Stress-rest cyclicity in the pathogenesis of restraint-induced stress gastric ulcers in rats

Physiology&Behavior.Vol. 45, pp. 809-813. ©Pergamon Press plc., 1989. Printed in the U.S.A.

0031-9384/89 $3.00 + .00

Stress-Rest Cyclicity in the Pathogenesis of Restraint-Induced Stress Gastric Ulcers in Rats R O B E R T M U R I S O N , *t J. B R U C E O V E R M I E R t

A N D G A R Y B. G L A V I N : ~

*Department of Physiological Psychology, University of Bergen, Norway -pDepartment of Psychology, University of Minnesota, Minneapolis, MN .~Department of Pharmacology and Therapeutics and Department of Surgery University of Manitoba, Winnipeg, Canada R e c e i v e d 26 S e p t e m b e r 1988

MURISON, R., J. B. OVERMIER AND G. B. GLAVIN. Stress-restcyclicityin thepathogenesis of restraint-inducedstressgastric ulcers in rats. PHYSIOL BEHAV 45(4) 809-813, 1989.--Temporal patterns of stress and rest have been shown to influence extent of shock-induced pathology. In the present study, the influence of stress-rest cycles was studied on amount of gastric ulceration after two forms of immobilization stress in rats. In Experiment 1, rats were subjected to different patterns of cold supine restraint interspersed with rest periods. A single 180 minute exposure produced more extensive ulceration than did a series of six 30 minute stress periods interspersed with 30 minute rest periods in the home cage. Different results were found in Experiment 2 using the stress of restraint in water and stress/rest patterns parallel to those used in Experiment 1. Previous reports have suggested that a "priming" stress might activate mechanisms protective against gastric ulceration. This was also investigated in Experiment 2 when animals were subjected to either a single 150 minute stress period, a 30 minute priming exposure to the same stressor 150 minutes prior to a 150 minute second exposure, or a 30 minute priming exposure 30 minutes prior to a 150 minute second exposure. No evidence was found for protective effects. In fact, a priming stress 30 minutes prior to final exposure enhanced ulceration. The studies provide some supporting evidence for the role of cycles in determining extent of stress pathology. Such data must be accounted for in any description of the mechanisms of stress-related ulceration. Gastric ulceration

Restraint

Immersion stress

Stress-rest cycles

A number of methods have been employed to study the etiology of stress-related gastric erosions ( " u l c e r a t i o n " ) in the rat, including exposure to electric shock stress (9, 19, 22), feeding scheduleinduced activity stress (13,16), restraint stress alone (3), or restraint combined with either cold (15) or water immersion (6, 7, 12). Whereas there is a considerable body of information concerning the various factors which may influence the severity of shock-induced gastric ulceration [e.g., (23)], there is not the corresponding body of information concerning factors involved in the development of restraint-stress ulceration. In this paper, we report two studies which attempt to explore some of these factors for two forms of restraint stress. Using a shock-avoidance task, Brady (2) found that the development of gastrointestinal erosions in monkeys was dependent on, amongst other things, the time parameters of cyclic stress and nonstress (or " r e s t " ) periods. Monkeys developed gastrointestinal erosions only when the animals were subjected to a series of six-hour stress periods interspersed with six hours of rest. Brady (2) concluded that the crucial factor in the development of ulcers was the relationship between stress and rest periods. In a

similar study using rats, Rice (17) found a peak development of gastric ulceration using either a five or six hour stress/rest pattern. A " r e b o u n d " phenomenon has been invoked to account for the effects of cyclic stress-rest pattems involving shock stress (5). Thus, at least with regard to shock stress, there is reason to believe that the particular temporal pattern of stress and rest in a cyclic stress/rest paradigm is of considerable significance for the severity of the resulting gastric erosions, and understanding these cyclic effects may yield insight into the underlying physiologic mechanisms. With regard to restraint-stress techniques, little is known about the importance of such cyclicity. However, a number of studies have indicated that allowing animals a rest after a single period of restraint leads to substantial increases in the severity of ulceration (3, 12, 21), possibly due to " r e b o u n d " effects on the cholinergic (vagus) system. On the other hand, Bonfils et al. (1) compared a single 24-hour restraint stressor with cyclic 24-hour stressor followed by 24-hour rest for several cycles and found maximum gastric pathology after a single stress period and no rest with less pathology observed following various numbers of cycles of

1Requests for reprints should be addressed to Dr. R. Murison, Department of Physiological Psychology, Arstadveien 21, N-5009 Bergen, Norway.

