Gastric acid secretion stimulated by centrally injected nociceptin in urethane-anesthetized rats.
ABSTRACT Nociceptin is a preferred endogenous ligand for the orphan opioid receptor-like 1 (ORL1) receptor. Central administration of nociceptin showed various pharmacological effects on analgesia, cardiovascular and renal responses, food intake, and so on. In the present study, we investigated the effect of nociceptin injected into the central nervous system (CNS) on gastric acid secretion in the perfused stomach of urethane-anesthetized rats. Injection of nociceptin (0.55-5.52 nmol per rat) into the fourth cerebroventricle stimulated gastric acid secretion and the secretion was inhibited in atropine-treated (1 mg/kg, i.v.) and vagotomized rats. The secretion induced by nociceptin (1.65 nmol) was not inhibited by the central injection of naloxone (275 nmol, a non-selective antagonist of opioid receptors). The secretion was significantly inhibited by the central injection of [Phe(1)psi(CH(2)-NH)Gly(2)]nociceptin-(1-13)-NH(2) ([F/G]nociceptin-(1-13), 0.21 nmol, an antagonist of ORL1 receptor), although [F/G]nociceptin-(1-13) alone at higher doses (2.10 and 7.31 nmol) markedly stimulated gastric acid secretion. In the 0-40 min period, the secretion induced by nociceptin was inhibited at least partially by CompB (68.8 nmol, a nonpeptidic antagonist of ORL1 receptor). Injection of nociceptin (5.52 nmol) into the lateral cerebroventricle also stimulated the secretion. Injection of nociceptin did not modify gastric acid secretion stimulated by 2-deoxy-D-glucose (200 mg/kg, i.v.). In conclusion, nociceptin injected into the CNS stimulated gastric acid secretion in rats via the ORL1 receptors and through mechanisms involving the vagus nerve.
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ABSTRACT: Nocistatin (NST) and Nociceptin/Orphanin FQ (N/OFQ) are derived from the same precursor protein, pre-proN/OFQ, and exert opposite effects on the modulation of pain signals. However, the role of the peripheral N/OFQ and the NOP receptor, which is located at the endings of sensory nerves, in inflammatory pain was not ascertained. NST administered intrathecally (i.t.) prevented the nociceptive effects induced by i.t. N/OFQ and PGE₂. Moreover an up regulation of N/OFQ was shown in the rat in response to peripheral inflammation. Here, we investigated the effects of intraplantar (i.pl.) administration of functional N/OFQ and NOP receptor antagonists in a rat model of inflammatory pain. Our findings showed that i.pl. injection of (±)-J 113397, a selective antagonist of the NOP receptor, and NST, the functional N/OFQ antagonist, prior to carrageenan significantly reduced the paw allodynic and thermal hyperalgesic threshold induced by the inflammatory agent. The resulting antiallodynic and antihyperalgesic effects by co-administering NST and (±)-J 113397 prior to carrageenan were markedly enhanced, and the basal latencies were restored. Thus, it is likely that the peripheral N/OFQ/NOP receptor system contributes to the abnormal pain sensitivity in an inflammatory state.Pharmacology Biochemistry and Behavior 11/2011; 100(3):639-44. · 2.61 Impact Factor
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ABSTRACT: 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 microg/rat, or by the intraperitoneal (ip) route, at 10 microg/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, alpha-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 microg/rat) and ip (10 mg/kg) injected, did not modify the response to icv and ip N/OFQ. Pretreatment with alpha-helical CRF(9-41) (25 microg/rat icv or 250 microg/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.Regulatory Peptides 12/2008; 154(1-3):32-8. · 2.06 Impact Factor
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ABSTRACT: Previous studies show that the opioid peptide nociceptin stimulates food intake. Here, we studied nociceptin receptor knockout (NOP KO) mice in various behavioral paradigms designed to differentiate psychological and physiological loci at which endogenous nociceptin might control feeding. When presented a choice under food restriction, NOP KO mice displayed reduced preference for high sucrose diet, but lower intake of high fat diet under no-choice conditions. These responses were absent under ad libitum feeding conditions. Conditioned place preference to high fat diet under food-deprived conditions was unaltered in NOP KO mice, suggesting no difference in reward responses. Furthermore, operant food self-administration under a variety of conditions showed no genotype-dependent differences, suggesting no differences in the motivational properties of food. Taste reactivity to sucrose was unchanged in NOP KO mice, though NOP KO mice had altered aversive reactions to quinine solutions under ad libitum feeding, suggesting minor differences in the affective impact of palatable and unpalatable tastants. Although NOP KO mice re-fed following food-deprivation showed normal increases in plasma glucose and insulin, multidimensional scaling analysis showed that the relationship between these measures, body weight and plasma leptin was substantially disrupted in NOP KO, particularly in fasted mice. Additionally, the typical positive relationship between body weight and plasma leptin was considerably weaker in NOP KO mice. Together, these findings suggest that endogenous nociceptin differentially modulates diet preference depending on macronutrient content and homeostatic state, independently of the motivating, rewarding or orosensory properties of food, but may involve metabolic or postingestive processes.Physiology & Behavior 01/2009; · 3.16 Impact Factor