Physiology&Behavior.Vol. 53, pp. 577-581, 1993 0031-9384/93 $6.00+ .00 Copyright© 1993PergamonPressLtd. Printed in the USA. Some Psychosomatic Causal Factors of Restraint-in-Water Stress Ulcers R O B E R T M U R I S O N *1 A N D J. B R U C E O V E R M I E R ' ~ *Division of Physiological Psychology, Department of Biological and Medical Psychology, University of Bergen, Norway and -kDepartment of Psychology, University of Minnesota, Minneapolis, M N 55455 Received 26 May 1992 MURISON, R. AND J. B. OVERMIER. Somepsychosomaticcausalfactors ofrestraint-in-waterstress ulcers.PHYSIOL BEHAV 53(3) 577-581, 1993.--Rats were stressed by 75 min restraint in a tUbesuspendedverticallywhiledry (19°C) or partiallyimmersed in tanks of water at different temperatures (19, 27, 35°C), either in a conscious state or while under pentobarbital anesthesia. Restraint was followed by 75 min rest in the home cage and then sacrificed under halothane anesthesia. Assessmentof the degree of gastric erosion indicated that restraint alone, whether the animal was rendered unconscious or not, was not sufficientto induce ulceration. However, in conscious animals, the addition of partial immersion did induce ulceration that was inverselyrelated to the temperature of the water bath. This effect was not merely the result of brain stem and spinal reflex processes, because unconscious animals exposed to the most severe conditions (19°C) showed no ulceration. Stress Gastriculcer Consciousness Thermal challenge HISTORICALLY, a wide variety of stress techniques have been used to model presumed psychosomatic gastric erosions and ulcers, including approach/avoidance conflict (39), unsignalled shock avoidance (6), and a variety of forms of simple restraint alone (4,32) or in combination with altered body position, cold, shock, or partial immersion in water (11,32,34). Common practice has been to adopt a procedure that works, with little direct investigation as to the factors that might play the causal role for the observed ulcers or erosions. Indeed, we have been using restraint plus partial immersion in room temperature water ( 1920°C) as an ulcer-inducing technique to study proactive and retroactive psychological factors that modulate the vulnerability to this ulcer-inducing technique [e.g., (24,26-28)], but we have failed to systematically explore a number of factors in this situation that may be critical for ulcer formation. This restraintin-water technique is used by others as well (1,2,14,31,35). But little is known about the factors in the complex situation that are causal of ulcer itself or whether, indeed, psychological processes are critical, as is implied by the label psychosomatic which is often applied. The present experiment sought to address this problem by isolating specific situational factors that contribute to the observed induced gastric ulceration. At issue here are three questions. These address, respectively, the roles of psychological factors, restraint, and ambient temperature. The first question to be addressed here is whether psychological factors contribute to the induced ulcerative processes. Is Body heat loss Restraint Temperature the ulcerogenesis we observe a passive phenomenon caused by the physical properties of the restraint in room temperature acting at lower levels of the central nervous system, and independent of any psychological processing, or is it dependent upon supramesencephalic function? That is, are distress, fear, and threat of drowning (8,33) causal factors. This same question has arisen previously with respect to stress-induced spinal hypoalgesia; there, two procedures have been used to address this issue. One tested for psychological involvement in this stress-induced effect in decerebrate rats (13,37); the other tested for psychological involvement in rats anesthetized with pentobarbital (19,36). Each of these two methods has the advantage that they do not directly interfere with the spinal reflex mechanisms or the brain stem supraspinai modulators of these reflexes, thus allowing the inference that any observed effects of the pentobarbital on the modulation of the reflexes must arise from alteration of higher neural processes. Pentobarbital anesthesia and decerebration have an identical pattern of effects in distinguishing opioid and nonopioid hypoalgesias in identifying supramesencephalic involvement in the former (16,17). Grau (13) and Maier (19), among others, have shown that these higher central processes are associative and memory dependent--that is, processes best characterized as psychological, although they, of course, have a physiological substrate. The dependence of the restraint-in-water stress ulcer upon higher central neural processes that presumably underlie cognitive processes was assessed herein using pentobarbital anes- Requests for reprints should be addressed to Robert Murison, PhysiologicalPsychology, Department of Biological and Medical Psychology, University of Bergen, Arstadveien 2 l, N-5009 Bergen, Norway. 