809

MURISON, OVERMIER AND GLAVIN

~l()

TIME

(mira)

i 0

~

i 60

i

i 120

,

J 180

,

i 240

i

i 300

30

t

20

Q=~o.p 1

2

~Y/A m

FTA ~

E

E

V//lll/lll/~

V//lllll//A

m

gYA

E

[I/////////A

I< nLU

1o

o

.J

1

g///////////////////////////////A

3

(6 x 3 0 )

2

3

(3 x 6 0 )

(1 x 18o)

TREATMENT

FIG, 1. Temporal patterns of stress (cold supine restraint) and rest employed in Experiment 1.

stress-rest. Temporal patterns of stress and rest are therefore of interest in the development of restraint-stress ulceration and should be explored to determine if cyclicity and cycle parameters modulate the ulcerative process. [Experiments 1 and 2 are reported together because of their clear interrelatedness, although they employed animals of different origin, and were performed at different laboratories (Experiment 1 in Winnipeg and Experiment 2 in Bergen).] EXPERIMENT 1 In the first experiment we chose to compare the effects of three stress/rest pattems on ulcer formation in rats. On the basis of the above-mentioned studies, it was reasonable to expect that some pattern of intermittent stress-rest periods might be more effective than a single longer stress session in precipitating gastric erosions. METHOD

The subjects were 30 male Holtzman rats (a Sprague-Dawley derived strain from Holtzman Co., Madison, WI), aged 90 days at the start of the experiment. Animals were randomly assigned into 3 experimental groups. Prior to the first stress session, all animals were deprived of food, but not water, for 24 hours. The stressor used in this experiment was the supine restraint stress as described by Vincent et al. (20) in an ambient temperature of 4-6°C. The animals were restrained by taping them to a wooden board with three strips of adhesive tape placed over the thorax and abdomen, and also over each limb. Each limb was drawn out at an angle of 45 ° angle from the animal's body before being taped. Animals of the first group (n = 10) were subjected to a series of six 30 minute restraint periods, each interspersed with a 30 minute " r e s t " period, during which time they were returned to their home cage, without access to either food or water. Animals of a second group (n = 10) were subjected to three 1 hour restraint periods, interspersed with 1 hour rest periods in the home cage, without access to food and water. Animals of a third group (n = 10) were subjected to a single 3 hour supine restraint session. Thus, all animals were subjected to a total of 3 hours of supine restraint stress in cold: the groups differed in the number of restraint and rest periods employed to achieve this total three hours of restraint (Fig. 1). After the final restraint phase for each animal, the rat was sacrificed by decapitation; the stomach was removed, everted, and examined for the size of any gastric erosions,

C~OUPS

FIG. 2. Cumulative ulceration length (mm +sem) following different patterns of stress-rest exposure using cold supine restraint stress.

RESULTS

Data analysis was performed on the square root of the cumulative length of gastric ulceration (Fig. 2). The square root transformation was used because it reduces heterogeneity of variance in this measure. Analysis of variance of these transformed data yielded marginally significant differences between the three groups, F(2,27)= 3.3, p =0.051. The analysis did indicate a significant linear trend, F(1,27)=24.4, p<0.02, with ulceration length being inversely related to the number of stress exposures (Gp 1 < Gp 2 < Gp3). Animals exposed to 6 × 30 minutes of supine restraint stress exhibited less severe ulceration than those exposed to the single 180 minute stress period (p<0.02). DISCUSSION

