ABSTRACT
The aim of the present paper was to study the effects of GABAA receptor-positive modulators (L-838417 and NS11394) showing a preference for α2/3 subunits of the GABAA receptor, in models of pain, anxiety, learning, memory and motor function. These compounds have been suggested to have a favourable therapeutic profile over nonselective compounds such as diazepam. In this study, we tested both compounds for their effects in rat models of formalin-induced pain, spinal nerve-ligation-induced mechanical allodynia, plus maze, open field, rotarod, balance beam walking, contextual fear conditioning and Morris water maze. Both compounds exerted analgesic, but no anxiolytic effects. However, they induced motor side-effects, and learning and memory impairment at similar doses. Therefore, the anxiolytic effect and the lack of side-effects of these compounds, as described in the literature, could not be confirmed in the present study.
Subject(s)
Benzimidazoles/pharmacology , Fluorobenzenes/pharmacology , GABA-A Receptor Agonists/pharmacology , Receptors, GABA-A/drug effects , Triazoles/pharmacology , Allosteric Regulation , Analgesics/administration & dosage , Analgesics/pharmacology , Analgesics/toxicity , Animals , Anxiety/drug therapy , Benzimidazoles/administration & dosage , Benzimidazoles/toxicity , Disease Models, Animal , Dose-Response Relationship, Drug , Fear , Fluorobenzenes/administration & dosage , Fluorobenzenes/toxicity , GABA-A Receptor Agonists/administration & dosage , GABA-A Receptor Agonists/toxicity , Male , Maze Learning/drug effects , Memory Disorders/chemically induced , Motor Activity , Pain/drug therapy , Pain/physiopathology , Rats , Rats, Wistar , Receptors, GABA-A/metabolism , Triazoles/administration & dosage , Triazoles/toxicityABSTRACT
ATP is an extracellular regulator in numerous physiological and pathologic processes. Recently, 7 different subtypes of purinoceptors were identified on either the basolateral or the luminal membrane of pancreatic duct cells. However, the in vivo regulatory role of ATP in pancreatic function has not been established. We investigated the possible regulatory role of endogenous ATP in pancreatic function by measuring ATP concentrations and ATPase activity in pancreatic juice obtained from anesthetized rats and guinea pigs and from human patients undergoing endoscopy. Juice was collected from the main pancreatic duct in rats and guinea pigs under basal conditions or during stimulation with CCK, bombesin, or secretin. In guinea pigs, CCK, bombesin, and secretin did not affect ATP output, although they did stimulate fluid secretion. ATPase activity in the juice was evaluated by measuring the rate of hydrolysis of added ATP. Consistent with the low ATP concentrations in rat pancreatic juice, we found high levels of ATPase activity in this species. This was confirmed by HPLC, which also showed the metabolites of ATP hydrolysis. Ecto-ATPase activity was demonstrated by enzyme histochemistry in both the pancreatic acini and ducts in rats, but it was not detectable in guinea pigs and humans. These differences in ATP levels and ATPase expression may indicate significant species differences in the purinergic regulation of pancreatic secretion.