577 578 thesia, and paralleled those prior experiments that used it so successfully to address this question of the contribution of psychological processes to the degree of stress-induced hypoalgesia. Although two earlier studies (21,25) showed the presence of ulcer in rats anesthetized with urethane after 3 h of restraint-inwater stress (21) or in cooled (25) rats, these studies cannot be considered definitive. This is because urethane anesthesia itself elicits levels of corticosterone of the same order as those found in highly stressed animals (3). In addition, in one of the two (25), one must question to what extent the animals were effectively rendered unconscious, because they continued to exhibit such gross body movements as head turning and rearing during the experiment. Furthermore, no unanesthetized animals were included to study the effects of the anesthetic drug itself. Also, some forms of anesthesia are not unknown as direct causal factors in ulcerogenesis (9). Because of these difficulties, we chose in the present study to treat animals with pentobarbital at a dose known to induce a state of deep unconsciousness (5,38), yet leave spinal reflexes (19,25) and vagal output to the stomach intact (42). A second question to be addressed is whether the observed ulcerogenic effect of restraint-in-water stress is attributable to the restraint alone, or is the partial immersion in water a critical element. The question arises because restraint alone, when extreme and prolonged (20 h or more), is known to be ulcerogenic (4,29). We have assumed that our previously obtained gastric erosions induced by restraint-in-water stress were the product of an interaction between the stress of restraint and the stress of partial immersion in water, because the degree of restraint used was neither extreme nor prolonged: the rats were able to move within the tube (indeed, the rats can simply walk through the tubes if placed in their home cages) and the period of restraint has been 2.5 h or less rather than of the order of 20 h or more [at which time severity of restraint is known to be important: (4)]. Nonetheless, the ulcerogenic contribution of the water immersion factor over and above that of the restraint has not been directly assessed. The third question concerns the role of ambient water temperature. The water temperature we have used earlier is known to elicit distress swimming activity, but activity that is not different than obtained at substantially higher water temperatures and quite different from the panic swimming behaviors elicited by water temperatures below 15°C (41). However, the water bath temperature × degree of ulceration has not been directly assessed in our model. If partial immersion in water is critical, is it the additional stress from body heat loss due to bath temperature that is the critical factor? Do animals exposed to the presumably stressful experience of restraint in a neutral temperature (35°C) water develop ulcer? This question arises because others using dry restraint commonly combine the technique with exposure to 4°C cold room to facilitate ulceration (10). Using restraint in cold room, two studies have shown the amount of ulceration developing during, respectively, 2.5 h or 24 h to be related to ambient air temperature (7,20). Although gastric acid secretion is but one factor implicated in the processes leading to formation of gastric ulceration, this variable has been studied in relation to ambient air and water temperature in restrained animals. In animals restrained in air, a linear inverse relationship is found between air temperature and acid secretion (40). However, in animals restrained in water, maximal acid secretion is found at an ambient water temperature of 25°C, with secretion at 20 ° not differing from that in nonimmersed but restrained animals (1). This is important because the degree of ulceration under water restraint is 10-25 times as great as MURISON AND OVERMIER that seen under simple restraint, and one might be led to expect from these data that greatest ulcer would be found in animals restrained in 25 ° water. The exposure to intense cold presumably works in part because cold stimulates both TRH release (an ulcerogenic hormone) (12,15) and gastric acid production (1,2,40). METHOD Subjects The rats were 25 Sprague-Dawley rats received from Mollegaard (Denmark) at 70 days of age. At 85 days of age they were weighed, moved to individual plastic cages with slotted floors, and assigned to one of six weight-matched groups. The rats weighed from 372 to 420 g, and the group mean weights ranged from 393 to 397 g. Each day thereafter, at 1000 