3
The Basis of Stress and Distress Not Induced by Pain

INTRODUCTION

The nonpain causes of stress in laboratory animals can be grouped into three general categories: experimental methods, external (environmental) sources, and internal, physiologic (endocrinologic, biochemical, or neurologic) causes. Those categories can be used to facilitate consideration of the issue, but are not mutually exclusive. For example, a stressful experiment might later trigger a fear response in an animal the next time it is removed from its cage, even in the absence of external stressors; focusing on the method of removal from the cage will probably not relieve the fear. Similarly, stress produced by social isolation, social aggression, inappropriate caging, or careless husbandry practices might be manifest when an animal is used in an experiment; addressing the experimental design is not likely to be very useful. And experimental and environmental stresses are likely to cause changes in physiologic functions.

Environmentally caused stress, unlike pain, can have vastly different causes. No common pathway exists by which all non-pain-inducing stressors exert their influence. Rather, it appears that environmental stress results from a combination of various stressors and their impact on an organism's ability to adapt to them. Recognition, or anticipation, that a particular event will be perceived as an important stressor by an animal requires knowledge not only of the stressor, but of the species-typical responses to situations and of the experience of the particular animal.

It should be obvious that stress can result from husbandry practices, experi-



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Recognition and Alleviation of Pain and Distress in Laboratory Animals 3 The Basis of Stress and Distress Not Induced by Pain INTRODUCTION The nonpain causes of stress in laboratory animals can be grouped into three general categories: experimental methods, external (environmental) sources, and internal, physiologic (endocrinologic, biochemical, or neurologic) causes. Those categories can be used to facilitate consideration of the issue, but are not mutually exclusive. For example, a stressful experiment might later trigger a fear response in an animal the next time it is removed from its cage, even in the absence of external stressors; focusing on the method of removal from the cage will probably not relieve the fear. Similarly, stress produced by social isolation, social aggression, inappropriate caging, or careless husbandry practices might be manifest when an animal is used in an experiment; addressing the experimental design is not likely to be very useful. And experimental and environmental stresses are likely to cause changes in physiologic functions. Environmentally caused stress, unlike pain, can have vastly different causes. No common pathway exists by which all non-pain-inducing stressors exert their influence. Rather, it appears that environmental stress results from a combination of various stressors and their impact on an organism's ability to adapt to them. Recognition, or anticipation, that a particular event will be perceived as an important stressor by an animal requires knowledge not only of the stressor, but of the species-typical responses to situations and of the experience of the particular animal. It should be obvious that stress can result from husbandry practices, experi-

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Recognition and Alleviation of Pain and Distress in Laboratory Animals mental procedures, social interactions, feeding regimens, lighting, odors, noises, and so forth. It is not possible to list all possible stressors, because the variety of experiences and responses of animals is vast. This chapter will therefore concentrate on environmental and ecologic factors that have been demonstrated in humans and animals to be important contributors to stress. They are not all-inclusive causes of stress, but are intended to represent major categories that can be useful options for consideration. The categories are derived from what is known about causes of stress in animals in general, including wild animals and humans, as well as laboratory animals. Even ecologic stressors that have no obvious impact on laboratory animals (e.g., predator-prey relations and foraging) have implications for research animals that should be considered. Stress is a normal feature of life and serves important adaptive functions. The physiologic processes involved in the flight of an antelope being chased by a cheetah and in the cheetah that pursues it are examples of the normal adaptive functions of stress. Those processes allow both animals to maximize their physiologic resources in a situation of vital concern to each of them. Stress is also common in captive environments. It can be produced by pain and by extreme variations in ambient temperature, illness, demanding tasks, and almost any situation that an animal perceives as threatening or that puts it in a state of uncertainty and conflict (Hennessy and Levine, 1979; Weinberg and Levine, 1980). It is important to recognize the presence and varied sources of stress for ethical reasons and because the physiologic changes associated with stress are likely to affect experimental data. Research designs and experimental procedures should be planned to minimize stress. Although stress has normal adaptive functions, stress in captive environments can lead to pathologic changes, such as gastric ulcers, and to outcomes that are maladaptive. When that occurs, it can be said that the animal is not only stressed, but distressed. As stated in Chapter 1, distress is a state in which an animal is unable to adapt completely to stressors; it differs from stress only in the manifestation of maladaptive behaviors or other pathologic processes. Pain is an example of a stressor. The primary biologic function of pain is to signal potential or actual tissue damage. An animal in pain characteristically shows postures or behaviors that alleviate or terminate the pain (see Chapter 4). When an animal in pain is prevented from assuming those postures or performing those behaviors, or if they are not effective, it might show maladaptive responses. It is then in distress. Most environmental stressors lack the specificity of pain, both with respect to the sensory systems that mediate them and with respect to the physiologic and behavioral reactions they elicit. The potency of many stressful conditions or events can change quickly. Moreover, one animal adapts readily to a particular environmental stressor, and another does not. The difference can be the result of habituation, a learned association with other environmental events, or the acquisition by one animal, but not the other, of the ability to cope with the stressful circumstance.

