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© Copyright 2004 The British Pharmacological Society

099P University of Newcastle
Winter Meeting December 2004

NR2b antagonists, CP101,606 and RO-256981, increase gastric emptying in the conscious rat

Chris J. Gardner, Jill Darton, Julia E. Smith, Wendy Winchester, Celestine T. O’Shaughnessy, Chas Bountra. Neurology & GI CEDD, GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex, CM195AW.

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Gardner CJ
Darton J
Smith JE
Winchester W
O’Shaughnessy CT
Bountra C

Gastric function can be modulated by vago-vagal reflexes, and it is known that glutamate is a transmitter in vagal afferent fibres innervating the gut (Hornby, 2001). Moreover, NMDA receptor recruitment (at the level of the nucleus tractus solitarius) has been shown to be involved in the central processing of gastrointestinal sensory information evoked by gastric distension and duodenal nutrient stimuli (Berthoud et al., 2001). In the present study, the effects of two NR2b (sub-unit of NMDA receptors) antagonists, CP101,606 and Ro 25-6981 on gastric emptying were determined in the conscious rat.

The methods used were based on those described by Droppleman et al. (1980). Experiments were performed on m ale CD rats (Charles River; 180 – 300g), which were fasted overnight before the experiment. On the day of the experiment, each rat received a dose of either test compound or vehicle at 15, 30 or 60 min before the semisolid nutrient test meal was administered orally. 60 mins after meal administration, the rats were sacrificed and their stomach excised. The difference between the weight of the full and emptied stomach was subtracted from the weight of the administered meal. The percentage change in gastric emptying were tested for statistical significance compared to vehicle control using one-way ANOVA and Dunnett’s tests. The effect of a known gastroprokinetic agent, metoclopramide (D2/ 5-HT3 receptor antagonist) was also tested.

Metoclopramide, 0.3, 1, 3& 10mg kg-1 i.p. (n=4 per dose), produced dose-related increases in gastric emptying of the administered test meal of; 0, 46, 71 & 114%, respectively. This increase in emptying reached significance at the top dose used (p=0.002). CP101,606, 3, 10 & 30mg kg-1 s.c. (n=6 per dose) also produced significant dose-related increases in gastric emptying of the test meal of; 75% (p=0.01), 86 % (p=0.003) and 107% (p=0.0004), respectively. Ro-256981, 3, 10 & 30mg kg-1 s.c. (n=6 per dose) also produced increases in gastric emptying of 35%, 54 % and 21% respectively, but the increase was only significant at the 10mg/kg dose (p=0.02).

The data from this study indicate that NR2b antagonists are gastroprokinetics in rat, and may therefore be useful in the treatment of functional bowel disorders.

Berthoud et al., (2001) Brain Res., 915, 143-154.
Droppleman et al. (1980) J. Pharmacol. Methods, 4, 227-230.
Hornby (2001) Am. J. Physiol., 280, G1055-G1060.