Contrary to our expectations, the exposure of animals to a single three hour supine restraint session was more effective in producing gastric ulceration than patterns of intermittent stress and rest. This finding is contrary to earlier studies with shock-stress, and to any hypothesis of cholinergic "rebound," although the direction of differences is in accordance with the data of Bonfils et al. (2) using restraint stress for longer periods. Furthermore, the total length of experimental period from start to finish of the experiment was also shortest for the group which received the single three hour stress exposure but which developed the most ulceration. EXPERIMENT 2 Even within the restraint-ulceration literature, there is considerable diversity as to the exact method of restraint stress chosen to induce gastric ulceration. There is little information about how these different stressor procedures differ from each other, and whether similar parametric manipulations under any one form of restraint stressor have parallel effects under another form of that stressor. If we are to make any sense of the ulcerogenic process, it is important to also investigate whether similar results are obtained under another ulcerogenic restraint stress procedure. In the first study described above, the ulcerogenic stress procedure chosen was that of supine restraint in a cold environment. In this second experiment, we firstly undertook to investigate ~hether parallel effects of stress-rest cycles would be obtained using another, although superficially similar, stressor-restraint in water. Par6 (14), employing direct comparisons of the two methods, reports that

STRESS-REST CYCLES AND ULCERATION

restraint in water is more ulcerogenic than supine restraint in 130and 280-day-old Long-Evans rats. A second issue to be addressed within Experiment 2 is that of the elicitation of gastroprotective mechanisms, or "priming." Repeated exposure to ulcerogenic stressors has been shown to have modifying actions on ulcerogenesis. One such action is protective. For example, pretreatment of rats with orally delivered ethanol leads to gastroprotection which becomes apparent when the animals are treated 15-minutes later with a considerably stronger ethanol treatment (18). This effect also appears to result when the final ulcerogenic stressor is other than ethanol; indeed, Glavin, Lockhart, Rockman, Hall and Kiernan (4) report that 7 days pretreatment with mild restraint stress (1 hour at normal temperature) or 20% ethanol protected rats against subsequent exposure to both 3 hours of cold restraint stress and 100% ethanol. The initiation of gastroprotective processes by a potential ulcerogenic stress is of considerable interest in allowing studies of the mechanisms active in such cytoprotection. In the present study, we therefore undertook to also investigate whether water-restraint stress of short duration would activate such protective mechanisms and thus attenuate the extent of ulceration in response to a later similar but more severe stressor exposure.

811

TIME

(rnirO

i

0

,

i

BO

,

;

120

G=~oup 1

~

~

2

m

3

W///ZII///////A

6 7

I

180

I

I

240

I

I

I

300

l~J

m

m ~//////////////A

V////£££//~///////////~

N -I , 5

,

V//~////~£////////£///~

~ ~

V////////~///////////////~

W/////////////////////////~

B FIG. 3. Temporal pattems of stress (restraint in room temperature water) and rest employed in Experiment 2.

METHOD

Subjects The subjects were 51 male M¢llegard, SD rats (a SpragueDawley derived strain, M¢llegaard, Denmark), aged 95 days at the start of food deprivation procedures. Animals were handled and weighed prior to rehousing in single cages, and were assigned to the 7 experimental (n = 6) groups and Control group (n = 9) on the basis of matching for weight (mean group weight = 381.2--- 4 g). Twenty-four hours before the initiation of the stress sessions, all animals were deprived of food and grid floors were placed into the cages to prevent ingestion of bedding or faecal material. Water remained available. Restraint Tubes For the water-restraint stress, the rats were restrained in a tube suspended in room temperature water. The tubes had inside dimensions of 6 cm diameter and 19 cm length. One end was capped with a fine wire 2 mm screen mesh; the other was closed behind the rat by passing two parallel bolts across the end of the tube. The tubes were perforated with three rings each of four 8 mm holes that were placed equidistant around the tube with the rings separated from each other by 5 cm and centered on the length of the tube. Placement of the rat was simple because the rats would run into the tubes when placed at the open end. After placement of the rat, the tube was suspended vertically by swiveling hooks in a 20 litre tank of 19.3---0.2°C water, with the top of the tube 3 cm above the surface, ensuring that the rat's head was safely above the water. Although the degree of physical restraint was significant, the rats did have the possibility of small rotational and vertical movements as well as movement of their limbs within the tubes. Because Bonfils et al. (1) have shown that degree of gastric ulceration from physical restraint alone is inversely proportional to the amount of movement possible, and in our tubes that amount is likely about 2 mm (11), the substantially greater amounts of erosions seen here are likely the result of the additional stress caused by suspension in the water. Procedures Animals of the 7 experimental groups and 1 Control group