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Recognition and Alleviation of Pain and Distress in Laboratory Animals This discussion underscores the basic principle that all environmental effects are revealed by individual animals—an obvious point that is often disregarded. To be valid, judgments made about such matters as the suitability of caging arrangements, feeding regimens, and the behavioral or psychologic needs of captive animals must be based on familiarity with the normal behavior of individual animals and a professional evaluation of the situation approached from individual animals' points of view. ECOLOGY AND THE CAPTIVE ENVIRONMENT As a first step in approaching the environment from the animal's point of view, the distinction made by field biologists between habitat and ecology is useful (Vernberg and Vernberg, 1970). Habitat refers to all measurable aspects of the physical and biotic environment. Habitats are what we usually have in mind when we think of environments. They are described without reference to any particular class of organisms on which they might impinge. A monkey, an ocelot, and a sloth occupying the same tropical forest share the same habitat. Ecology, however, always presumes a specific animal (or other biologic entity). It is the focus on the interrelationships between the entity and its environment that characterizes the ecologic perspective. To the extent that the monkey, the ocelot, and the sloth are active at different times during the daily cycle, differ in their social lives, and differ in the foods and other vital resources they require and in how they take these resources from the environment, they differ in their ecologies. The distinction between habitat and ecology can also be applied to captive environments. Although the habitat of the captive environment is dictated largely by human design, it is useful to consider it in terms of the kind of ecology that it provides. Attention is thereby focused on the nature of the relationships that a specific animal establishes with its surroundings. It is essential to bear in mind that ecologic relationships are inherently reciprocal or transactional. The animal and the captive environment are each organized, dynamic entities and should be looked at in terms of their own needs and objectives. The captive environment is designed and maintained by humans for their own purposes. It not only imposes constraints on the kinds of relationships with the habitat that are possible for the animals residing therein, but also reflects the interests of the human proprietors. Those interests are usually mixed and might not be wholly compatible. For example, they might include some combination of economic concerns, the purposes for which the human organization exists (e.g., research, animal production, or public exhibition), and the desire to maintain animals in conditions that are conducive to good health, that minimize distress, and that foster their overall well-being. To the extent that humane concerns and animal well-being are at issue, those responsible for the care and management of animals should consider the captive environment from the standpoint of the resident animals; that is, it is the animals'

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Recognition and Alleviation of Pain and Distress in Laboratory Animals ecology, not their habitat, that provides the relevant perspective. From that perspective, the significance of physical structures and routine procedures, as well as infrequent environmental events, will be different from the significance based on the habitat perspective. How does one approach the captive environment from the ecologic perspective of the animals? Professional judgment, empathy, and intuition are indispensable aids; but they are also very fallible guides and cannot always substitute for more reliable and objective kinds of information. At the most basic level, birds and mammals—indeed, all animals—have fairly strict requirements with respect to nutrients, water, ambient temperature, humidity, illumination, background noise, and light-dark cycles. Although specific recommendations for dealing with those aspects of an animal's ecology in a captive setting are more often based on professional judgment and opinion than on systematic research, their importance for well-being is widely recognized, and they are usually treated straightforwardly as requirements of good husbandry (see NRC, 1985). Other ecologic characteristics of captive environments are considered less often, although they can have an important influence on stress and distress (Hughes and Duncan, 1988). On the basis of general ecologic considerations, it can be assumed that the following constitute six major dimensions that are relevant to stress and distress for species housed in a captive environment: relations with conspecifics, predator-prey relations, shelter, spatial architecture, feeding and foraging, and environmental events. Each is discussed in some detail below. RELATIONSHIPS WITH CONSPECIFICS Other members of the same species as a given animal usually have significant influences on stress and distress in the animal. The nature of those influences varies widely among species and among individuals within species. Age, sex, and early experience have powerful effects on the extent to which animals will seek, tolerate, or be distressed by the close presence of other members of their species. In many species, seasonal and other cyclic variations in the reproductive state of an animal can affect its social tolerance and sociability. In determining the potential contribution of social factors to stress and distress, one must consider social space and crowding, deprivation, and social stimulation. Social Space The tendency of animals to space themselves in relation to each other is a general feature of social behavior (Waser and Wiley, 1979). The most common means of establishing and maintaining social spacing are overt aggression (e.g., biting and scratching) and aggressive displays (e.g., threat postures and vocaliza-