h, the rats in their racks were transported to the dimly illuminated experimental room to accustom them to this activity. Apparatus The restraint-in-water devices were plastic tubes with internal dimensions of 17.5 cm by 6 cm in diameter with the top end capped with a fine mesh screen and the bottom (behind the rat) secured with two parallel bolts approximately 1 cm apart. Each tube was perforated with three sets of four 8-ram holes arrayed around the tube. After placing the rats into the tubes, each tube was suspended vertically in a 20 or 38 liter tank; some of these tanks were empty while others contained water at temperatures 19, 27, or 35°C +_ 0.2°C. The water depth was adjusted such that there was 5 cm of space within the tube that was above the water surface; this insured that the rats head was completely and safely out of the water. Procedures At 87 days of age, all animals were placed on food deprivation, but water was freely available. Then, 48 h later, they received one of six treatments designed to address the three questions outlined. One group (dry, n = 4) was placed into the restraining tubes, and the tubes were then suspended vertically in the experimental room at 19°C for 75 rain. A second group (dry-unc, n = 4) was treated identically except that each rat received an intraperitoneal (IP) injection of 50 mg/kg of sodium pentothal 10 min before being suspended vertically in the empty tanks placed in the experimental room. Three groups (water-19, water27, and water-35, each n --- 4) were placed into the restraining tubes, and then the tubes were suspended in 19°C, 27°C, or 35°C water baths, respectively, for 75 min. A final group (waterunc, n = 5) was treated identically to group water- 19 except that it received 50 mg/kg of sodium pentothal IP l0 rain before being placed into tubes and suspended in a 19°C water bath. The body temperature of the water-unc rats was monitored by rectal thermometer so that we could prevent, if necessary, a drop to a body temperature lower than that typically seen in conscious animals subjected to the same water bath treatment (24-25 °C); this was to be done by moving the animals to a 25°C bath, but this was necessary for only one rat whose body temperature reached 24 ° after 70 min. After being suspended for 75 min, each animal was removed from its tube, rectal temperature (designated T1)taken, and returned to its home cage for a further 75 rain (30). Upon removal from the restraint tube, the fur of the dry group rats was dampened to stimulate the same postbath grooming activity seen in the water groups. At the end of the rest period, the animals were quickly anesthetized with halothane, assessed for rectal RESTRAINT IN WATER temperature (designated T2), and sacrificed by cervical dislocation. The degree of gastric erosion and ulceration was assessed. The stomachs were removed by an experimenter blind to group assignment. Stomachs were cut along the lesser curvature, everted, washed, and swabbed clean, and each erosion counted and measured under a magnifying lens and lamp. All erosions found were in the glandular portion of the stomach, and these were typically marked by clotted blood. RESULTS The amount of ulceration induced by the different treatments, together with body temperature data at the two time points measured (at the end of the restraint period and at the end of the home cage recovery period), are presented in Table 1. Although this was run as a single experiment, it was motivated by three distinct questions. Therefore, the analysis and discussion of the data will be separated into that relevant to each question. Each question was addressed by a separate analysis of variance of the data. Although the ns are small, the data are sufficiently clear on the questions at hand as to permit inferences without replication. To reduce heterogeneity of variances in those groups manifesting ulceration, the reported analyses of cumulative ulcer length were performed on square root transformations of the raw data. If the raw data are analyzed using nonparametric tests, the between-group contrasts parallel exactly those obtained using parametric tests. Higher Central Processes Our initial question concerned the effects of pentobarbital anesthesia on ulcer development. Here, we compared animals subjected to our water restraint procedure with and without prior injection with pentobarbital (water-unc and water-19 groups, respectively), and animals subjected to restraint after pentobarbital injection but not immersed in water (dry-unc). Anesthetized but nonimmersed animals (dry-unc) did not develop any ulcer. Neither did any of the pentobarbital-treated animals subjected to water immersion stress (water-unc), despite being immersed in 19°C water. Compared to their conscious control group (water-19) immersed at the same water temperature, the difference in amount of ulcer was significant, F(1, 7) = 39.57, p < 0.001. This effect obtained even though the pentobarbital-treated immersed animals had lost more body heat (as indexed by body temperature) during both the wet phase, F(1, 7) = 8.68, p < 0.05, and the home cage rest period, F(I, 7) = 38.58, p < 0.001. 