dynorphins and 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic-acid

1. Various neurotransmitters in the brain regulate gastric acid secretion. Previously, we reported that the central injection of kappa-opioid receptor agonists stimulated this secretion in rats. Although the existence of kappa(1)-kappa(3)-opioid receptor subtypes has been proposed, the character is not defined. We investigated the interactions between kappa-opioid receptor subtypes and glutamate, gamma-amino-butyric acid (GABA) or 5-hydroxy tryptamine (5-HT) receptors in the rat brain. 2. Gastric acid secretion induced by the injection of U69593 (8.41 nmol, a putative kappa(1)-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 micro g kg(-1) per 10 min, i.v., GABA(A) receptor antagonist). The secretion induced by bremazocine (8.52 nmol, a putative kappa(2)-opioid receptor agonist) was inhibited by bicuculline infusion, but not by CNQX. The secretion induced by naloxone benzoylhydrazone (224 nmol, a putative kappa(3)-opioid receptor agonist) was slightly and partially inhibited by CNQX and bicuculline. 3. 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, GABA(B) and 5-HT(2/1C) receptors did not inhibit the secretions by kappa-opioid receptor agonists. 4. In rat brain regions close to the lateral cerebroventricle, kappa-opioid receptor systems (kappa(1)>kappa(3)>>kappa(2)) are regulated by the non-NMDA type of glutamate receptor system, and kappa(1)- and kappa(2)-opioid receptor systems are regulated by the GABA(A) receptor system. The present findings show pharmacological evidence for kappa-opioid receptor subtypes that regulate gastric acid secretion in the rat brain.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Animals; Baclofen; Benzeneacetamides; Benzomorphans; Bicuculline; Brain; Dynorphins; gamma-Aminobutyric Acid; Gastric Acid; Injections, Intraventricular; Ketanserin; Male; Perfusion; Piperazines; Pyrrolidines; Rats; Rats, Wistar; Receptors, GABA-A; Receptors, Glutamate; Receptors, Kainic Acid; Receptors, N-Methyl-D-Aspartate; Receptors, Opioid, kappa; Receptors, Serotonin; Stomach

The role of N-methyl-D-aspartate (NMDA) excitatory amino acid receptors in D-amphetamine (AMPH)-induced behavioral changes and increased expression of the nuclear transcription factors, c-fos and zif/268, and preprodynorphin (PPD) mRNA in various regions of rat forebrain was investigated with quantitative in situ hybridization histochemistry. Three hours after a single injection of AMPH (5 mg/kg, i.p.), the mRNA expression of zif/268, but not c-fos, in dorsal striatum (caudate nucleus) and cerebral cortex (sensorimotor cortex), and PPD mRNA in dorsal striatum, was upregulated. Pretreatment of rats with MK-801 (0.5 mg/kg, i.p.) attenuated AMPH-induced striatal and cortical expression of zif/268 mRNA and striatal expression of PPD mRNA, without affecting the behavioral alterations induced by AMPH. A similar, dose-dependent suppression of AMPH-induced zif/268 and PPD mRNA in striatum and cortex was also revealed after systemic administration of (+/-)-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP) at doses of 5 and 10 mg/kg. CPP, only at the higher dose, slightly attenuated behavioral activity induced by AMPH. MK-801 and CPP (at higher dose) alone suppressed basal (constitutive) zif/268 mRNA levels in both striatum and cortex regions. No significant effect of either antagonist was found on constitutive expression of striatal PPD mRNA. These studies indicate that NMDA receptors mediate, at least in part, activation of zif/268 and PPD gene expression in striatum and sensorimotor cortex by a single injection of AMPH. Furthermore, NMDA receptor-mediated gene regulation more likely is involved in long-term neuronal plasticity to drug exposure than in acute drug effects since NMDA receptor antagonists had little or no effect on the acute behavioral actions of AMPH.

Topics: Animals; Behavior, Animal; Dextroamphetamine; Dizocilpine Maleate; Dynorphins; Gene Expression; Glutamic Acid; Image Processing, Computer-Assisted; In Situ Hybridization; Male; Neostriatum; Neurons; Piperazines; Protein Precursors; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; RNA, Messenger; Up-Regulation

It has been proposed that the endogenous opioid dynorphin A (Dyn A) contributes to the pathogenesis of posttraumatic spinal cord injury (SCI). Dyn A-related peptides given intrathecally (i.t.) produce hindlimb paralysis. These include Dyn A(1-17), Dyn A(1-13), Dyn A(2-17), and Dyn A(3-13). Because Dyn A(2-17) and Dyn A(3-13) are inactive at opiate receptors, Dyn A-induced paralysis may include a non-opioid component. Recently, it has been reported that competitive N-methyl-D-aspartate (NMDA) antagonists block the loss of tail-flick reflex caused by i.t. administration of Dyn A(1-13). In the present studies we examined whether competitive [(4-[3-phosphonopropyl]-2-piperazine-carboxylic acid (CPP)] or non-competitive (dextrorphan) NMDA antagonists could attenuate paralysis induced by Dyn A(1-17) or Dyn A(2-17). CPP or dextrorphan each significantly attenuated the neurologic dysfunction and mortality associated with Dyn A(1-17) administration. In addition, CPP and dextrorphan significantly reduced the neurologic dysfunction caused by Dyn A(2-17)(all P less than 0.05). From these data we suggest that the non-opioid component of Dyn A-induced paralysis is mediated in part by the NMDA receptor.

Topics: Animals; Binding, Competitive; Dextrorphan; Dynorphins; Hindlimb; Male; Morphinans; Paralysis; Peptide Fragments; Piperazines; Rats; Rats, Inbred Strains; Receptors, N-Methyl-D-Aspartate; Receptors, Neurotransmitter