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Recognition and Alleviation of Pain and Distress in Laboratory Animals tions). Spacing behavior can be organized with respect to a specific location or with respect to the area surrounding an animal, regardless of where it happens to be. Dens, nest sites, and the location of a food source are examples of particular places where intruders are likely to meet with an aggressive response. The space that an animal maintains between itself and other animals can be called its personal space. Intrusion of other animals into this area is not tolerated and leads to aggression toward the intruder or withdrawal by the animal intruded on. The size of personal space varies with species and sex and with the familiarity of the intruder. More gregarious species have smaller personal space; that is, they are more tolerant of intruders than species that are normally solitary. Tolerance for the proximity of other animals is usually greater between members of opposite sex than between members of the same sex, between immature animals than between animals that are reproductively mature, and between immature and reproductively mature animals than between animals that are reproductively mature. Tolerance is likely to be least between unfamiliar, reproductively mature animals of the same sex, particularly males. The expression of species differences in personal space are not limited to relations with conspecifics; they can also be reflected in the way animals react to proximity of people and to petting and other forms of human contact (Hediger, 1955). Crowding Crowding represents more than an encroachment on personal space. Experimental studies with various species of rodents have shown that, when the number of animals confined to a particular area increases beyond a critical point, normal patterns of social organization and social interaction break down, aggression increases, and reproductive failures that are traceable to physiologic causes occur. Information on other vertebrate species, although less complete, is in general agreement with those findings (Archer, 1970). Deprivation Social deprivation includes several kinds of conditions or procedures. Although they share the element of restricting or preventing social access to other animals, their consequences and their bearing on questions of stress and distress in captive animals are not the same. The most important factors are related to the age at which deprivation occurs and the nature of the animal's previous social experience. Nurturance and early social experience: The young of many animal species depend on their mothers for warmth and protection. Newborn mammals universally depend on their mothers for food and often receive from their mothers various forms of stimulation that influence their behavioral and physiologic development. For example, olfactory stimulation from a mother rat contributes to the integration of

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Recognition and Alleviation of Pain and Distress in Laboratory Animals nursing in infants and modulates their activity levels (Hofer, 1978). The basic requirements for food and warmth are universally recognized and are routinely met in the laboratory when contact with the mother is not possible. Beyond those basic needs, the young of many mammalian species require stimulation from conspecifics, or from appropriate social substitutes, to ensure normal behavioral development and adult social competence (Newton and Levine, 1968). Although there is no question that the behavior of animals deprived of such stimulation from birth is atypical, it has not been established that they are chronically stressed. However, the behavior of many adult animals deprived of social interaction in early life is obviously maladaptive. Self-mutilation, hair-pulling, stereotypic behaviors, extreme timidity or aggressiveness, and inability to mate or provide adequate care to offspring are examples of maladaptive behaviors that might result from social deprivation and be taken as de facto evidence of distress. A concern with the well-being of captive animals and with their long-range utility for research and reproduction warrants provision of opportunities for social interaction of developing animals with members of their own species and in some cases with humans (e.g., in the case of dogs), unless deprivation of such opportunities is a carefully articulated requirement for a specific research project. Disruption of infant-parent bonds: Given the opportunity, the young of some avian and mammalian species will form an emotional bond or attachment to their mother or an appropriate substitute. In those species, social deprivation occurs if an immature animal that has formed such a bond is separated from its attachment figure (Reite and Field, 1985). The acute responses indicate stress. Whimpering and other high-pitched vocalizations typically increase and are accompanied by corresponding changes in general activity, heart rate, and cortisol concentrations. Those reactions are adaptive under natural circumstances, in that they attract caregivers and prepare a young animal for vigorous action. If prolonged, however, they can become distressful and lead to increased vulnerability to disease. Distress is likely to be less intense and persistent in animals that no longer depend entirely on an attachment figure for nutritional and emotional support, that have access to familiar companions or a substitute attachment figure, and that remain in familiar surroundings after separation. In some species, such as primates, mothers also show an emotional response to separation from their infants. Their behavioral and physiologic reactions appear to be similar to those of an infant, although less persistent and intense. Disruption of adult bonds: The term social deprivation can also be applied to adult animals that are separated from familiar companions. The question of whether social bonds or emotional attachments that develop between adults are similar in form or intensity to attachments between parent and young has seldom been examined systematically. On the basis of comparisons between two primate species, one monogamous and the other polygamous, it appears that pair-living monogamous adults respond to separation in a manner that is similar to, but less intense and prolonged than, the response of immature animals to separation from an