579 TABLE 1 MEAN (+SEM) VALUESOF CUMULATIVEGASTRICULCERATION (mm) AND BODY TEMPERATUREMEASURES(IN °C) TAKEN AT THE END OF THE RESTRAINTPERIOD (T1) AND AT THE END OF THE HOME CAGE REST PERIOD (T2) Treatment Group Dry-Unc Water-Unc Dry Water-19 Water-27 Water-35 Cumulative Ulceration 0 0 0 23.7 (10.35) 12.3 (6.43) 0.5 (0.58) Temperature T1 Temperature T2 33.38 (0.36) 24.14 (0.22) 37.35 (0.12) 25.18 (0.36) 32.35 (0.47) 36.97 (0.1) 33.28 (0.37) 26.42 (0.5) 36.38 (0.29) 32.08 (0.75) 35.80 (0.32) 36.77 (0.15) The results indicate that water immersion is a necessary condition for the development of gastric erosions within the time frame employed here when ambient temperature is kept constant across conditions. Earlier studies have employed so-called dry restraint [e.g., (22,29)], but the time required to induce measurable amounts of ulceration is in the order of 20 h, and, even then, the levels of ulcers induced are typically low (e.g., less than 2 ram). Temperature Our final question here concerned the relationship between the ambient water temperature and the amount of ulceration developing in the water-immersed animals. Here we compared groups of animals restrained and immersed in water at the three temperature (water- 19, water-27, water-35). The ulcer data differed for the three groups immersed at the various water temperatures, F(2, 9) = 9.39, p <0.01. Amongst the three groups, both those immersed at 19 and 27 degrees developed more ulceration than those immersed at 35 degrees, all F 18.16 and 7.94, all p 0.002 and 0.02, respectively, and a linear trend of decreasing ulcer with increasing temperature was found across the three water temperatures tested (p < 0.0 l). As seen in Table l, the animals immersed in 35°C water failed to show any reduction in body temperature, whilst both those immersed at 19°C and 27°C showed body temperature drops. Animals immersed at 19°C showed lower body temperature both at Tl and T2 measurements (all p < 0.001) than both water-27 and water-35 group animals. Immersion The second question was whether water immersion was a necessary condition for the development of gastric ulceration in our tube-restrained animals. Here we compared rats receiving our usual immersion procedure in 19°C water (water-19) with those receiving identical treatments but not exposed to water (dry group). Whereas animals immersed in room temperature water (water-19) exhibited a mean of 23.7 mm, none of the restrained but nonimmersed animals (dry) exhibited any ulceration, F(I, 6) = 30.53, p < 0.002. The two groups differed in their temporal patterns of body temperature changes, F(1, 6) = 61.02, p < 0.001. Relative to mean normal body temperature of 37.5 °C, the water-restrained animals (water- 19) lost body temperature during their water immersion period, but exhibited significant recovery during the 75 min poststress phase (p < 0.001). Nonimmersed (dry) animals actually showed a small but significant fall in body temperature during the same period (p < 0.05). DISCUSSION TO summarize our results, we have found that consciousness is a necessary factor in the development of this particular type of stress-induced pathology. Our results unequivocally show that animals rendered unconscious by pentobarbital anesthesia did not develop erosions, despite being subjected to the same restraint-in-water procedures as other groups, and despite an even greater loss in body temperature than the conscious animals that did develop high levels of ulceration. This effect cannot be ascribed simply to a cutoff of neural communication between the brain and stomach, because pentobarbital does not block vagal output to the stomach--in fact, vagal output may be enhanced (18). The expression psychosomatic, as applied to ulcers, implies the participation of central psychological processes in the development of the pathology. Our data indicate that such supramesencephalic processes are necessary for induction of gastric 580 MURISON AND OVERMIER ulceration, and that the expression psychosomatic is appropriate here. We have tbund that water immersion contributes significantly to the gastric ulceration induced in restraint-in-water stress. Indeed, restraint in our plastic tubes at room temperature, without the additional factor &partial immersion in water, is insufficient a stressor to induce observable gastric erosions within 75 rain. Earlier studies (29) using these tubes have demonstrated small amounts of observable ulceration but only after long (24 h) periods