tetrodotoxin and Stomach-Ulcer

Recent studies demonstrated that experimental ulcers are associated with changes in the properties of voltage-sensitive sodium currents in sensory neurons. We hypothesized that nerve growth factor (NGF) contributes to these changes. Gastric ulcers were induced by acetic acid injection into the wall of the rat stomach. NGF expression was determined by ELISA and immunohistochemically. Sensory neurons were labeled by injection of a retrograde tracer into the gastric wall. Sodium currents were recorded in gastric sensory neurons from nodose and dorsal root ganglia cultured for 24 h in the presence of NGF or a neutralizing NGF antibody, respectively. Gastric ulcer formation caused a rise in NGF concentration within the gastric wall and an increase in NGF immunoreactivity. Exposure to NGF caused a significant increase in the TTX-resistant sodium current, whereas the TTX-sensitive sodium current remained unchanged. This was associated with an acceleration of the recovery from inactivation in spinal sensory neurons. Production and release of NGF in the gastric wall may contribute to sensitization of primary afferent neurons during gastric inflammation.

Topics: Anesthetics, Local; Animals; Cells, Cultured; Electrophysiology; Ganglia, Spinal; Gastric Mucosa; Hyperalgesia; Immunohistochemistry; Male; Nerve Growth Factor; Neurons, Afferent; Rats; Rats, Sprague-Dawley; Sodium Channels; Stomach; Stomach Ulcer; Tetrodotoxin

Voltage-dependent Na+ currents are important determinants of excitability. We hypothesized that gastric inflammation alters Na+ current properties in primary sensory neurons.. The stomach was surgically exposed in rats to inject the retrograde tracer 1.1'-dioctadecyl-3,3,3,'3-tetramethylindocarbocyanine methanesulfonate and saline (control) or 20% acetic acid (ulcer group) into the gastric wall. Nodose or thoracic dorsal root ganglia (DRG) were harvested after 7 days to culture neurons and record Na+ currents using patch clamp techniques.. There were no lesions in the control and 3 +/- 1 ulcers in the ulcer group. Na+ currents recovered significantly more rapidly from inactivation in nodose and DRG neurons obtained from animals in the ulcer group compared with controls. This was partially a result of an increase in the relative contribution of the tetrodotoxin-resistant to the peak sodium current. In addition, the recovery kinetics of the tetrodotoxin-sensitive current were faster. In DRG neurons, gastric inflammation shifted the voltage-dependence of activation of the tetrodotoxin-resistant current to more hyperpolarized potentials.. Gastric injury alters the properties of Na+ currents in gastric sensory neurons. This may enhance excitability, thereby contributing to the development of dyspeptic symptoms.

Topics: Acetic Acid; Anesthetics, Local; Animals; Disease Models, Animal; Ganglia, Spinal; Gastritis; Hyperalgesia; Ion Channel Gating; Male; Membrane Potentials; Neurons, Afferent; Nodose Ganglion; Patch-Clamp Techniques; Rats; Rats, Sprague-Dawley; Sodium; Sodium Channels; Stomach; Stomach Ulcer; Tetrodotoxin

1. The effects of the ulcerogen cysteamine (2-aminoethanethiol HCL) on spontaneous activity and evoked responses of rat isolated small intestine preparations were investigated in vitro. 2. Cysteamine induced concentration-dependent relaxations of isolated segments of the rat duodenum, jejunum and ileum. These actions were manifest simultaneously in both the circular and longitudinal muscle layers, where the responses displayed a similar profile. 3. Treatment with tetrodotoxin (0.1 microM) or cold storage of individual preparations to prevent nerve-mediated responses abolished the effects of cysteamine. The presence of atropine (0.1 microM), propranolol (3.0 microM) and phentolamine (3.0 microM) in the bathing solution did not affect the cysteamine-evoked relaxations, suggesting cysteamine was stimulating non-adrenergic, non-cholinergic (NANC) intrinsic inhibitory nerves. 4. Applied cysteamine reversibly reduced GABA- and DMPP-evoked NANC nerve-mediated relaxations via actions unrelated to the receptors for these agents. 5. Methysergide-sensitive (direct) actions of 5-HT on the muscularis but not 5-HT neurally evoked responses were blocked by cysteamine. 6. It would appear that cysteamine has excitatory and inhibitory actions on enteric inhibitory nerves as well as specifically interfering with myogenic but not neural actions of 5-HT.

Topics: Animals; Cold Temperature; Cysteamine; Female; In Vitro Techniques; Intestine, Small; Male; Muscle, Smooth; Neurons; Neurotransmitter Agents; Rats; Rats, Inbred Strains; Stomach Ulcer; Tetrodotoxin

1. The role of local sensory neurones in modulating the extent of gastric mucosal damage induced by close-arterial infusion of platelet-activating factor (Paf 50 ng kg-1 min-1 for 10 min) has been investigated in the anaesthetized rat. 2. Local intra-arterial infusion of the neurotoxin, tetrodotoxin (TTX), substantially augmented the mucosal damage induced by Paf, as assessed by both macroscopic and histological techniques. 3. In rats pretreated with capsaicin 2 weeks prior to study, to induce a functional ablation of primary afferent neurones, gastric damage induced by Paf was significantly augmented. 4. Administration of morphine (0.75-3 mg kg-1 i.v.) or its peripherally acting quaternary analogue, N-methyl morphine (15 mg kg-1 i.v.), also significantly enhanced the gastric damage induced by Paf. 5. The potentiation by morphine of Paf-induced gastric damage was inhibited by administration of the opioid antagonists, naloxone (1 mg kg-1 i.v.) or the peripherally acting N-methyl nalorphine (3 mg kg-1 i.v.). 6. Administration of TTX or morphine alone, or pretreatment with capsaicin did not induce any detectable mucosal damage, suggesting that interference with local sensory neuronal activity itself does not directly induce mucosal disruption. 7. These results indicate that peripheral opiate-sensitive afferent sensory neurones play a physiological defensive role in the mucosa, attenuating the extent of gastric damage induced by Paf.

Topics: Animals; Capsaicin; Infusions, Intra-Arterial; Male; Morphine; Narcotics; Neurons, Afferent; Platelet Activating Factor; Rats; Rats, Inbred Strains; Stomach Ulcer; Tetrodotoxin