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Recognition and Alleviation of Pain and Distress in Laboratory Animals attachment figure. In contrast, polygamous adults show no reaction to separation from familiar companions of the opposite sex (Mendoza and Mason, 1986). Positive Social Stimulation Play, grooming, huddling, and merely sitting quietly in physical contact are normal and recurrent activities for many highly social animals. Such activities are sought, and they have been shown in some species to have reward properties—e.g., dogs (Stanley and Elliot, 1962), primates (Mason, 1967), and rats (Latané and Hothersall, 1972). They have also been shown to have immediate effects on emotional arousal. For example, being groomed, petted, or stroked can bring about a prompt reduction in signs of distress in various species (Mason, 1965; Gantt et al., 1966). Stroking and handling by humans can be a practical and effective technique for calming animals in situations where they are distressed, particularly animals that have been positively socialized by humans. The procedure should be used with caution, however, with animals that are not accustomed to human contact or animals that might transmit disease. It is reasonable to assume that being able to engage in positive social behaviors will contribute to an animal's comfort and well-being, although there are few pertinent systematic data. It is also common to assume that depriving an animal of the opportunity to engage in such behaviors is an important source of stress. Although that assumption seems plausible, it has not been adequately tested and cannot be accepted uncritically as applying to all animals. The importance or attractiveness to an animal of opportunities for positive social stimulation will depend on its species, age, and prior social experience. Whatever distress results from depriving an animal of positive social stimulation will presumably be least severe for species or individual animals that are weakly gregarious, fearful, or highly aggressive, for older animals, and for animals whose social experience has been narrow. PREDATOR-PREY AND DEFENSIVE RELATIONSHIPS Predation concerns the capture and consumption for food of one animal by another. Predator-prey relationships are a normal aspect of the natural history of virtually all species. Some biologic groups near the top of the food chain are primarily predators (e.g., many carnivores); others are primarily preyed on (e.g., rabbits and most ungulates); and many species are both predators and prey (e.g., rats, pigs, and primates). Because of the close association of predation with evolutionary success, avoidance of and defense against predators and capture of prey have had profound influences on the evolution of animal behavior (Bertram, 1978). Although actual predation is ordinarily not a factor in well-managed captive environments, evolved patterns of predator-prey behavior can enter into an animal's relations with caretakers, with other species of animals that it encounters, and with