were subjected to different patterns of water-restraint stress and rest or handling procedures. As illustrated in Fig. 3, Group 1 was subjected to a series of six 30-minute sessions of restraint in water interrupted by 30 minute rest periods during which animals were replaced in their home cages, without food and water, giving a total of 3 hours of stress. The animals were sacrificed by decapitation at the end of the final water-restraint period. For Group 2, animals were subjected to three 1-hour water-restraint sessions, interspersed with two 75 minute rest periods. Animals were sacrificed immediately on removal from the final stress period. Animals of Group 3 were subjected to 2 stress periods, each of 90 minutes, with a 150 minute rest period between, and sacrificed after removal from the final stress period. Group 4 animals were subjected to a single 150 minute water-restraint period, and were sacrificed immediately after removal from the immersed restraint tubes. Group 5 animals were subjected first to a brief (30 minute) session of restraint in water, before being returned to their home cages for 150 minutes without food or water. At the end of this period, these animals were returned to the water-restraint stress for a further 150 minutes before sacrifice. Animals of Group 6 were subjected to a brief (30 minute) restraint in water stress and allowed a shorter (30 minute) interval before being returned for a final 150 minute stress exposure prior to sacrifice. Group 7 animals were subjected to a single 150 minute period of restraint in water, and were then returned to their home cages for a further 180 minutes before sacrifice. Control group (Group 8) animals were not subjected to water-restraint stress, but were sacrificed after the appropriate period of food deprivation. On sacrifice, the stomach was removed, cut along the lesser curvature, and everted. The stomach was then examined for the extent of any gastric erosions by an experienced investigator who was blind as to the individual animal's group assignment. RESULTS

Ulceration To reduce heterogeneity of variance, analysis of the data on cumulative length of ulceration was performed on data subjected to a square root transformation. Animals of the eight groups exhibited different cumulative lengths of gastric erosions, F(7,43) =

812

MURISON, OVERMIER AND GLAVIN

60

Z

4o

0 I-

3o

LU

0

J Z)

to 0 v.~mmm..mm..amm

1

2

3

4

5

6

7

8

T R E A T M E N T GROUPS FIG. 4. Cumulative ulceration length (mm - sem) after different temporal patterns of restraint-in-water and rest periods.

14.7, p<0.001 (see Fig. 4). In the light of the data from Experiment l, which employed supine restraint stress, we sought first to determine whether a similar linear trend occurred here over those groups which most closely paralleled those employed in Experiment 1, that is groups 1, 2, 3, and 4. No such linear trend was obtained, F(1,43) = 1.78, ns, indicating a fundamental difference in the pattern of data from the two methods. In contrast, test for quadratic trend over these four groups did yield a significant F, F(1,43)= 6.6, p < 0 . 0 2 . As can be seen from Fig. 3, this reflects the smaller degree of ulceration in those animals (Group 4) sacrificed immediately after a single 150 minute period of stress exposure. No significant differences were found between the three other groups (1, 2 and 3) contributing to this quadratic trend, F(1,43)= 1.9, ns. Thus for at least these three conditions, patterns of rest and stress were not of any great consequence for the amount of ulceration observed. Examination of Fig. 4 suggests that the higher levels of ulceration in Groups 1, 2, and 3 compared to Group 4 might have arisen because of the intermittent rest periods between consecutive stress periods. And the power of the rest effect is demonstrated again when comparison is made between animals given the same single stress period of 150 minutes, but manipulating whether the animal was sacrificed immediately (Group 4: m e a n - - 8 . 6 mm) or after a rest period (Group 7: m e a n = 4 8 . 3 ) , lsd test, p < 0 . 0 0 1 . The second issue to be addressed was that of priming. Contrary to what might be expected on the basis of other reports, presentation of a such a priming stress period of 30 minutes led to increased ulceration after the final 150 minute stress period, F ( 1 , 4 3 ) = 5 . 3 , p < 0 . 0 3 (Group 4 vs. Groups 5 and 6). In an attempt to understand this data more clearly, post hoc tests were performed on the groups concerned (4, 5, and 6). This revealed that those animals exposed to 30 minutes of stress terminating 30 minutes before initiation of the final stress (Group 6) exhibited more ulceration than animals given no priming stress (Group 4), lsd test p < 0 . 0 1 . Priming stress terminating 150 minutes prior to final stress had no significant effect on the outcome of the final stress period as demonstrated by nonsignificance in comparisons of either Group 4 vs. Group 5, or Group 5 vs. Group 6.