of such restraint. Even then, the small amounts of ulceration may introduce serious errors of measurement. Thirdly, the amount of ulceration developing during restraint, combined with partial immersion in water, is inversely related to the temperature of the surrounding water. Immersion in 35°C water failed to induce pathology, in contrast to immersion at either 27°C or 19°C. Striking here is that although the water19 animals suffered greater body temperature loss during immersion than the water-27 animals, and failed to return to the same body temperature at the end of the poststress rest in the home cage, this degree of ulceration was numerically double but not significantly more than in the water-27 animals. This null direct contrast effect, however, is due to the lack of power inherent in small ns with large variance present in this comparison of ulcer lengths between the water-19 and water-27 groups. We feel comfortable, therefore, in relying on the statistically significant linear relationship between amount of pathology and body temperature loss. It is important to note that our animals immersed in water at a temperature (19°C) previously shown not to elicit a signif- icant increase in gastric acid secretion (1) developed greater ulcer than those animals immersed in water at a temperature (25°C) approximate to that which has been shown to elicit a 100~ increase in gastric secretion. These results confirm that although gastric acid is a necessary condition for ulcerogenesis to occur. the extent of ulceration in the restraint-in-water procedure is unrelated to the actual amount of acid secreted. Furthermore, they suggest that the process of ulcerogenesis under restraint in water may have different dynamics than that under cold restraint, because in the latter case the relationship between ambient air temperature and gastric acid output mirrors that between temperature and incidence of ulceration (7,20,40). In the present study, we have attempted to elucidate just a few of the important variables involved in the development of stress-induced gastric ulceration in animals. Our results confirm that psychological, as well as physical, factors play an important role in acute ulcerative processes as employed here, and complement the demonstrations that psychological factors may proactively sensitize or protect the animal from ulcer induced by the techniques employed here (23). ACKNOWLEDGEMENTS This research was supported by a grant to Dr. Murison from the Norwegian Research Council for Science and the Humanities (NAVF). Dr. Overmier's participation was made possible by support from the National Science Foundation. The authors gratefully acknowledge the technical assistance of Randi Espelid and Nina Konglevoll, and helpful discussions with Dr. Finn Jellestad. REFERENCES I. Arai, 1.; Hirose, H.; Muramatsu, M.; Aihara, H. Effects of restraint and water-immersion stress and insulin on gastric acid secretion in rats. Physiol. Behav. 40:357-361; 1987. 2. Arai, I.; Muramatsu, M.; Aihara, H. Body temperature dependency of gastric regional blood flow, acid secretion and ulcer formation in restraint and water-immersion stressed rats. Jpn. J. Pharmacol. 40: 501-504; 1986. 3. Bennet, M. C.; Diamond, D. M.; Fleshner, M.; Rose, G. M. Serum corticosterone level predicts the magnitude of hippocampal primed burst potentiation and depression in urethane-anesthetized rats. Psychobiology 19:301-307; 1991. 4. Bonfils, S.; Lambling, A. Psychological factors and psychopharmacological actions in the restraint-induced gastric ulcer. In: Skoryna, S. C., ed. Pathophysiology of peptic ulcer. Toronto: McGill University Press; 1963:153-171. 5. Borchard, R. E.; Barnes, C. D.; Eltherington, L. G. Drug dosage in laboratory animals: A handbook. New Jersey: Telford Press; 1991. 6. Brady, J. V. Ulcers in "executive" monkeys. Sci. Am. 199:95-100: 1958. 7. Buchell, L; Gallaire, D. Ulcere de contrainte chez le rat. 1. Influence, sur la frequence des ulceres, du jeune et de la temperature de l'environment associes a des immobilisations de durees variables. Arch. Sci. Physiol. 21:527-536; 1967. 8, Cannon, W. B. "Voodoo" death. Am. Anthropol. 44:169; 1942. 9. Cheney, D. H.; Slogoff, S; Allen, G. W. Ketamine-induced stress ulcer in the rat. Anesthesiology 40:531-535; 1974. 10. Glavin, G. B. Restraint ulcer: History, current research and future implications. Brain Res. Bull. 5(Suppl. 1):51-58; 1980. 11. Glavin, G. B.; Murison, R.; Overmier, J. B.; Parr, W. P.; Bakke, H. K.; Henke, P. G.; Hemandez, D, E. The neurobiology of stress ulcers. Brain Res. Rev. 16:301-343; 1991. 12. Goto, Y.; Tacbr, Y. Gastric erosions induced by intracisternal thyrotropin-releasing hormone (TRH) in rats. Peptides 6:153-156; 1985. 13. Grau, J. W. The central representation of an aversive event maintains the opioid and nonopioid forms of analgesia. Behav. Neurosci. 