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Recognition and Alleviation of Pain and Distress in Laboratory Animals members of its own species. Under normal conditions, the intrusions are unlikely to pose a serious threat to the well-being of captive animals. Nevertheless, sensitivity to the conditions that elicit predatory tendencies or defensive reactions in captive animals might help to prevent or manage stress or distress. A particularly potent elicitor of predatory behavior is movement. It is conceivable that frequent intermittent provocation and frustration of predatory tendencies can be a stressor for some highly predatory species. But it is more likely that predatory behavior will be an indirect cause of stress, because it is unknowingly triggered by humans and punished because it is misinterpreted. For example, specific actions by caretakers or handlers might accidentally elicit a predatory attack in an otherwise trustworthy animal; because the response is unanticipated, painful to the handler, and seemingly unprovoked, it could cause the person to retaliate, or at least put a strain on future relations with the animal. The threshold for predatory behavior is likely to be lower in an animal that has been deprived of food or is anticipating being fed. Defensive reactions, like predatory behavior, are usually immediate reactions to specific ''releasing" stimuli. An animal might signal that it is in a defensive mood by changes in posture (e.g., crouching), facial expression (e.g., exposing teeth), vocalizations (e.g., growling), and behavioral signs of autonomic arousal (e.g., piloerection, defecation, urination, and trembling). Any event that an animal perceives as threatening can provoke defensive behavior. Such events are not uncommon in captive environments. Defensive reactions can be elicited by the mere presence of a perceived predator; but if exposure is repeated or prolonged and there are no additional adverse consequences, the response is likely to dissipate through habituation. Any abrupt, careless, or unusual action by caretakers or handlers can provoke a defensive reaction, even if the action causes no pain. The animal's response might consist of vigorous efforts to escape, immobility ("freezing," or feigning death), or attack, depending on the species and circumstances. Many animals will bite if pressed in situations where they cannot escape. Defensive reactions are more likely to occur when an animal is anxious or fearful, as in a novel setting, or is being physically restrained, undergoing an unfamiliar procedure, or in pain. The presence of newborn animals can also lower the threshold for defensive reactions—particularly in females, but also in males of some species. SHELTER The availability of nest boxes, nesting materials, dens, and the like is widely recognized as essential for some species to carry out various biologic functions (e.g., birth and early infant care in rats, mice, rabbits, and some nonhuman primate species). If such facilities are provided permanently, they will be used regularly and routinely by some species. The presence or absence of dens and cover can affect stress and distress in ways that cannot be anticipated. For example, domestic rats

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Recognition and Alleviation of Pain and Distress in Laboratory Animals that have had access to burrows reportedly are more difficult to handle and more aggressive toward conspecifics than those raised in open cages (Price, 1985). The findings suggest that dens or cover can help an animal to cope with stress by giving it a place to hide, but make it less able to cope in other circumstances. These comments are intended to suggest possible sources of stress for some animals, not as a blanket recommendation for shelters, dens, or covers for all laboratory animals that might use them in their natural habitat. SPATIAL ARCHITECTURE Space is an important dimension in the daily lives of animals. The volume of space used, the distribution of activities within a defined area, and the kinds of activities that occur vary with species (Waser and Wiley, 1979). For arboreal animals, perches, swings, and climbing devices can increase the effective volume of space and help to promote gross motor activity and possibly contribute thereby to the health of the animals. Running wheels and appropriate areas for defecation and urination, digging, dust-bathing, claw-sharpening, gnawing, and the like can also provide outlets for species-typical activities. It is generally assumed that caging arrangements that deprive an animal of the opportunity to engage in species-typical activities are stressful and lead to the development of pacing and similar stereotyped motor patterns, to self-mutilation, and to other undesirable behaviors (Morris, 1964; Meyer-Holzapfel, 1968). That is possible, but it is difficult to establish specific cause-effect relations. The features of the cage that are supposedly the problem are seldom known with certainty, and it is rarely possible to relate particular patterns of abnormal behavior to specific deficiencies in cage design. Furthermore, although some behaviors might constitute distorted or compensatory responses to the frustration of a particular species-typical "need," as is generally supposed, others might simply be common elements in the species' normal repertoire that are readily available and easily performed in the captive environment. Even if a given pattern of behavior is abnormal for a species, it is often not clear whether it should be regarded as a sign that the animal is in a state of distress or has developed an adaptive mode of coping with constraints or tensions caused by the captive environment (Price, 1985; Dantzer, 1986). At our current state of knowledge, the goal should be to provide environments that enable and promote species-typical activity. However, decisions to provide environmental devices to encourage and sustain species-typical activities should be made carefully. The benefits of a particular addition might be negligible or have only short-term effects. Possible benefits should also be weighed against the costs of constructing, installing, and maintaining the equipment and against the problems that the devices might create in decreased sanitation and increased risk of injury to the animals.

