The nociceptin receptor antagonist [Nphe1,Arg14,Lys15]nociceptin/orphanin FQ-NH2 blocks the stimulatory effects of nociceptin/orphanin FQ on the HPA axis in rats.
Nociceptin/orphanin FQ (N/OFQ) is an opioid-related peptide that stimulates corticosterone release after i.c.v. administration in non-stressed rats. We employed in situ hybridization histochemistry to investigate N/OFQ-stimulated activation of the HPA axis at the hypothalamic and pituitary level. We have demonstrated that N/OFQ-induced activation of the HPA axis is mediated via the central N/OFQ peptide receptor (NOP) using the recently described selective NOP antagonist [Nphe(1),Arg(14),Lys(15)]nociceptin/orphanin FQ-NH(2) (UFP-101). We found that, at 30 min post-i.c.v. injection, N/OFQ dose-dependently increased plasma adrenocorticotrophin hormone and corticosterone compared with the vehicle-injected controls. N/OFQ (1.0 microg) significantly increased CRF mRNA but not AVP mRNA within the parvocellular hypothalamic paraventricular nucleus compared with the control group, and significantly increased pro-opiomelanocortin (POMC) mRNA in the anterior pituitary. While UFP-101 (1.0 microg) alone had no significant effect on plasma corticosterone concentration it blocked the effect of N/OFQ (1.0 microg) on plasma corticosterone levels when compared with N/OFQ administered alone. UFP-101 also blocked the N/OFQ-induced increase in CRF mRNA and POMC mRNA. These results demonstrate that centrally administered N/OFQ activates the HPA axis via up-regulation of CRF and POMC mRNA and stimulation of corticosterone release in rats. Further, we have demonstrated for the first time that the selective NOP receptor antagonist UFP-101 blocks these effects indicating that N/OFQ-induced HPA axis activation is mediated via central NOP receptors.
Leggett
J D
JD
Department of Anatomy, University of Bristol, Southwell Street, Bristol BS2 8EJ, UK. James.Leggett@bristol.ac.uk
Harbuz
M S
MS
Jessop
D S
DS
Fulford
A J
AJ
D000324:Adrenocorticotropic Hormone / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D003345:Corticosterone / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects*; D017403:In Situ Hybridization / Q000379:methods; D007276:Injections, Intraventricular / Q000379:methods; D008297:Male; D018847:Opioid Peptides / Q000494:pharmacology*; D010913:Pituitary-Adrenal System / Q000187:drug effects*; D011863:Radioimmunoassay / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley; D011957:Receptors, Opioid / Q000819:agonists*; D013329:Structure-Activity Relationship; D013997:Time Factors; D014665:Vasodilator Agents / Q000494:pharmacology*; D000094942:Nociceptin Receptor; D000097629:Nociceptin
D000324:Adrenocorticotropic Hormone; D003345:Corticosterone; D018847:Opioid Peptides; D011957:Receptors, Opioid; D014665:Vasodilator Agents; D000094942:Nociceptin Receptor; D000097629:Nociceptin; C479838:(Nphe(1),Arg(14),Lys(15))N-OFQ NH(2); C000722285:Oprl1 protein, rat