The hypothalamus–pituitary–adrenal axis does not influence the protective effects of nociceptin/orphanin FQ on the rat gastric mucosa Daniela Grandi a , Elvira Solenghi a , Remo Guerrini b , Maria Broccardo c , Simona Agostini c , Carla Petrella c , Sergio Scaccianoce c , Giovanna Improta c , Giuseppina Morini a, ⁎ a Department of Human Anatomy, Pharmacology and Forensic Medicine, University of Parma, Italy b Department of Pharmaceutical Sciences and Biotechnology Center, University of Ferrara, Italy c Department of Physiology and Pharmacology, University Sapienza of Rome, Italy abstract article info Article history: Received 23 July 2008 Received in revised form 3 November 2008 Accepted 6 November 2008 Available online 21 November 2008 Keywords: Mifepristone α-helical CRF 9–41 Adrenalectomy Nociceptin Ethanol-induced gastric lesions Rat The participation of hypothalamus–pituitary–adrenal axis in the gastroprotective effects of nociceptin/ orphanin FQ (N/OFQ) has been investigated. Gastric mucosal lesions were induced by intragastric administration of 50% ethanol, 1 ml/rat. Rats received N/OFQ either by the intracerebroventricular (icv) route, at 3 μg/rat, or by the intraperitoneal (ip) route, at 10 μg/kg, 30 min before ethanol administration. The protective effect of icv and ip administered N/OFQ was assessed in adrenalectomized rats and in rats pretreated with the glucocorticoid receptor antagonist, mifepristone, or with the CRF receptor antagonist, α- helical CRF 9–41 . The damaging effect of ethanol was apparently not influenced by adrenalectomy. N/OFQ markedly reduced macroscopically and histologically assessed gastric mucosal damage. The extent of reduction by N/OFQ was comparable in adrenalectomized and in sham-operated rats, with either icv or ip route of administration. Pretreatment with mifepristone, both icv (80 μg/rat) and ip (10 mg/kg) injected, did not modify the response to icv and ip N/OFQ. Pretreatment with α-helical CRF 9–41 (25 μg/rat icv or 250 μg/ kg ip), had no effect on the reduction of gastric damage produced by icv or ip N/OFQ. Present findings suggest that the gastroprotective effects of N/OFQ on ethanol-induced damage do not involve the endocrine pathway through the HPA axis. © 2008 Elsevier B.V. All rights reserved. 1. Introduction The neuropeptide nociceptin/orphanin FQ (N/OFQ), its receptor (NOP), and their mRNA s are widely distributed in the central nervous system [1,2] and in the periphery [3,4], where they constitute a neurotransmitter system involved in several functional responses including some gastrointestinal activities [3–5]. Recent evidences suggested potential interactions between the N/ OFQ-NOP receptor system and the hypothalamus–pituitary–adrenal (HPA) axis. Icv injection of N/OFQ significantly increases circulating adrenocorticotropic hormone and corticosterone levels in unstressed and mildly stressed rats [6–8]. The increase in levels of both hormones peaked between 15 and 30 min after N/OFQ injection and returned to basal levels within 60 min [7]. The HPA axis has also a role in the anxiety-modulating effects exerted by N/OFQ [9,10]. In addition, N/OFQ and corticotropin-releasing factor (CRF), the main regulator of the HPA axis, appear to be linked in the regulation of a number of central and peripheral functions. The anorectic effect of CRF, given icv or into the bed nucleus of the stria terminalis, and the faecal pellet output stimulated by icv and ip CRF were both reversed by N/OFQ, leading to the hypothesis of a functional antagonism between the two neuropep- tides [11–13]. Conversely, the hyperphagic effect [8] and the inhibition of gastric emptying [14]caused by central N/OFQ in rats were abolished in adrenalectomized (ADX) rats, counteracted by mifepristone and by the non-selective CRF antagonist, alpha-helical CRF 9–41 , indicating a functional agonism between the HPA axis and N/OFQ. Furthermore, evidence is provided that both the HPA axis and N/ OFQ are of relevance in the maintenance of gastric mucosal integrity. Despite the difference in the experimental conditions, ablation of adrenal glands is commonly considered to impair the defensive mechanisms of the gastric mucosa. Controversial data have been reported concerning glucocorticoids and their influence on rat gastric mucosa. In absence of ulcerogenic stimuli, glucocorticoids appear to be inactive following a single [15] or repeated [16] administration of low to moderate doses, while they are ulcerogenic following repeated administration of large doses [17,18]. By contrast, exogenous gluco- corticoids are shown to prevent damage by ulcerogenic stimuli [19], and accordingly, endogenous glucocorticoids released by stressful stimuli, have been established to exert a gastroprotective effect [20,21]. CRF, icv administered, inhibits gastric hemorrhagic lesions induced by water- and cold-restraint in rats [22–24], while being Regulatory Peptides 154 (2009) 32–38 ⁎ Corresponding author. Department of Human Anatomy, Pharmacology and Forensic Medicine, University of Parma, Via Volturno 39, 43100 Parma, Italy. Tel.: +39 0521 903937; fax: +39 0521 903852. E-mail address: giuseppina.morini@unipr.it (G. Morini). 0167-0115/$ – see front matter © 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.regpep.2008.11.002 Contents lists available at ScienceDirect Regulatory Peptides journal homepage: www.elsevier.com/locate/regpep