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Recognition and Alleviation of Pain and Distress in Laboratory Animals FEEDING AND FORAGING Research on captive animals has emphasized nutritional requirements while neglecting other aspects of feeding behavior. Captive animals are typically offered a well-balanced diet on an established schedule; the procedure is efficient and economical, and it places no demands on the individual animal. The situation is quite different in natural environments. It is obvious that carnivores and omnivores are different from frugivores and herbivores, not only in what they eat, but in virtually every aspect of their feeding behavior. Feeding ecology refers to all attributes of an animal's relation with the environment from the standpoint of gaining sustenance. The amount of time spent in searching for food, food preferences and aversions, the ways foods are gathered and prepared, the frequency and size of meals, and degree of tolerance of monotonous diets are all facets of feeding ecology (Schoener, 1971). Sensitivity to a species' feeding ecology can provide useful clues as to how an animal will respond to the diet and feeding routines of a captive environment (Breland and Breland, 1961). Failure to recognize the importance of ecologic factors in the feeding situation and to take them into account can lead indirectly to conditions that contribute to stress and threaten well-being. The amount of experimental data on feeding behavior in captive environments is much greater for the domestic variety of the Norway rat than for other species. The rat is a classic omnivore and is timid in its approaches to novel foods, so extrapolation from it to other species should be viewed with caution. In the absence of firm evidence on most species, the following generalizations are offered as tentative guidelines. Adaptability Most species show considerable flexibility in accommodating to the foods and feeding routines of a captive environment. Assuming that an animal is regularly provided a fresh, palatable diet that is adequate in quality and quantity to meet its nutritional needs, established feeding regimens are seldom a direct cause of stress or distress. Response to Novel Foods Some species are very cautious about new foods; a sudden change in the taste, appearance, odor, or texture of foods might reduce intake to stressful levels, even though the nutritional value of the new food is as good as or superior to that of the former. If new foods are introduced, they should be introduced gradually. The new food and the standard diet should both be offered until there is evidence that adequate amounts of the new food are being eaten.

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Recognition and Alleviation of Pain and Distress in Laboratory Animals Need for Variety The monotony of an unchanging diet can reduce food intake and lead to weight loss and stress. Variety in the diet can be a stimulant. Broad changes in the composition of the daily ration might not be advisable, however, from the standpoint of either animal nutrition or economy. Treats and tidbits offered as occasional supplements can serve as "appetizers" and lead to increased intake of the standard food. Free Choice Allowing animals to choose freely from a broad range of foodstuffs differing in nutritional value can result in nutritional imbalances. Moreover, rodents fed ad libitum have shorter lives, have a greater incidence of neoplasia, and might develop more disease (Abelson, 1992). Animals are likely to select foods on the basis of superficial qualities, such as odor and taste, rather than on the basis of nutritional properties. Food Wastage Nonhuman primates are wasteful feeders. An animal might take several pieces of food and discard all but one or drop a piece of food after one or two bites and then select an identical new item and treat it in the same manner. As a result of such behavior, a food container can be emptied quickly. If discarded food falls through the cage floor and cannot be retrieved, the animal might not consume enough to sustain itself, even though an adequate quantity of food is provided initially. It cannot be assumed that an animal will eventually learn to stop dropping food. Transition from Milk to Solid Foods Weaning and the transition from milk to solid foods can be stressful. The transition to solid foods is a developmental process that takes time to complete. Weaning by the biologic mother can be stressful for both parties. It is accomplished gradually, however, and usually is not finished before the young animal is able to sustain itself entirely on solid foods. That observation has important implications for animals that are being hand-reared or whose access to solid foods is restricted for research purposes. The rate of the transition to solid foods is influenced by a number of factors and varies widely with species. Guinea pigs are capable of sustaining themselves on solid foods at birth; rabbits, rats, cats, and dogs take considerably longer; and in some primate species weaning is not completed before the sixth month of life or later. The observation that an immature animal is ingesting small quantities of solid foods is not a reliable indication that it is capable of maintaining itself without milk. The rate at which a young animal makes the

