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Neuroscience &Biobehavioral Reviews, Vol. 4, pp. 77-86. Printed in the U.S.A. The Role of Endorphins in Stress: Evidence and Speculations SHIMON AMIR, 2 ZAVIE W. BROWN AND ZALMAN AMIT Center for Research on Drug Dependence, Department of Psychology, Concordia University 1455 de Maisonneuve Blvd. West, Montreal, Quebec, Canada Received 2 November 1979 AMIR, S., Z. W. BROWN AND Z. AMIT. The role of endorphins in stress: Evidence and speculations. NEUROSCI. BIOBEHAV. REV. 4(1) 77-86, 1980.--Several lines of evidence suggest that the endogenous opioid peptides endorphins may play a role in the defensive response of the organism to stress. The present paper summarizes these findings as well as evidence linking endorph/ns to the anterior pituitary polypeptide hormone adrenocorticotropin (ACTH). Evidence is presented that endorphins may function as trophic hormones in peripheral target organs such as the adrenal medulla and the pancreas. As such they may be part of the physiological mechanisms that mediate adrenaline and glucagon release in response to stress. Endorphins (enkephalins) are also suggested to play a role in the control of the pituitary gland during stress. In such capacity they may act as hormone-releasing or inhibiting factors. Finally, endorphins appear to play a role in the behavioral concomitants of stress. In such capacity eodorphins are suggested to function as modulators of neural systems that mediate the elaboration and expression of the reactive/affective components of stress. Speculations on the mode of interaction between eodorphins and ACTH in the global response to stress are discussed. Stress Endorphins Enkephalins ACTH Opiate receptor Analgesia Affect Pituitary gland Adrenal medulla functioning Pain THERE is growing awareness that opioid peptides endorphins represent a new class of neurotransmitters and modulators, common to the central and somatic divisions of the nervous and endocrine systems, and that they may serve to regulate neural and endocrine functions that play a role in the elaboration of adaptive behavior [15, 25, 55, 68, 79, 119, 128, 130, 169, 170, 185, 228]. It is becoming increasingly evident, however, that these peptide systems may not func- tion tonically but that they influence physiological and be- havioral processes in a rather selective manner, only under specific environmental conditions or endogenous factors (e.g. [1, 36, 42, 48, 49, 58, 62, 86, 89, 91, 95, 100, 109, 113, 127, 137, 142, 146, 157, 194, 230, 240]). Evidence accumu- lated recently indicate that endorphins are released from the pituitary gland in response to stress concomitantly with the hormone adrenocorticotropin (ACTH), and that structural relationships exist between the two classes of polypeptides [94,156]. Furthermore, there is evidence that stress may activate endorphin systems in the brain as well [3,190]. These findings suggest that endorphins may play a role in the global defensive response to stress, and that their physiological functioning may be related in some fashion to the functions to the hormone ACTH. ACTH is known primarily for its role in the release of steroid hormones from the adrenal cortex and for its direct metabolic effects, which enable the organism to better adjust to extreme changes in circumstances [63,204]. Additionally, ACTH possesses var- ious central nervous system effects, which are independent of its somatotropic functions, and it appears to influence motivation and arousal and other central processes that play a role in adaptive behavior [33, 52, 56, 79, 130, 168]. In the present article we review evidence on the involve- ment of endorphins in the global response of the organism to stress. We describe findings that endorphins and ACTH are part of the same neuroendocrine system but that they may normally produce differential physiologic and behavioral ef- fects. Furthermore, we propose several hypotheses concern- ing a functional link between the endorphins and physiolog- ical mechanisms that play a role in stress. Finally we exam- ine findings on the role of endorphins in the behavioral re- sponse to stress and suggest that they may mediate the elab- oration and expression of the reactive/affective components of stress. BIOCHEMICAL EVIDENCEFOR THE INVOLVEMENT OF ENDORPHININ STRESS The opioid peptides betaoendorphin and enkephalin occur in cells and processes of the central and autonomic nervous system and in the central and somatic divisions of the endocrine system. Beta*endorphin is found in the pituitary gland [14, 85, 106, 152, 195, 219], particularly in the pars intermedia and adenohypophysis [24,188]. Additionally, it occurs within the brain, with a single cell group in the hypothalamus and large axons innervating iimbic and mid= brain structures [37,191]. Enkephalin systems, with multiple 1Presented at a Workshop on Stress and Environmentally Induced Analgesia, Eastern Psychological Association annual meeting, Philadel- phia, PA, April 1979. ~Present address: Isotope Department, Center for Neuroscience and Behavioural Research, The Weizmann Institute of Science, Rehovot, Israel. 77
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Page 1: Endorphin III

Neuroscience & Biobehavioral Reviews, Vol. 4, pp. 77-86. Printed in the U.S.A.

The Role of Endorphins in Stress: Evidence and Speculations

S H I M O N A M I R , 2 Z A V I E W. B R O W N A N D Z A L M A N A M I T

Center for Research on Drug Dependence, Department o f Psychology, Concordia University 1455 de Maisonneuve Blvd. West, Montreal, Quebec, Canada

Rece ived 2 N o v e m b e r 1979

AMIR, S., Z. W. BROWN AND Z. AMIT. The role of endorphins in stress: Evidence and speculations. NEUROSCI. BIOBEHAV. REV. 4(1) 77-86, 1980.--Several lines of evidence suggest that the endogenous opioid peptides endorphins may play a role in the defensive response of the organism to stress. The present paper summarizes these findings as well as evidence linking endorph/ns to the anterior pituitary polypeptide hormone adrenocorticotropin (ACTH). Evidence is presented that endorphins may function as trophic hormones in peripheral target organs such as the adrenal medulla and the pancreas. As such they may be part of the physiological mechanisms that mediate adrenaline and glucagon release in response to stress. Endorphins (enkephalins) are also suggested to play a role in the control of the pituitary gland during stress. In such capacity they may act as hormone-releasing or inhibiting factors. Finally, endorphins appear to play a role in the behavioral concomitants of stress. In such capacity eodorphins are suggested to function as modulators of neural systems that mediate the elaboration and expression of the reactive/affective components of stress. Speculations on the mode of interaction between eodorphins and ACTH in the global response to stress are discussed.

Stress Endorphins Enkephalins ACTH Opiate receptor Analgesia Affect Pituitary gland

Adrenal medulla functioning Pain

THERE is growing awareness that opioid peptides endorphins represent a new class of neurotransmitters and modulators, common to the central and somatic divisions of the nervous and endocrine systems, and that they may serve to regulate neural and endocrine functions that play a role in the elaboration of adaptive behavior [15, 25, 55, 68, 79, 119, 128, 130, 169, 170, 185, 228]. It is becoming increasingly evident, however, that these peptide systems may not func- tion tonically but that they influence physiological and be- havioral processes in a rather selective manner, only under specific environmental conditions or endogenous factors (e.g. [1, 36, 42, 48, 49, 58, 62, 86, 89, 91, 95, 100, 109, 113, 127, 137, 142, 146, 157, 194, 230, 240]). Evidence accumu- lated recently indicate that endorphins are released from the pituitary gland in response to stress concomitantly with the hormone adrenocorticotropin (ACTH), and that structural relationships exist between the two classes of polypeptides [94,156]. Furthermore, there is evidence that stress may activate endorphin systems in the brain as well [3,190]. These findings suggest that endorphins may play a role in the global defensive response to stress, and that their physiological functioning may be related in some fashion to the functions to the hormone ACTH. ACTH is known primarily for its role in the release of steroid hormones from the adrenal cortex and for its direct metabolic effects, which enable the organism to better adjust to extreme changes in circumstances [63,204]. Additionally, ACTH possesses var- ious central nervous system effects, which are independent

of its somatotropic functions, and it appears to influence motivation and arousal and other central processes that play a role in adaptive behavior [33, 52, 56, 79, 130, 168].

In the present article we review evidence on the involve- ment of endorphins in the global response of the organism to stress. We describe findings that endorphins and ACTH are part of the same neuroendocrine system but that they may normally produce differential physiologic and behavioral ef- fects. Furthermore, we propose several hypotheses concern- ing a functional link between the endorphins and physiolog- ical mechanisms that play a role in stress. Finally we exam- ine findings on the role of endorphins in the behavioral re- sponse to stress and suggest that they may mediate the elab- oration and expression of the reactive/affective components of stress.

BIOCHEMICAL EVIDENCE FOR THE INVOLVEMENT OF ENDORPHIN IN STRESS

The opioid peptides betaoendorphin and enkephalin occur in cells and processes of the central and autonomic nervous system and in the central and somatic divisions of the endocrine system. Beta*endorphin is found in the pituitary gland [14, 85, 106, 152, 195, 219], particularly in the pars intermedia and adenohypophysis [24,188]. Additionally, it occurs within the brain, with a single cell group in the hypothalamus and large axons innervating iimbic and mid= brain structures [37,191]. Enkephalin systems, with multiple

1Presented at a Workshop on Stress and Environmentally Induced Analgesia, Eastern Psychological Association annual meeting, Philadel- phia, PA, April 1979.

~Present address: Isotope Department, Center for Neuroscience and Behavioural Research, The Weizmann Institute of Science, Rehovot, Israel.

77

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78 AMIR. BROWN AND AMIq

cell groups and relatively short axons occur within the brain and spinal cord [23, 24, 59, 235], the gastrointestinal tract [4,182], the pancreas [93], in sympathetic ganglia [53, 200- 202] and in many gland cells as well as in nerve fibers in the adrenal medulla [147, 154, 201, 202]. Beta-endorphin and enkephalin are fragments of the hormone beta-lipotropin (endorphin: beta-lipotropin 61-91; enkephalin: beta- lipotropin 61-65) [45,144]. This pituitary polypeptide hor- mone [ 140,148] is contained within a 31,000-dalton glycopro- tein molecule known as pro-opiocortin, which also contained within its sequence the hormone ACTH [156, 186, 193]. Endorphins and ACTH are present within the same se- cretory granules in pituitary corticotrophic cells [ 178,238] and there is immunocytochemical evidence that they also coexist within the brain [37, 130, 131,151,235]. Furthermore, there is evidence that the same environmental and endogenous stimuli trigger the mobilization of endorphins and ACTH from the pituitary for physiological functioning and that the same biochemical processes are regulating this effect. Stres- sors known to activate the pituitary-adrenal axis (e.g. limb fracture, foot shock, heat stress, insulin-induced hypo- glycemia, ingestion of hypenonic saline, immobilization) have been reported to decrease anterior pituitary endorphin con- tent and to trigger a parallel increase in plasma endorphin and ACTH levels [13, 22, 94, 132, 192, 198, 241]. A rise in plasma endorphin and ACTH levels has also been observed following adrenaleetomy, metyrapone or morphine adminis- tration, electroconvulsive treatment and in various patholog- ical conditions related to pituitary hyperfunctioning [2, 61, 43, 66, 70, 77, 94, 105, 132, 231,241]. Both stress-induced and morphine-induced release of endorphins and ACTH were found to be blocked by the administration of the syn- thetic glucocorticoid dexarnethasone and by hypophysec- tomy [70,94]. In in vitro preparations, endorphins and ACTH were found to be released from pituitary cells in response to purified hypothalamic corticotropin releasing factor, hypothalamic extract and lysine vasopressin [94, 183,224]. This effect was found to be blocked by dexamethasone and by the administration of dopamine and its agonist apomor- phine [223,224]. Alterations in brain levels of endorphins have also been reported following exposure to stress. Foot shock or heat stress have been shown to cause an increase [3, 155, 240] or a decrease [190,192] in regional or whole brain enkephalin content. However, failure to induce any change in brain enkephalin content after such treatment has also been reported [67]. Similarly, immobilization stress has been reported not to produce any changes in hypothalamic immunoreactive ACTH concentrations [129]. Repeated ex- posure of immature rats to heat stress resulted in an increase in endogenous opioid content and in opiate receptor binding capacity in brain [221]. Finally, psychological stress (con- ditioned fear) has been reported to result in an increase in opiate receptor occupancy in brain, suggesting a possible rise in peptide activity [39,40]. Social isolation, another form of psychological stress resulted in an increase in the number of opiate receptor binding sites in brain [34].

Taken together, the above findings suggest that activation of endorphin systems may be an integral part of the global defensive response of the organism to stress. Additionally, the findings outlined suggest that endorphins and ACTH, which appear to coexist in two distinct neuroendocrine sys- tems (i.e. pituitary and brain), may function in a coordinated manner to mediate both the physiological and the behavioral consequences of stress.

ENDOCRINE FUNCTIONS FOR ENDORPHIN DURING STRESS

The fact that endorphin is released from the pituitary to the circulation in response to stress suggests that it may function as atrophic hormone at peripheral target organs, and that like ACTH, it may modulate the activity of endocrine systems that play a role in stress. Several studies suggest that endorphins may play a role in the control of catecholamine release from the adrenal medulla. Stress- induced adrenaline release from the adrenal medulla is con- trolled predominantly by trans-synaptic input from the splanchnic nerve [38, 139, 176, 220]. Morphine has been shown to influence adrenaline synthesis and storage and to stimulate adrenaline release from the adrenal medulla di- rectly, even after chronic and complete denervation of this gland [10, 11,248]. Furthermore, a population of high affinity opiate binding sites with sensitivity to sodium ions similar to that of brain opiate receptors has been described in bovine adrenal medulla [41]. It is conceivable that circulating endorphins could exert exclusive morphine-like adrenaline releasing effects via opiate receptor systems in the adrenal medulla and that this physiological mechanism may function in parallel to the sympatho-adrenal axis that normally control adrenaline release. Indeed, a hypothalamo-anterior pituitary system that modify adrenaline release from the adrenal medulla has been described [12,138] and endorphin has been shown to act as a trophic hormone in kidney tissue [96].

Furthermore, the presence of enkephalins in sympathetic ganglia [53,200-202] and in cells and nerve terminals in the adrenal medulla [147, 154, 199, 201,202,211] suggest a role for opioid peptides in the neural control of the adrenal medulla. Enkephalins could interact with adrenaline-release mechanisms after they have been secreted from the splan- chnic nerve in response to stress along with other transmitter substances (i.e. acetylcholine) that play a role in the control of adrenaline release from the adrenal medulla. Alterna- tively, enkephalin could be released from the adrenal medulla and act on "opiate-autoreceptors" on the gland ceil, to regulate adrenaline secretion in response to stress. Fi- nally, enkephalins could be released from the adrenal medulla into the circulation concomitantly with adrenaline and exert hormone-like effects at other target organs. It should be noted that despite the rapid enzymatic degradation of enkephalin and the reported lack of analgesic effects fol- lowing intravenous administration of the peptide [98], pe- ripherally secreted enkephalins could still play some, as yet unidentified physiological or behavioral role in stress. This possibility is backed by the findings that systemic adminis- tration of enkephalins to experimental animals may result in behavioral change [119].

Endorphins may also play a role in the control of the hypothalamo-pituitary-adrenal cortex axis. Endorphins and opiates have been reported to stimulate in vitro corticos- terone synthesis [74,206]. Since some opiate receptor bind- ing sites occur in the adrenal cortex [41 ] it is conceivable that endorphin, like ACTH, could exert some corticotropic ef- fects in animals, when released into the circulation in re- sponse to stress. Alternatively, endorphin or enkephalin could play a role in modulating stress-induced secretion of adrenal steroids indirectly, by stimulating or reducing a restraint on ACTH release from the pituitary gland. The re- lease of ACTH in response to stress is triggered by the action of corticotropin releasing factor (CRF) on the pituitary gland [197,229]. CRF is located in neurosecretory cells in the su-

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ROLE OF ENDORPHINS IN STRESS 79

praoptic and periventricular nuclei of the hypothalamus, where high content of opiate receptors and of enkephalin and endorphin immunoreactive material has been reported [37, 59, 136] and where stress-induced changes in enkephalin levels have been observed [190,192]. The opiate antagonists naloxone and naitrexone have been shown to block stress- induced corticosterone release in mice [75, 76, 78] while endorphin has been reported to induce ACTH secretion from the pituitary in rats [225]. Taken together, these data suggest that hypothalamic opioids may play a role as corticotropin releasing agents or that they interact with other factors (i.e. CRF) that play a more direct mediational role in the release of ACTH in response to stress. Interestingly, evidence ac- cumulated in recent years strongly supports the notion that multiple releasers rather than a unique neurohormone is mediating the secretion of ACTH from the pituitary during stress [197].

Opiate receptors occur in the pituitary gland, particularly in the posterior (neural) lobe, and in the pancreas [108,207]. Furthermore, enkephalin containing neurons project from the hypothalamus to the neural lobe [189], and enkephalin- like immunoreactivity has been found in pancreatic glucagon cells [93]. These findings suggest a role for opioid peptides in the control of hormones such as vasopressin, glucagon and insulin which play a role in the global response to stress [107, 108, 116, 158,239]. Finally, endorphin and enkephalin have been reported to play a role in the release of the anterior pituitary hormones prolactin and growth hormone, which also play a role in the response to stress [35, 58, 84, 88, 149, 161, 205, 226]. The findings outlined above suggest that endorphins may play a role in the control of hormone secre- tion in both the central (i.e. pituitary hormones) and periph- eral (i.e. adrenal and pancreas hormones) divisions of the endocrine system. In addition they suggest a rink between enkephalin and components of the central and autonomic nervous system that trigger hormone release from these endocrine systems in response to stress. Thus the findings suggest that endorphin and enkephalin may be part of the diffuse neuroendocrine system that may account for the coordinated secretion of hormone substances during stress. This idea fits well with the findings that endogenous opioids and ACTH are mobilized simultaneously in response to stress and it supports the notion that the two classes of pep- tides exert parallel trophic effects as pan of the adaptive response to stress.

BEHAVIORAL ROLE FOR ENDORPHIN DURING STRESS

The formation and execution of adaptive behavior de- pends to a large extent on a well coordinated interplay be- tween neural systems that mediate sensory, motivational and affective processes within the brain. Endorphins possess central nervous system effects [68, 169, 171] and there is evidence that they may play a role in the elaboration and expression of the emotional response to stress.

Acute exposure to stressors such as electric shock, cold water swim, restraint, insulin-induced hypoglycemia, as well as psychological stress has been reported to modify pain responsiveness in a large number of laboratory studies [ 125]. Stress-induced analgesia was subsequently found to depend on the functional integrity of the pituitary gland [6, 27, 28, 102], to correlate with changes in endorphin activity [3,155] and opiate receptor occupancy in the brain [39,40], and to be blocked, in pan, by the opiate antagonist naloxone [3, 9, 29, 30, 42]. Hypnotic analgesia in conditions of stress was also partially reversed by naioxone [71], but no effect of naloxone

~:~observed in other ~ases of hypnotic analgesia [87,159]. The changes in pain responsiveness induced by stress re- sembled the analgesia induced by morphine [42] as well as that induced by exogenously administered endorphins [222], suggesting an opiate like role for endogenous endor- phin/enkephalin systems in such effect [26,209]. Evi- dence from human studies suggest that a well defined sep- aration exists between the peripheral or internal sensation of pain and the central elaboration of that sensation (i.e. the emotional component of pain) [18,163]. Since morphine has been shown to exert its analgesic effects primarily by mod- ifying the emotional component of pain [111,167] it is con- ceivable that stress-induced analgesia, which presumably acts at least in part via endorphin release, may exert com- parable selective effects. When placed on a hot metal plate (51°C) within a Plexiglas enclosure rats typically exhibit two distinct behavioral responses: a paw withdrawal accom- panied by vigorous licking, and jumping that ultimately leads to escape. Analysis of the temporal relationships between the two response latencies suggest that the paw lick response (short latency) may represent the sensory/perceptual com- ponents of pain while the escape behavior (long latency) may represent the reactive/affective components of pain [9,69]. Using this paradigm it was reported that immobilization stress, which induces the release of endorphins from the pituitary gland [13, 57, 124], had a selective effect on escape but it did not influence paw lick behavior [6,9]. In these studies naloxone or hypophysectomy blocked the effect of immobilization stress on escape but they did not influence paw lick behavior. Elsewhere, naloxone was reported to exert selective effects on jumping from a hot plate in mice, suggesting that hot piate-stress may be sufficient to activate endorphin systems so that previous exposure to stress may not be necessary to demonstrate a selective involvement of endorphins in the affective component of pain [6, 27, 28, 102]. Finally, chronic administration of the opiate antagonist naltrexone resulted in enhanced sensitivity to foot shock- induced attenuation of escape from a hot plate in rats [5]. Chronic opiate receptor blockade was found previously to increase the number of opiate receptor binding sites in the brain as well as to result in supersensitivity to the analgesic effect of morphine [141,212]. Interestingly, acute stress has been shown to potentiate the hyperalgesic effect of naloxone [118] as well as it's ability to antagonize morphine analgesia [99,245] while hypophysectomy has been reported to block the hyperalgesic effect of naloxone [90]. Naloxone was found to induce contractions in ileum preparations taken from stressed guinea pigs, but it failed to do so in ileum preparations taken from non stres~d animals [32].

Unlike acute stress, which typically reduces pain respon- siveness, prolonged exposure to stress (anxiety) could lead to enhanced reactivity to pain [16, 17, 184]. Such effect may be linked to a chronic reduction in the functional availability of endorphin [203], or to a change in endorphin/ACTH ratio. Stress-induced analgesia adapts upon repeated exposure to the stressor [9,31], and such treatment may also lead to hyperresponsiveness to pain and to a decreased endorphin activity in brain [155]. Furthermore, ACTH administration to normal or hypophysectomized-stressed rats enhanced es- cape from a hot plate [6]. Additionally, such treatment par- tially reversed the analgesic effect of cold water swim [46]. Finally, chronic elevated plasma levels of ACTH, induced by adrenalectomy was associated with increased sensitivity to pain in rats [102].

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80 AMIR, BROWN AND AMIT

Other studies also provide evidence that endorphin systems may play a role in modifying emotional tone during stress. Thus, endorphins or enkephalins has been suggested to be released in response to a stimulus that signalled shock [39,40] while naloxone was found to block animal's preference for a signalled versus unsignalled shock [64]. Naloxone has also been shown to enhance shock induced freezing in rats [65] al- though failure of naloxone to influence the fear-induced im- mobility reflex in rabbits [73] or the fear induced startle re- sponse in rats [50] has also been observed. Exposure of ani- mals to a novel environment is a stressful event and the amount of exploration and activity under such circumstances could be used as a measure of emotional tone. A direct corre- lation was demonstrated between exploratory behavior in mice and enkephalin induced behavioral activation in these animals [123]. Furthermore, naloxone or naltrexone were found to depress exploratory behavior and entry into a novel environment in mice and rats [92, 121,123]. Finally, chronic administration of naloxone prevented the increase in activity seen in rats upon repeated exposure to the testing environ- ment [8]. Some stressful situations with an apparent emo- tional component may lead to changes in body temperature (emotional hyperthermia). Such changes are linked to an in- crease in plasma endorphin-like immunoreactivity and they are found to be blocked by the opiate antagonist naloxone [22]. Interestingly, endorphins have been suggested to play a role in behavioral adaptation to heat stress [104], while noise stress has been shown to mask the hypothermic effect of naloxone in rats [210]. Non-traumatic noice-light stress has also been shown to increase grooming behavior in a novel environment [122]. This effect was found to be blocked by naltrexone, suggesting the involvement of an endogenous opioid system in the expression of stress induced grooming [82,122]. Finally, endorphins have been reported to reduce distress vocalization in socially isolated chicks [175] while naloxone was found to increass such behavior in guinea pigs [101]. These studies suggested a role for endogenous opioids in mediating the affective component of social stress [34,174]. In humans, naloxone and naltrexone were found to exert negative effects on mood [162,214].

The evidence summarized in this section suggest that the elaboration and manifestation of behavior under conditions of stress may be linked to the function of endogenous opioid systems. More specifically, they suggest that endorphin may play a rather selective role in the elaboration of emotion during stress. The endorphin-induced changes in emotional tone do not depend on the presence of any particular stres- sor. Indeed, endorphins are mobilized from the pituitary and in the brain in response to a large number of unrelated stres- sors including electric shock, restraint, leg fracture, insulin- induced hypoglycemia and more [13, 22, 94, 132, 192]. Fur- thermore, such changes may possess different behavioral consequences. Changes in emotional-tone in response to stress probably possess an adaptive value since they may enable the organism to better adjust to those stressful cir- cumstances that induced endorphin release. Such effect would be of particular importance in the case of stressors that involve physical injury (i.e. acute analgesia). Inter- estingly, the response to some forms of pain may not depend on activation of endogenous opioid systems. While several experiments have demonstrated lower pain resistance fol- lowing naloxone administration, thus implicating endorlahins in the normal response to pain [36, 43, 69, 109, 127, 146], others have failed to demonstrate such effect [86, 89, 100, 1711.

Changes in endorphin activity may also lead to maladap- tive consequences. For example, if endorphin release per- sists in the presence of a stressor, a condition which may result from a defect in feed back control, the development and execution of goal directed behavior (i.¢. fight, escape) may be disrupted. Indeed, changes in affective-tone are common characteristics of certain stress related pathological conditions in humans (i.e. schizophrenia, depression), and it may be linked to an abnormal activation of endorphin sys- tems in response to stress [228]. Reports of high plasma and CSF endorphin levels [54, 150, 214,216,233] and of reduced sensitivity to pain [47,97] in humans suffering from affective illness, and of the beneficial effect of naloxone in such con- ditions [62, 95, 145, 214, 234] give support to such idea. However, the existence of contradictory evidence narrows the generality of such effect [1, 49, 61, 113, 137, 187, 230].

A coordinated role for pituitary endorphin and ACTH in the behavioral response to stress is suggested from the find- ings that they are released from anterior pituitary corticotrophs in parallel in response to stress, and that the same regulatory mechanisms are mediating the release of these peptides I94]. Pituitary endorphin and ACTH represent a distinct system that is separated from brain endorphin and ACTH [44. 126, 129, 133, 191, 200]. It is conceivable however that small amounts of these peptides may enter the brain via the vascu- lar system or through the CSF after being mobilized from the pituitary during stress [19, 20, 119, 130, 167, 172, 180, 227]. In addition, endorphin (enkephalin) may be mobilized in re- sponse to stress within the brain [155]. Endorphin and ACTH could exert opposing effects via the same receptor mechanisms and function as regulators of neural systems that mediate adaptive behavior during stress. ACTH, like endorphins, possess affinity for opiate receptors in vitro [81, 215,217,218, 242, 249]. Furthermore, ACTH was found to counteract morphine analgesia [81, 83,242,244] as well as to antagonize morphine-induced behavioral activation in mice [120]. Moreover, ACTH was found to antagonize the morphine-induced reduction in spinal reflex activity in the cat and the depressant action of morphine on monosynaptic activity of frog isolated spinal cord in vitro [135,249]. Fi- nally, ACTH fragments were found to mimic the inhibitory effect of morphine on the electrically evoked contraction of the mouse vas deferens [181]. This effect as well as the effect of ACTH on grooming behavior and reproductive function was found to be blocked by naloxone and naltrexone [80, 82, 115, 181, 247] although a synergistic effect of naloxone on ACTH [21] or no interaction between ACTH and naltrexone has also been observed I51]. Finally, naloxone was found to block ACTH intravenous self-administration in rats [117]. The above findings provide evidence for the existence of a common site of action for endorphins and ACTH [7, 134, 232, 242]. They also suggest that ACTH may function in the capacity of an endogenous antagonist for opiate receptor systems in the brain [134,217,218,242]. Opposing effects of endorphins and ACTH on neural excitability [165, 170, 196, 243,246] and neurotransmitter functioning in the brain [114, 153, 166, 213] have been demonstrated.

Additionally, endorphins and ACTH may function via separate neural systems in the brain [110]. Endorphin or enkephalin may modulate the function of limbic mechanisms that play a role in the elaboration of emotion. The occur- rence of dense population of opiate receptors [136, 143, 179] and of opioid neurons in limbic structures [103, 208, 237], and their interaction with central catechotamine neurons [72] is in line with such idea. Furthermore, the occurrence of

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ROLE OF ENDORPHINS IN STRESS 81

ACTH containing neurons in the hypothaiamus, thalamus, midbrain, amygdaia and reticular formation [173, 177, 236] suggest the presence there of ACTH receptor systems, and it is in line with the proposed role of ACTH of central or pitui- tary origin in the central mediation of motivation and arousal during stress [33,160].

The research on endorphins outlined above suggests that these opiate-like peptides may play a role in the global re- sponse of the organism to stress. Endorphins appear to be part of a diffuse neuroendocrine system that also contains the hormone ACTH. Endorphins and ACTH appear to func- tion in parallel in peripheral target organs and in the brain. In particular, endorphins may function as trophic hormones, to stimulate adrenaline release, or as releasing or inhibiting fac- tors in the pituitary gland. In the brain endorphins may func- tion to modulate neural systems that play a role in the elab- oration and expression of the emotional components of be- havior during stress.

The proposed behavioral role of endorphins in the media-

tion of emotion during stress is analogous to the observed analgesic effects of exogenously administered opiates. As discussed, opiates appear to exert selective effects on the affective component of pain, leaving the sensory component relatively infact. Similarly, the endogenous opiate system may serve to modulate the affective reaction to stressful stimuli while ACTH may be involved in the perception of that stimuli and in preparatory functions that lead to the response. In view of the fact that endorphins and ACTH are released from the pituitary simultaneously in response to stress, a coordinated action of endorphin and ACTH would allow for the production of adaptive behavior.

ACKNOWLEDGEMENTS

We would like to thank Miss King-Yee Man for careful typing of the manuscript. Dr. Shimon Amir was supported by the Medical Research Council of Canada. Dr. Zavie Brown was supported by the National Research Council of Canada.

REFERENCES

1. Abrams, A., D. Braff, D. Janowsky, S. Hall and D. Segal. Unresponsiveness of catatonic symptoms to naloxone. Phar- makopsychiatry 11: 177-179, 1978.

2. Akil, H., S. J. Watson, J. D. Barchas and C. H. Li. b-Endorphin immunoreactivity in rat and human blood: radioimmunoassay, comparative levels and physiological al- terations. Life Sci. 24: 1659--1666, 1979.

3. Akil, H., J. Madden, R. L. Patrick and J. D. Barchas. Stress- induced increase in endogenous opiate peptides: Concurrent analgesia and its partial reversal by naloxone. In: Opiates and Endogenous Opioid Peptides, edited by H. W. Kosterlitz. Amsterdam: North Holland, 1978, pp. 63-70.

4. Alumets, J., R. Hakansson, F. Sundler and K. I. Chang. Leu- enkephaiin-like material in nerves and enterochromaffin cells in the gut. Histochemistry 56: 187-196, 1978.

5. Arnir, S. and Z. Amit. Enhanced analgesic effects of stress following chronic administration of naltrexone in rats. Eur. J. Pharmac., in press.

6. Amir, S. and Z. Amit. The pituitary gland mediates acute and chronic pain responsiveness in stressed and non-stressed rats. Life Sci. 24: 439-448, 1979.

7. Amir, S., R. Blair, P. Shizgal and Z. Amit. Dual mechanism mediating opiate effect? Science 205: 424--425, 1979.

8. Amir, S., M. Solomon and Z. Amit. The effect of acute and chronic naloxone administration on motor activation in the rat. Neuropharmacology 18: 171-173, 1979.

9. Amir, S. and Z. Amit. Endogenous opioid ligands may mediate stress-induced changes in the affective properties of pain re- lated behavior in rats. Life Sci. 23: 1143-1152, 1978.

10. Anderson, T. R. and T. A. Siotkin. The role of neural input in the effects of morphine on the rat adrenal medulla. Biochem. Pharmac. 25: 1071-1074, 1976.

11. Anderson, T. R. and T. A. Slotkin. Effects of morphine on the rat adrenal medulla. Biochem. Pharmac. 24: 671-679, 1975.

12. Axelrod, J. Dopamine-beta-hydroxylase: Regulation of its syn- thesis and release from nerve terminals. Pharmac. Rev. 24: 233-243, 1972.

13. Baizman, E. R., B. M. Cox, O. H. Osman and A. Goldstein. Experimental alterations of endorphin levels in rat pituitary. Neuroendocrinology 20: 402-424, 1979.

14. Baizman, E. R. and B. M. Cox. Endorphin rat pituitary glands: Its distribution within the gland and age related changes in gland content in male and female rats. Life Sci. 22: 519-526, 1978.

15. Barchas, J. D., H. Akil, G. R. Elliott, R. B. Holman and S. J. Watson. Behavioral neurochemistry: Neuroregulators and be- havioral states. Science 200: 964-973, 1978.

16. Barsky, A. J. III. Patients who amplify bodily sensations. Ann. Int. Med. 91: 63-70, 1979.

17. Beecher, H. K. Relationship of significance of wound to pain experience. J. Am. Med. Ass. 161: 1609-1613, 1966.

18. Beecber, H. K. Subjective response and reaction to sensation: reaction phase as effective site for drug action. Am. J. Med. 20: 107-113, 1956.

19. Bergland, R. M. and R. B. Page. Pituitary-brain vascular rela- tions: A new paradigm. Science 204: 18-24, 1979.

20. Bergland, R. M. and R. B. Page. Can the pituitary secrete directly to the brain? (Affirmative anatomical evidence) Endo- crinology 102: 1325-1338, 1978.

21. Bertolini, A., S. Senedani and M. Castelli. Behavioral effects of naioxone in rats. Experimentia 34: 771-772, 1978.

22. Blasig, J., V. Hollt, U. Baverle and A. Herz. Involvement of endorphin in emotional hyperthermia of rats. Life Sci. 23: 2525-2532, 1978.

23. Bloom, F., E. Battenberg, J. Rossier, N. Ling and R. Guille- min. Neurons containing b-endorphin in rat brain exist sepa- rately from those containing enkephalin: Immunohistochemical studies. Proc. natn. Acad. Sci. U. S. A. 75: 1591-1595, 1978.

24. Bloom, F. E., E. Battenberg, J. Rossier, N. Ling, J. Lep- paluoto, T. M. Vargo and R. Guillemin. Endorphins are located in the intermediate and anterior lobes of the pituitary gland, not in the neurohypophysis. Life Sci. 20: 43--48, 1977.

25. Bloom, F., D. Segal, N. Ling and R. Guillemin. Endorphins: profound behavioral effects in rats suggest new etiological fac- tors in mental illness. Science 194: 630-632, 1976.

26. Bodnar, R. J., D. D. Kelly, M. Brutus and M. Glusman. Stress-induced analgesia: A review of neural and hormonal mechanisms. Neurosci. Biobehav. Rev. 4: 87-100, 1980.

27. Bodnar, R. J., D. D. Kelly, A. Mansour and M. Glusman. Differential effects of hypophysectomy upon analgesia induced by two glucoprinvic stressors and morphine. Pharmac. Biochem. Behav. 11: 303-308, 1979.

28. Bodnar, R. J., M. Glusman, M. Brutus, A. Spiaggia and D. D. Kelly. Analgesia induced by cold-water stress: attenuation fol- lowing hypophysectomy. Physiol. Behav. 23: 53-62, 1979.

29. Bodnar, R. J., D. D. Kelly, A. Spiaggla, C. Ehrenberg and M. Glusman. Dose-dependent reductions by naloxone of analgesia induced by cold water stress. Pharmac. Biochem. Behav. g: 667-672, 1978.

30. Bodnar, R. J., D. D. Kelly, A. Spiaggia, C. pavlides and M. Glusman. Stress-induced analgesia: Effect of naloxone follow- ing cold water swims. Bull. Psychon. Soc. 12: 125-128, 1978.

Page 6: Endorphin III

82 AM1R, B R O W N A N D AMIT

31. Bodnar, R. J., D. D. Kelly, A. Spiaggia and M. Glusman. Stress-inducnd analgesia: Adaptation following chronic cold water swims. Bull. Psychon. Soc. 11: 337-340, t978.

32. Bodycote, I. J. and G. B. Chesher. Naloxone induced contrac- ture of ileum from stressed guinea pigs. Eur. J. Pharmac. 57: 259-261, 1979.

33. Bohus, B. Effects of ACTHdike neuropcptides on animal be- havior and man. Pharmacology 18:113-122, 1979.

34. Bonnet, K. A., J. M. Hiller and E. J. Simon. The effect of chronic opiate treatment and social isolation on opiate receptor in the rodent brain. In: Opiates and Endogenous Opioid Pep- tides, edited by H. W, Kosterlitz. Amsterdam: North Holland, 1976, pp. 335-344.

35. Bruni, J. F., D. Van Vugt, S. Marshall and J. Meites. Effect of naloxone, morphine and methionine enkephalin on serum pro- lactin, luteinizing hormone, follicle stimulating hormone, thyroid stimulating hormone and growth hormone. Life Sci. 21: 461--466, 1977.

36. Buchsbaum, M. S., G. C. Davis and W. E. Bunney. Naloxone alters pain perception and somatosensory evoked potential in normal subjects, Nature 270: 620--622, 1977.

37. Bugnon, C., B. Block, D. Lenys and D. Fellmann. Infundibular neurons of the human hypothalamus simultaneously reactive with antisera against endorphins, ACTH, MSH and beta-LPH. Cell Tissue Res. 199: 177-196, 1979.

38. Canon, W, B. Bodily changes in pain, hunger, fear and rage. In: Ciba Foundation Colloquia on Endocrinolo~'. New York: Appleton, 1915, pp. 1-12.

39. Chance, W. T., A. C. White, G. M. Krynoek and J. A. Rose- trans. Conditional fear-induced antinociception and decreased binding of (3H) N-Leu-enkephalin to rat brain. Brain Res. 141: 371-374, 1978.

40. Chance, W. T., A. C. White, G. M. Krynock and J. A. Rose- crans. Autoanalgesia: behaviorally activated antinociception. Eur. J. Pharmac. 44: 283-284, 1977.

41. Chavkin, C., B. M. Cox and A. Goldstein. Stereospecific opiate binding in bovine adrenal medulla. Molec. Pharmac. 15: 751-753, 1979.

42. Chesher, G. B. and B. Chart. Foot shock induced analgesia in mice: its reversal by naloxone and cross tolerance with mor- phine. Life Sci. 21: 1569--1574, 1977.

43. Csontos, K., M. Rust, V. Hollt, W. Mahr, W. Kromer and H. J. Teschemacher. Elevated plasma beta-endorphic levels in pregnant women and their neonates. Life Sci. 25: 835-844, 1979.

44. Cheung, A. L. and A. Goidstein. Failure of hypophysectomy to alter brain content of opioid peptides (endorphin$). Life Sci. 19: 1005-1008, 1976.

45. Crine, P., S. Benjannet, N. G. Seidah, M. Lis and M. Chretien. In vitro biosynthesis of beta endorphin in pituitary gland. Proc. natn. Acad. Sci. U. S. A. 74: 1403-1406, 1977.

46. Criswell, H. E. and M. David. Partial antagonism of stress induced analgesia by ACTH pretreatment. Soc. Neurosci. Abstr. 5: 1768, 1979.

47. Davis, G. C., M. S. Buchshaum and W. E. Bunney. Analgesia to painful stimulation in affective illness. Am. J. Psychiat. 136: 1148-1151, 1979.

48. Davis, G. C., M. S. Buchsbaum and W. E. Bunney Jr. Naioxone decreases diurnal variation in pain sensitivity and somatosensory evoked potentials. Life Sci. 23: 1449-1460, 1978.

49. Davis, G. C., W. E. Bunney, E. G. DeFraites, J. E. Kleinman, D. P. van Kammer, R. M. Post anti R. J. Wyatt. Intruveoous naloxone administration in schizophrenia and ~rective illness. Science 197: 74-77, 1977.

50. Davis, M. Morphine and naloxone: effects on conditioned fear as measured with the potentiated startle paradigm. Fur. J. Pharmac. 54: 341-347, 1979.

51. De Wied, D., B. Bohus, J. M. Van Ree and I. Urban. Behav- ioral and electrophysiological effects of l~p t i~s related to lipotropin (b-LPH). J. Pharmac. exp. Ther. 204: 570-580, 1978.

52. De Wied, D., A. Witter and H. M. Greven. Behaviorally active ACTH analogues. Biochem. Pharmac. 24: 1463--1468, 1975.

53. Di Guilio, A. M., H. Y. T. Yang, B. E. Lutold, W. Fratta and E. Costa. On the enkephalin content of sympathetic ganglia. The Pharmacologist 20: 167, 1978.

54. Domschke, W., A. Dickschas and P. Mitznegg. C. S. F. beta- endorphin in schizophrenia. Lancet 1: 1024, 1979.

55. Donovan, B. T. The behavioral actions of the hypothalamic peptides: a review. Psychol. Med. 8: 305--316, 1978.

56. Dunn, A. J. and W. H. Gispen. How ACTH acts on the brain. Biobehav. Rev. 1: 15--23. 1977.

57. Dunn, J. D., W. J. Schindler, M. D. Hutchins, L. E. Scheving and C. Turpen. Daily variation in rat growth hormone concen- tration and effect of stress on periodicity. Neuroendocrinology 13: 69--78, 1974.

58. Dupont, A., L. Cusan, M. Garon, F. Labrie and C. H. Li. b-Endorphin: Stimulation of growth hormone release in vivo. Proc. hath. Acad. Sci. U. S. A. 74: 358-359, 1977.

59. Elde, R., T. Hokfelt, O. Johansson and L. Terenius. lm- munohistochemical studies using antibodies to leucine- enkephalin: Initial observations on the nervous system of the rat. Neuroscience 1: 349--355, 1976.

60. Elsobky, A., J. O. Dostrovsky and P. D. Wall. Lack of effect of naloxone on pain perception in humans. Nature 263: 783-784. 1976.

61. Emrich, H. M., V. Hollt, W. Kissling, M. Fischler, H. Laspe, H. Heinemann, D. V. Zerssen and A. Herz. beta-Endorphin- like immunoreactivity in cerebrospinal fluid and plasma of patients with schizophrenia and other neuropsychiatric disor- ders. Pharmakopsychiatry 12: 269--276, 1979.

62. Emrich, H. M., C. Cording, S. Piree, A. Kolling, D. V. Zerssen and A. Herz. Indication of an antipsychotic action of the opiate antagonist naloxone. Pharmakopsychiatry 10: 265--270, 1977.

63. Engel, F. L. and H. E. Liebovitz. Extra target organ actions of anterior pituitary hormones. In: The PituitaD" Gland, Vol. 2_ edited by G, W. Harris and D. T. Donovan. London: But- terworths, 1966, pp. 563-588.

64. Fanselow, M. S. Naloxone attenuates rat's preference for signaled shock. Physiol. Psychol. 7: 70-74, 1979.

65. Fanselow, M. S. and R. C. Bolles. Naloxone and shock elicited freezing in the rat. J. cornp, physiol. Psychol. 93: 736-733, 1979.

66. Fischer, J. and C. Moriarty. Control of bioactive corticotropin release from neuro-intermedia lobe of the rat. Endocrinology 100: 1047-1054, 1977.

67. Fratta, W., H. Y. Yang, J. Hong and E. Costa. Stability of met- enkephalin content in brain structures of morphine dcl)end- ent or foot shock-stressed rats. Nature 2611." 452--453, 1977.

68. Frederickson, R. C. A. Enkephalin pental)eptides: A review of current evidence for a physiological role in vertebrate neuro- transmission. Life Sci. 21: 23--42, 1977.

69. Frederickson, R. C. A., V. Burgis and J. D. Edwards. Hyperalgesia induced by naioxone follows diurnal rh~hm in responsivity to painful stimuli. Science 1911: 756--758, 1977.

70. French, E. D., F. E. Bloom, C. Rivier, R. Guillemin and J. Rossier. Morphine or stress induced increases of plasma b-endorphin and prolactin are prevented by dexamethason pre- treatment. Soc. Neurosci. Abstr. 4: 1285, 1978.

71. Frid, M. and G. Singer. Hypnotic analgesia in conditions of stress is partially reversed by naloxone. Psychopharmacology 63: 211-215, 1979.

72. Fuxe, K., K. