Involvement of glutamate and γ-amino-butyric acid receptor systems on gastric acid secretion induced by activation of κ-opioid receptors in the central nervous system in rats

Various neurotransmitters in the brain regulate gastric acid secretion. Previously, we reported that the central injection of κ-opioid receptor agonists stimulated this secretion in rats. Although the existence of κ1–κ3-opioid receptor subtypes has been proposed, the character is not defined. We investigated the interactions between κ-opioid receptor subtypes and glutamate, γ-amino-butyric acid (GABA) or 5-hydroxy tryptamine (5-HT) receptors in the rat brain. Gastric acid secretion induced by the injection of {"type":"entrez-nucleotide","attrs":{"text":"U69593","term_id":"4205069","term_text":"U69593"}}U69593 (8.41 nmol, a putative κ1-opioid receptor agonist) into the lateral cerebroventricle was completely inhibited by the central injection of 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, 10.9 nmol, an antagonist for non-N-methyl-D-aspartate (non-NMDA) receptors) and by bicuculline infusion (222 μg kg−1 per 10 min, i.v., GABAA receptor antagonist). The secretion induced by bremazocine (8.52 nmol, a putative κ2-opioid receptor agonist) was inhibited by bicuculline infusion, but not by CNQX. The secretion induced by naloxone benzoylhydrazone (224 nmol, a putative κ3-opioid receptor agonist) was slightly and partially inhibited by CNQX and bicuculline. Treatment with CNQX and bicuculline inhibited gastric acid secretion induced by the injection of dynorphin A-(1-17) into the lateral, but not the fourth, cerebroventricle. Antagonists for NMDA, GABAB and 5-HT2/1C receptors did not inhibit the secretions by κ-opioid receptor agonists. In rat brain regions close to the lateral cerebroventricle, κ-opioid receptor systems (κ1>κ3≫κ2) are regulated by the non-NMDA type of glutamate receptor system, and κ1- and κ2-opioid receptor systems are regulated by the GABAA receptor system. The present findings show pharmacological evidence for κ-opioid receptor subtypes that regulate gastric acid secretion in the rat brain. Keywords: Gastric acid secretion, opioid receptor subtype, glutamate, γ-amino-butyric acid, central injection Introduction Recent advances have shown that gastric functions including acid secretion are regulated not only by the peripheral but also by the central nervous system (CNS) (Fox & Burks, 1988; Grijalva & Novin, 1990; Tache et al., 1991; Geoghegan & Pappas, 1997). Many studies concerning the central effects of various neurotransmitters and neuropeptides on gastric acid secretion have revealed mechanisms by which the brain regulates gastric acid secretion (Yang et al., 1993; Yoneda & Tache, 1995; Geoghegan & Pappas, 1997). Glutamate is a primary excitatory neurotransmitter in the CNS, and subtypes of ionotropic glutamate receptors have been classified as N-methyl-D-aspartic acid (NMDA), kainate and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. It has been reported that the central injection of NMDA and kainate potently stimulated gastric acid secretion in rats (Kaneko & Tache, 1995; Yang et al., 2000). In addition, we reported that the injection of kainate, but not AMPA, into the lateral cerebroventricle stimulated secretion in the perfused stomach of urethane-anesthetized rats (Tsuchiya et al., 2001). It was reported that the injection of muscimol, an agonist for the A-type receptor of γ-amino-butyric acid (GABA), into the lateral cerebroventricle (i.c.v. administration) stimulated gastric acid secretion in rats (Del Tacca et al., 1990; Namiki et al., 1993; Lin, 1995). Neuroactive steroids and anesthetics such as pentobarbital have been confirmed to bind potently and selectively to ionotropic GABAA receptors in the CNS (Lambert et al., 1995). Previously, we reported that i.v. injection of anesthetics (Lin et al., 1988) and the injection of neuroactive progesterone metabolites into the lateral cerebroventricle (Watanabe et al., 2000) stimulated gastric acid secretion centrally in rats. The importance of the lateral hypothalamus close to the lateral cerebroventricle in the control of gastric function has been established (Tache, 1987; Stanley et al., 1997). The NMDA and kainate receptors (Van Den Pol et al., 1994; Vignes and Collingridge, 1997; Eyigor et al., 2001) and GABAA receptors (Pirker et al., 2000) are distributed throughout the rat brain, including the hypothalamus, although a heterogeneous distribution of the receptor subunits was observed. These findings showed the involvement of NMDA, kainate and GABAA receptors in the CNS on gastric acid secretion. Gastric acid secretion is also regulated by the opioid system in the CNS. Fox & Burks (1988) reported that the i.c.v. injection of μ-opioid receptor agonists such as morphine inhibited gastric acid secretion, and we reported that the injection of morphine into the fourth cerebroventricle inhibited secretion in rats (Ishihara et al., 2001a). Although Fox & Burks (1988) reported that κ-opioid receptor agonists did not produce a significant change in gastric acid secretion after i.c.v. injection in rats, we reported that the injection of dynorphin A-(1-17) (an endogenous and nonselective agonist for κ-opioid receptors) into the lateral cerebroventricle stimulated gastric acid secretion in rats (Ishihara et al., 2001b). The mRNA and the proteins of the κ-opioid receptor are expressed at a high density in the rat hypothalamus (Mansoure et al., 1995). The existence of κ-opioid receptor subtypes has been proposed; arylacetamides, such as (5α,7α,8β)-(+)-N-methyl-N-(7-[1-pyrrolidinyl]-1-oxaspiro[4.5]dec-8-yl)benzeneacetamide ({"type":"entrez-nucleotide","attrs":{"text":"U69593","term_id":"4205069","term_text":"U69593"}}U69593), bind to a subset of sites (κ1), and the κ2 site has moderate affinity for bremazocine, and naloxone benzoylhydrazone (NBH) labels a population of distinct sites (κ3) under κ-opioid receptor-selective conditions (Satoh & Minami, 1995; Dhawan et al., 1996; Law & Loh, 1999). Although it was suggested that the cloned κ-opioid receptor corresponds to the κ1 subtype and that the κ2 subtype resulted from a heterodimer of κ1- and δ- (Jordan & Devi, 1999) or μ-opioid receptors (Simonin et al., 2001), cloning of each subtype and functional characterization are necessary to support the proposed subtypes. We reported that the injections of {"type":"entrez-nucleotide","attrs":{"text":"U69593","term_id":"4205069","term_text":"U69593"}}U69593 (a putative agonist for the κ1-opioid receptor), bremazocine (for κ2) and NBH (for κ3) into the lateral cerebroventricle stimulated gastric acid secretion in rats (Ishihara et al., 2001a),( 2001b). However, it has not been established whether these three proposed agonists for κ1–κ3-opioid receptors activate the respective subtypes specifically in the CNS. In addition, it has not been determined whether the κ-opioid receptor system interacts with other receptor systems such as glutamate and GABA receptors in the CNS and thus stimulates gastric acid secretion in rats. In this study, we investigated the involvement of glutamate, GABA and the 5-hydroxy tryptamine (5-HT) receptor system on gastric acid secretion stimulated by the respective agonists for κ1–κ3-opioid receptors in the CNS in the perfused stomach of urethane-anesthetized rats. It is proposed that gastric acid secretion induced by the injection of κ-opioid receptor agonists into the lateral cerebroventricle is mediated by the non-NMDA type of glutamate receptor and GABAA receptor systems, and that the contributions of both receptor systems are different between the subtypes of the κ-opioid receptors in the CNS in rats. To our knowlege, this is the first report that pharmacologically shows the existence of subtypes of κ-opioid receptors that regulate gastric acid secretion in the rat brain.