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Recognition and Alleviation of Pain and Distress in Laboratory Animals transition from milk to solid foods depends on such factors as the quantity and quality of solid food provided, the time available to acquire an appetite for solid foods, and facilitation provided by observing the feeding behavior of older animals. Food Searching Searching or foraging for food is a normal part of the feeding behavior of many species. The activity of searching for food appears to be somewhat independent of the immediate need for food, its consumption, or its availability. Whether depriving a species of the opportunity to search for food causes stress or distress has seldom been examined experimentally. It seems unlikely that it constitutes an important source of stress or distress for most species. Nevertheless, there is some evidence that providing materials that encourage foraging can have indirect benefits, such as reducing aggression, boredom, or other undesirable behaviors in animals living alone or in social groups (Chamove et al., 1982; Bloomstrand, 1987; Line and Houghton, 1987; Chamove and Anderson, 1988; Lindberg and Smith, 1988; Moazed and Wolff, 1988; Novak and Suomi, 1988; Bloom and Cook, 1989; Bloomsmith, 1989; Boccia, 1989; Maki et al., 1989; DiGregorio, 1990; Visalberghi and Vitale, 1990; Bayne et al., 1991). Predictability of Feeding Times Animals on a fixed feeding schedule come to anticipate the time of day when food will be provided. Substantial deviations from established schedules can cause frustration accompanied by increased activity in stress-responsive physiologic systems. The frustration appears to be a reaction to the deviation from the regular feeding time, rather than a response to food deprivation itself. ENVIRONMENTAL EVENTS For the most part, captive animals are in a passive position with respect to environmental events. Management procedures and routines might be designed to minimize stress and distress of animals, but the animals themselves are not in control of these activities and usually have little, if any, influence on how they are carded out. That contrasts sharply with the natural situation, where animals have responsibility for their own maintenance and well-being. In a natural setting, animals must become familiar with their surroundings, investigate objects or events that are out of the ordinary, and take the initiative in dealing with their problems. For most animals, the elements of novelty and predictability of environmental events and the ability to control the environment are related to stress and distress in captive settings. Experiments on the effects of novelty, predictability, and lack of control have been oriented mainly toward understanding the causes and conse-

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Recognition and Alleviation of Pain and Distress in Laboratory Animals quences of stress. Many studies have used electric shock as a stressor and have examined the effects of predictable vs. unpredictable electric shock and of providing animals with the means of escaping or avoiding shock or having control over it. The effects of novelty have been investigated by placing animals in wholly unfamiliar settings or presenting new stimuli in familiar settings. In general, novelty, the absence of predictability, and the lack or loss of control cause an increase in the activity of stress-responsive physiologic systems (Hennessy and Levine, 1979; Weinberg and Levine, 1980). Similarly, the human handling of most animals reduces anxiety and fear, but the handling of animals unaccustomed to it can be a profound stressor (Gäartner et al., 1980). In that regard, it is wise to follow practices established by the institution or the research protocol in order to minimize stress in the animals and reduce variability between them. Many of the conditions that have been shown to be stressful in experimental research have parallels in common colony management procedures. Changing cages, confinement in a strange setting, physical restraint, venipuncture, injections, and modifications of established maintenance routines are examples of events that confront animals with novelty, unpredictability, and loss of control and that are potentially stressful. The magnitude and duration of the stressful effects of those events are influenced by many factors, including the number of previous exposures an animal has had to the particular conditions, its early experience, its temperament, and the skill and sensitivity of the persons carrying out the procedures. Predictability and a sense of control over research environments can be provided by enabling animals to adapt to novel environments. Adaptation is particularly important before animals are placed on experimental protocols that require restraint, for example. Letting dogs adapt to people through a process of socialization at appropriate ages and frequencies serves a similar purpose and reduces the fear and anxiety that might occur when they are approached or restrained by people. Transportation has long been known to cause stress in animals. Whether the stress is due to alterations in circadian rhythms, changes in familiar surroundings, noise and vibration, extreme temperature, dehydration, or some other cause is not known. However, standard practices should be implemented to ensure that transportation to and with a research institution follows accepted procedures and that newly arrived animals are given enough time to recover and to adapt to the new environment before they are placed in an experiment (Landi et al., 1982). Scheduling of direct flights, provision of enough food and water and of ventilation, and avoidance of extremes in temperatures to which the animals have not adapted are essential. Boredom is the response to the opposite of excessive novelty and unpredictability. It is caused by too little variety and change. The immediate surroundings of many captive animals seem barren, unchanging, and nonstimulating. Few things provoke their attention or maintain their interest, and they can do little to relieve the apparent monotony of the situation.