DISCUSSION

The first question to be addressed in this experiment was whether or not the same, or similar, patterns of stress of restraint

in water and home cage rest as employed in Experiment 1 would result in similar between group patterns on the extent of gastric ulceration. Using the stress of restraint-in-water, no such similar pattern was obtained. The significant quadratic trend found reflects the lower levels of ulcer measured in animals sacrificed immediately after exposure to a single stress exposure compared to animals given a series of stress + rest treatments. In this respect at least, stress of restraint in water differs from that of cold supine restraint, to the extent that we can justifiably compare over experiments using animals of different origin and performed in different laboratories. In contrast to reports using other stressors, prior brief exposure to the ulcerogenic stress of restraint in water in this study did not appear to lead to activation of gastroprotective mechanisms as measured by the extent of ulceration after the final stressor. On the contrary, those animals which received a brief " p r i m i n g " stress shortly (30 minutes) before the final stress exposure exhibited increased ulceration. In this respect, therefore, the present form of ulcerogenic stress appears to differ significantly in nature from, for example, the ulcerogenic processes associated with alcohol ingestion. GENERAL DISCUSSION The two studies reported here dealt with various patterns of stress/rest exposure on extent of gastric ulcer formation. When total duration of stress is held constant, manipulations of these temporal factors will necessary confound one or more of differences in numbers of exposures, durations of individual exposures, number of rests and durations of individual rest periods. In Experiment 1, it was seen that the extent of ulceration decreased linearly with the number of exposures prior to sacrifice. A smiliar pattern of results was not found using restraint-in-water stress in Experiment 2: this difference in pattern emerges primarily from the small amounts of ulceration found in those animals subjected to the single stress exposure and sacrificed immediately. The most salient difference between water-restraint stress and the other forms of ulcerogenic manipulations mentioned here (supine restraint and alcohol ingestion) is that the rest period after water restraint may involve continued loss of body temperature. Although loss of temperature p e r se does not correlate with the extent of ulceration (10), this could be a major factor contributing to the ulcerogenic processes. The rest periods between exposure to water restraint may therefore act as a continuation of the stress period, or even in an exacerbatory fashion. Based upon this, the important factor would therefore appear to be the length of time between each stressor exposure and/or sacrifice, but this may interact with absolute stressor durations as well. As has been stated previously, and demonstrated again in Experiment 2, poststressor rest is of considerable importance for the ulcerogenic processes. Comparison of Groups 4 and 7 in Experiment 2 shows how powerful this effect may be, the former showing 8.6 mm and the latter 48.3 mm ulceration. Glavin (3) has suggested that this exacerbation is the result of a rebound of parasympathetic processes, although it must be said that this poststress rest effect is not always obtained (8). From Experiment 2, it can be seen that using a priming exposure, far from protecting against ulcerogenesis under the final stress, can in fact exacerbate that ulceration. Again, there is therefore reason to believe that the stress of restraint in water differs fundamentally from those stressors used in studies where prior exposure has a protective effect, and where prostaglandinrelated mechanisms have been invoked earlier. In this paper, we have provided some basic information concerning temporal cyclicity factors which influence ulceration under restraint stress of two types--supine cold and water re-

STRESS-REST CYCLES AND ULCERATION

813

straint. Clearly cyclicity and rest are critical factors and while short cycles are not highly ulcerogenic, a brief stressor " p u l s e " shortly prior to a longer stress exposure can have ulcerogenic priming effects. Whether one or several such priming " p u l s e s " is maximally exacerbating for ulcer formation is not clear at this time, and is the focus of current investigations. Despite the complexities of the present data, the paper provides a useful stimulus to the field by going substantially beyond the usual practice of exposing the subjects to a single phase of acute stress. The studies have not attempted to examine or propose underlying mechanisms but any model or hypothesis concerning such mech-

anisms will have to take into account the pattern of the above findings. ACKNOWLEDGEMENTS The work reported in this paper was supported by the Norwegian Research Council for Science and the Humanities (NAVF). Dr. Overmier's participation was made possible by grants from USPHS-NICHD and from the University of Minnesota to the Center for Research in Learning, Perception and Cognition and from the Norwegian Marshall Fund. The authors gratefully acknowledge critical commentary from Gary D. Coover and Hans Kristian Bakke.

