GV196771A, an NMDA receptor/glycine site antagonist, attenuates mechanical allodynia in neuropathic rats and reduces tolerance induced by morphine in mice.

The effects of the N-methyl-D-aspartate (NMDA) receptor/glycine site antagonist, GV196771A (E-4,6-dichloro-3-(2-oxo-1-phenyl-pyrrolidin-3-ylidenemethyl)-1H-indole-2-carboxylic acid sodium salt), on mechanical allodynia and on tolerance to the antinociceptive effects induced by morphine were evaluated. Its antiallodynic properties were studied in a model of chronic constriction injury applied to rat sciatic nerve. GV196771A (0.3-10 mg/kg, p.o.) dose-dependently inhibited established mechanical allodynia when tested 14 or 21 days after nerve ligation. In the formalin test in mice, GV196771A (10 or 20 mg/kg, p.o.), administered for 8 days together with morphine 10 mg/kg, i.p. inhibited morphine tolerance development in both early and late phases of the test. This finding reinforces the key role of the NMDA receptors in the plastic event, such as allodynia, which develops in some conditions of painful neuropathy. Moreover, the capability to strongly reduce morphine-induced tolerance suggests that GV196771A could be an alternative agent for the treatment of difficult pain states not only when given alone, but also in combination, in order to prolong the analgesic effects of the opiates.

Potent antihyperalgesic activity without tolerance produced by glycine site antagonist of N-methyl-D-aspartate receptor GV196771A.

Central sensitization is a condition of enhanced excitability of spinal cord neurons that contributes to the exaggerated pain sensation associated with chronic tissue or nerve injury. N-methyl-D-aspartate (NMDA) receptors are thought to play a key role in central sensitization. We have tested this hypothesis by characterizing in vitro and in vivo a novel antagonist of the NMDA receptor acting on its glycine site, GV196771A. GV196771A exhibited an elevated affinity for the NMDA glycine binding site in rat cerebral cortex membranes (pKi = 7.56). Moreover, GV196771A competitively and potently antagonized the activation of NMDA receptors produced by glycine in the presence of NMDA in primary cultures of cortical, spinal, and hippocampal neurons (pKB = 7.46, 8. 04, and 7.86, respectively). In isolated baby rat spinal cords, 10 microM GV196771A depressed wind-up, an electrical correlate of central sensitization. The antihyperalgesic properties of GV196771A were studied in a model of chronic constriction injury (CCI) of the rat sciatic nerve and in the mice formalin test. In the CCI model GV196771A (3 mg/kg twice a day p.o.), administered before and then for 10 days after nerve ligature, blocked the development of thermal hyperalgesia. Moreover, GV196771A (1-10 mg/kg p.o.) reversed the hyperalgesia when tested after the establishment of the CCI-induced hyperalgesia. In the formalin test GV196771A (0.1-10 mg/kg p.o.) dose-dependently reduced the duration of the licking time of the late phase. These antihyperalgesic properties were not accompanied by development of tolerance. These observations strengthen the view that NMDA receptors play a key role in the events underlying plastic phenomena, including hyperalgesia. Moreover, antagonists of the NMDA glycine site receptor could represent a new analgesic class, effective in conditions not sensitive to classical opioids.

Effects of a new 1,4-dihydropyridine, lacidipine, on gastrointestinal motility and other gastrointestinal functions.

Lacidipine is a new 1,4-dihydropyridine calcium entry blocker endowed with slow onset of action and potent and long-lasting antihypertensive activity. This study investigated the effect of lacidipine on some gastrointestinal functions, mainly gastrointestinal motility, in rats and dogs. In fasting conscious dogs chronically fitted with electrodes and strain gauges along the small bowel, lacidipine (12 micrograms/kg i.v. bolus or 10 micrograms/kg/h for 3 h) did not modify the migrating motor complex pattern or intestinal spike activity. In the rat, lacidipine proved less active (ED 50 greater than 100 mg/kg p.o.) than nitrendipine (ED 50 = 31 mg/kg p.o.) in inhibiting gastric emptying of a liquid meal, whereas the opposite was true after a solid meal (ED 50 = 10.9 and 35.0 mg/kg p.o., respectively). Lacidipine inhibited fecal pellet output at lower doses (ED 50 = 14.8 mg/kg p.o.) than nitrendipine (ED 50 = 40.1 mg/kg p.o.). On histamine-induced gastric acid secretion, the effect of 100 micrograms/kg i.v. lacidipine was moderate (maximum inhibition 45%). The gastrointestinal effects displayed by lacidipine appear at doses at least 5 and 50 times as high as those affecting blood pressure after intravenous and oral administration, respectively. Thus, lacidipine is unlikely to cause noteworthy unwanted effects on the gastrointestinal tract.