Intracerebroventricular calcitonin prevents stress-induced gastric dysfunction¹

Abstract

Background. Restraint stress produces gastric hypercontractility and acidity leading to stress ulceration. Intracerebroventricular (ICV) salmon calcitonin (sCT) decreases restraint injury and acidity, but its effects on restraint-induced hypercontractility are unknown.

Methods. Using stereotactic guidance, ICV catheters were placed into the lateral ventricle of adult male rats and calibrated gastric strain gauge transducers were implanted 5 days prior to restraint stress. sCT rats (n = 8) were pretreated with 5 μg of calcitonin ICV (10 μl volume), while controls (n = 10) received 10 μl of ICV saline prior to restraint for 2 h at 20°C followed by 2 h at 4°C. Gastric motility data were collected with AT-CODAS and analyzed with ADVANCED CODAS. Gastric volume, pH, and lesions were recorded following the stress.

Results. ICV calcitonin prevented gastric mucosal injury in all animals (0% vs 100%, P < .01) and elevated pH slightly (2.5 ± .3 vs 1.6 ± .1, P < .05). Stress caused the force of contractions to increase from 0.35 ± .1 to 1.38 ± .4 g in controls (P < .01), while treated animal’s force fell from .42 ± .1 to 0.2 ± .05 g (P < .01 vs control). Stress did not affect contractions/min (3.4 + .6 vs 3.5 + .3), but sCT increased frequency (2.5 + .4 to 5.0 + .2, P < .01). Stress prolonged contraction duration (11.5 + 1 to 16.5 + 1.7 s, P < .01), but stress’s effect was prevented by sCT (11.0 + .5 to 11.2 + .3, P < .01 vs control).

Conclusions. Pretreatment with 5 μg central sCT prevents the increased amplitude and duration of gastric contractions produced by restraint stress for 2 h, in association with gastroprotection.

Introduction

Stress from physical restraint, cold temperatures, or water immersion can produce acute gastric mucosal injury within hours in rodents. These stresses produce two gastric effects via cholinergic vagal pathways 1, 2, 3, 4, 5, acid secretion and hypercontractility. Restraint stress increases both the duration and the amplitude of gastric contractions, and these motility effects correlate with the degree of mucosal injury [6]. Both the gastric hypercontractility and acidity associated with restraint stress are required to produce the gastric mucosal injury 7, 7. Many other stresses such as sepsis, hyperthermia, and hemorrhagic shock do not lead to stress ulceration in this time frame, because these stresses are associated with suppression of gastric acidity caused by nitric oxide-dependent signaling within the central nervous system 8, 9.

Although first characterized as a circulating hormone-regulating calcium metabolism, calcitonin is also a neuromodulator and possible neurotransmitter [10]. The role of calcitonin in stress ulceration came under investigation in part because peripheral calcium levels decrease during restraint stress [11]. Soon thereafter, centrally administered calcitonin at ≤ 5 μg was reported to have gastroprotective effects [12]. The discovery of calcitonin’s gastroprotective effects was fortuitous, because although calcium levels decrease, subsequent data suggest that peripheral calcitonin levels are not altered by restraint stress [13].

Centrally administered calcitonin affects gastric function in several ways that may contribute to gastroprotection during restraint. Central calcitonin suppresses stimulated acid output 12, 14 and suppresses gastric emptying 14, 15 at doses of .01–5 μg, and these effects were absent when these doses were administered intravenously 12, 13, 14. These gastric suppressive effects of central calcitonin are opposite to the stimulatory effects of restraint stress on gastric acidity and emptying. However, it remains unknown whether the reported inhibition of gastric emptying may play a role in the gastroprotective effect of central calcitonin, perhaps reflecting an alteration of stress-induced hypercontractility.

The purpose of this study was thus to test the hypothesis that exogenous intracerebroventricular calcitonin would alter the gastric hypercontractility pattern produced by restraint stress.