with KCl or oxytocin were also tested in vitro. Uterine levels of cAMP were measured by enzyme immunoassay. The K(+) channel blockers tetraethylammonium and paxilline were used to study the role of K(+) channels in mediating the uterine effects of PNOC. Both PNOC and OPRL1 were present in the uterus. PNOC revealed a maximum contraction inhibition of approximately 30%, which was increased to 40% by naloxone. Naloxone and pertussis toxin significantly attenuated the G protein-stimulating effect of PNOC. The uterine cAMP levels were elevated by PNOC and naloxone and after preincubation with pertussis toxin. Tetraethylammonium and paxilline reduced the contraction-inhibiting effect of PNOC and naloxone to approximately 10% and 15%, respectively. We presume that PNOC plays a role in regulating uterine contractility at term. Its effect is mediated partly by stimulatory heterotrimeric G (G(s)) proteins coupled to OPRL1 receptors and elevated cAMP levels, and also by Ca(2+)-dependent K(+) channels. Our results demonstrate a novel action and signaling pathway for PNOC that might be a potential drug target.

Uterus-Relaxing Effects of Nociceptin and Nocistatin: Studies on Preterm and Term-Pregnant Human Myometrium In vitro

“…As reported earlier by our group [13,14]; N/OFQ and NST; the translation products of the PNOC gene; inhibit uterine contractions in the pregnant rat. Despite a large body of literature on the role of opioid peptides in pain modulation in humans; limited information is available on their actions in the human uterus.…”

“…We have previously demonstrated the CGRP-liberating effect of NST; and also the cAMP-accumulating and potassium channel opening effects of N/OFQ [13,14]. These mechanisms may additionally explain the uterus-relaxant effects of N/OFQ and NST and their intracellular signaling in the human uterus.…”

Effects of Nociceptin and Nocistatin on Uterine Contraction

“…A radioligand binding study has revealed that NOP-R is expressed in the rat myometrium (Klukovits et al, 2010). In the uteri of the nonpregnant female rat, the maximum binding capacity and the dissociation constant of the NOP-R do not differ significantly from those in the 22-day-pregnant rat myometrium.…”

“…The expressions of PNOC mRNA have been investigated in rat and human pregnant myometrial tissues (Deak, Klukovits, Kormányos, et al, 2013;Klukovits et al, 2010). In rats, PNOC mRNA levels of the pregnant myometrium increase significantly as term approaches.…”

“…(B) p < 0.001 as compared with human term myometrium. Data for this figure were taken from the articles Klukovits et al (2010) and Deak, Klukovits, Kormányos, et al (2013). understood through the expressions and effects of N/OFQ and NST in both rat and human pregnant myometria.…”