101: 272-288; 1987. 14. Hayase, M.; Takeuchi, K. Gastric acid secretion and lesion formation in rats under water-immersion stress. Dig. Dis, Sci. 31:166-171 : 1986. 15. Hernandez, D. E.: Arredondo, M. E.; Xue, B. G.; Jennes, L. Evidence for a role of brain thyrotropin-releasing hormone (TRH) on stress gastric lesions formation in rats. Brain Res. Bull. 24:693-695; 1990. 16. Klein, M. V.: Lovaas, K. M.: Yerman, G. W.; Liebeskind, J. C. The effects of decerebration and spinal transection on three discrete forms of stress-induced analgesia. Soc. Neurosci. Abstr. 9:795; 1983. 17. Klein, M. V.; Terman, G. W.; Liebeskind, J. C. Effects of pentobarbital on three forms of stress-induced analgesia. Soc. Neurosci. Abstr. 10:1105; 1984. 18. Lin, W. C.; Yano, S; Watanabe, K. Stimulation of gastric acid secretion by microinjection of pentobarbital into the ventromedial hypothalamus. Res. Commun. Chem. Pathol. Pharmacol. 60:269272; 1988. 19. Maier, S. F. Determinants of the nature of environmentally induced hypoalgesia. Behav. Neurosci. 103:131-143; 1989. 20. Martin, M. S.; Martin, E,; Lambert, R. The effect of ambient temperature on restraint ulcer in the rat. Digestion 3:331-337: 1970. 21. Murakami, M.; Lain, S. K.; Inada, M.; Miyake, T. Pathophysiology and pathogenesis of acute gastric mucosal lesions after hypothermic restraint stress in rats. Gastroenterology 88:660-665; 1985. 22. Murison, R.; Isaksen, E. Gastric ulceration and adrenocortical activity after inescapable and escapable pre-shock in rats. Scand. J. Psychol. Suppl, 1:133-137; 1982. 23. Murison, R.; Olafsen, K. Stress gastric ulceration in rats: Impact of prior stress experience. Neurosci. Biobehav. Rev. 15:319-326; 1991. 24. Murison, R.; Overmier, J. B. Interactions amongst factors which influence severity of gastric ulceration in rats. Physiol. Behav. 36: 1093-1097; 1986. 25. Niida, H.; Takeuchi, K.; Ueshima, K.; Okabe, S. Vagally mediated acid hypersecretion and lesion formation in anesthetized rat under hypothermic conditions. Dig. Dis. Sci. 36:441-448; 1991. R E S T R A I N T IN W A T E R 26. Overmier, J. B.; Murison, R. Post-stress effects of danger and safety signals on gastric ulceration in rats. Behav. Neurosci. 103:12961301; 1989. 27. Overmier, J. B.; Murison, R. Juvenile and adult footshock stress modulate later adult gastric pathophysiological reactions to restraint stresses in rats. Behav. Neurosci. 105:246-252; 1991. 28. Overmier, J. B.; Murison, R.; Ursin, H.; Skoglund, E. J. Quality of post-stressor rest influences the ulcerative process. Behav. Neurosci. 101:246-253; 1987. 29. Overmier, J. B.; Murison, R.; Skoglund, E. J.; Ursin, H. Safety signals can mimic responses in reducing the ulcerogenic effects of shock. Physiol. Psychol. 13:243-247; 1985. 30. Overmier, J. B.; Murison, R.; Ursin, H. The ulcerogenic effect of a rest period after exposure to water-restraint stress. Behav. Neurol. Biol. 46:372-382; 1986. 3 I. Par6, W. P. Strain, age, but not gender, influence ulcer severity induced by water-restraint stress. Physiol. Behav. 45:627-632; 1989. 32. Par6, W. P.; Glavin, G. B. Restraint stress in biomedical research: A review. Neurosci. Biobehav. Rev. 10:339-370; 1986. 33. Richter, C. P. On the phenomenon of sudden death in animals and man. Psychosom. Med. 19:191-198; 1957. 34. Takagi, K.; Kasuya, Y.; Watanabe, K. Studies on the drugs for peptic ulcer. A reliable method for producing stress ulcer in rats. Chem. Pharm. Bull. (Tokyo) 12:465-472; 1964. 581 35. Takeuchi, K.; Furukawa, O.; Okabe, S. Induction of duodenal ulcers in rats under water-immersion stress conditions: Influence of stress on gastric acid and duodenal alkaline secretion. Gastroenterology 91:554-563; 1986. 36. Terman, G. W.; Shavit, Y.; Lewis, J. W.; Cannon, J. T.; Liebeskind, J. C. Intrinsic mechanisms of pain inhibition: Activation by stress. Science 226:1270-1277; 1984. 37. Watkins, L. R.; Mayer, D. J. Organization of endogenous opiate and nonopiate pain control systems. Science 216:1185-1192; 1982. 38. Weihe, W. H. The laboratory rat. In: Poole, T. B., ed. The UFAW handbook on the care and management of laboratory animals. Harlow: Longman Scientific and Technical; 1987:309-330. 39. Weisz, J. D. The etiology of experimental gastric ulceration. Psychosom. Med. 19:61-73; 1957. 40. Witty, R. T.; Long, J. F. Effect of ambient temperature on gastric secretion and food intake in the rat. Am. J. Physiol. 219:1359-1362; 1970. 41. Woods, P.; Holland, C. Instrumental escape conditioning at different levels of drive stimulus intensity. J. Comp. Physiol. Psychol. 62: 403-408; 1966. 42. Yano, S; Lin, W. C.; Watanabe, K. Effect ofpentobarbital on gastric acid secretion elicited by secretagogues or electrical vagal stimulation in rats under urethane anesthesia. J. Pharmacobiodyn. 11:662-628; 1988.