REFERENCES 1. Bonfils, S.; Liefooghe, G.; Rossi, G.; Lambling, A. L'ulcere experimental de constrainte du rat blanc. Analyse des principaux facteurs determinants. Arch. Med. Appet. Dig. 48:449-459; 1959. 2. Brady, J. V. Ulcers in executive monkeys. Sci. Am. 199:95-103; 1958. 3. Glavin, G. B. Restraint ulcer: History, current research and future implications. Brain Res. Bull. 5(Suppl. 1):51-58; 1980. 4. Glavin, G. B.; Lockhart, L. K.; Rockman, G. E.; Hall, A. M.; Kieman, K. M. Evidence of "cross-stressor"-inducedadaptive gastric cytoprotection. Life Sci. 41:2223-2227; 1987. 5. Gliner, J. A.; Shemberg, K. M. Conditioned fear and gastric pathology in a continuing stress-rest paradigm in rats. J. Comp. Physiol. Psychol. 74:20-22; 1971. 6. Hayase, M.; Takeuchi, K. Gastric acid secretion and lesion formation in rats under water-immersion stress. Digest. Dis. Sci. 31:166-171; 1986. 7. Kitagawa, H.; Fujiwara, M.; Osumi, Y. Effect of water-immersion stress on gastric secretion and mucosal blood flow in rats. Gastroenterology 77:298-302; 1979. 8. McCutcheon, N. B.; Guile, M. N. Stomach mucosal lesions in stressed rats with and without post-stress rest. Physiol. Behav. 26:681-686; 1981. 9. Murison, R.; Isaksen, E.; Ursin, H. "Coping" and gastric ulceration in rats after prolonged active avoidance performance. Physiol. Behav. 27:345-348; 1981. 10. Murison, R.; Overmier, J. B.; Carmona, M. Gastric ulcerations in rats exposed to prepubertal shock stress. In: Weiner, H.; Florin, I.; Murison, R.; Hellhammer, D., eds. Frontiers in stress research. Toronto: Hans Huber Publishers; 1989:401-404. I1. 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.

12. Overmier, J. B.; Murison, R.; Ursin, H. The ulcerogenic effect of a rest period after exposure to water-restraint stress. Behav. Neural Biol. 46:372-382; 1986. 13. Par6, W. P. Activity-stress ulcer in the rat: Frequency and chronicity. Physiol. Behav. 16:699-704; 1976. 14. Par& W. P. A comparison of two ulcerogenic techniques. Physiol. Behav. 44:417-420; 1988. 15. Par6, W. P.; Glavin, G. B. Restraint stress in biomedical research: A review. Neurosci. Biobehav. Rev. 10:339-370; 1986. 16. Rea, M. A.; Hellhammer, D. H. Activity wheel stress: changes in brain norepinephrine turnover and the occurrence of gastric lesions. Psychother. Psychosom. 42:218-223; 1984. 17. Rice, H. K. The responding-rest ratio in the production of gastric ulcers in the rat. Psychol. Rec. 13:11-14; 1963. 18. Robert, A.; Nezamis, J. E.; Lancaster, C.; Davis, J. P.; Field, S. O.; Hanchar, A. J. Mild irritants prevent gastric necrosis through "adaptive cytoprotection" mediated by prostaglandins. Am. J. Physiol. 245: G113-G121; 1983. 19. Sawrey, W. L.; Weisz, J. D. An experimental method of producing gastric ulcers. J. Comp. Physiol. Psychol. 49:269-275; 1956. 20. Vincent, G. P.; Glavin, G. B.; Rutkowski, J. L.; Par6, W. P. Body orientation, food deprivation and potentiation of restraint-induced gastric lesions. Gastroenterol. Clin. Biol. 1:539-543; 1977. 21. Vincent, G. P.; Par6, W. P. Post stress development and healing of supine-restraint induced stomach lesions in the rat. Physiol. Behav. 29:721-725; 1982. 22. Weiss, J. M. Effects of coping responses on stress. J. Comp. Physiol. Psychol. 65:251-260; 1968. 23. Weiss, J. M. Behavioral and psychological influences on gastrointestinal pathology: experimental techniques and findings. In: Doyle Gentry, W., ed. Handbook of behavioral medicine. New York: Guilford Press; 1984:174-221.