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Recognition and Alleviation of Pain and Distress in Laboratory Animals It has been known for many years that animals are actively curious about their surroundings (Berlyne, 1960). Depending on the species, they will explore novel settings; manipulate puzzles, levers, chains, and ropes; look at photographs; and in various other ways voluntarily expose themselves to fresh and unusual objects and stimuli. They will also take advantage of the opportunity to control environmental events by such actions as turning lights and sounds off and on and performing actions that cause food to be delivered, even when adequate amounts of the same food are freely available. That animals engage in those activities does not necessarily mean that they have a strong need to do so. Many domesticated and wild animals spend long periods during the waking day lying down, sleeping, or sitting quietly. Nevertheless, by analogy with modern society's view of human nature, it might seem that a stimulating and responsive environment is a common requirement for well-being. Whether that is generally the case for captive animals has not been established, and opinions vary (Wemelsfelder, 1990). The assumption of a true need for varied activities and stimulation is the basis for current efforts at environmental enrichment. Enrichment can take various forms. One of the most common approaches is to provide toys, puzzles, or mechanical devices that animals can use if they choose, without forcing them to do so. Food is also used as a reward or incentive to encourage the use of enrichment devices (Markowitz, 1978, 1982; Line, 1987; Beaver, 1989; Fajzi et al., 1989; Bayne et al., 1991). The systematic study of environmental enrichment is just beginning, and many questions need to be investigated. Although it seems plausible that boredom is a serious problem for some captive animals and can cause stress or distress, there is little objective supporting evidence. Most likely, reactions to monotony will vary with species or strain of animal, with age, and with previous experience, but these possibilities have not been thoroughly investigated. The design and assessment of enrichment devices are also in their early stages. Designs are based mainly on intuition and guesswork, and there is no way to know in advance that a particular device will be used as expected or whether, if it is used, it will make a positive contribution to well-being. As with other cage amenities, the benefits of enrichment devices need to be established and weighed against the attendant costs and risks. RESEARCH APPROACHES Several generalizations about the effects of captive environments on stress and distress can be made. It is well established that the species or strain of an animal (its genetic makeup) is critical. Temperament and responsiveness differ widely, even among closely related species. Species that have departed only slightly from the wild state are likely to react more strongly to stressful conditions and to find more conditions stressful than species that have been selectively bred for adaptiveness to captive environments (Price, 1984). A wealth of scientific information indicates that an animal's early experience can have profound and lasting effects on the kinds

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Recognition and Alleviation of Pain and Distress in Laboratory Animals of situations it responds to as stressful and on the nature of its response (Newton and Levine, 1968). Age, sex, and seasonal variations are other factors known to affect the intensity of stress and distress and the situations that elicit these reactions. Most research thus far has been oriented toward theoretical issues, and this work needs to continue. But future research must explicitly include concern with identifying the actual conditions in the captive environment that are sources of stress and distress and the steps that can be taken to prevent or alleviate the conditions. That concern should be clearly reflected in research designs. The aim of experiments on stress and distress in captive environments is not to create a facsimile of the natural habitat in appearance or function, but to identify aspects of captive environments that impinge most directly on processes related to stress and distress and to determine how they do so. For example, one might expect a species that was solitary, timid, and heavily preyed on in its natural environment to react more intensely to the close presence of conspecifics, to handling and other routine caretaking procedures, and to being placed in novel settings than a species that was highly social, bold, and predatory. That is a testable possibility. It is equally important that the effectiveness of various living arrangements and techniques in alleviating stress and distress be investigated experimentally (see Chapters 4 and 5). Realistic recommendations based on experimental findings will need to consider economic and other practical concerns, in addition to matters related strictly to animal well-being. Although objective assessments of the sources and alleviation of stress and distress in captive animals constitute an ambitious and expensive program, it is clearly feasible and well within the capabilities of contemporary scientific methods. Ideally, the scientific investigation of stress and distress would be based on explicit and universally agreed-on definitions of these conditions. But such a connection has proved elusive. It is hoped that the definitions and concepts of stress and distress formulated in this report will take the terms one step closer to being readily useful in describing clinical signs. Physiologic assessments of stress have been carried out for a number of years, and a considerable amount of information is available on (often weak) interrelations between various measures and their functional significance. However, we need much more information on the interrelations between behavioral, physiologic, biochemical, reproductive, and clinical signs of stress. The association between behavioral and physiologic measures is not always strong, and in some cases these measures might not even be associated (e.g., Weinberg and Levine, 1980). The importance of firm baseline data (norms) is recognized; the conditions that contribute to departures from baseline values and the implications of such departures for physical health, reproduction, and vitality have been explored for some species in reasonable detail and are the objects of current research. That does not imply that stress research is in a mature state, particularly as it is related to matters of well-being, but knowledge and theoretical issues regarding stress are more completely developed than those regarding distress.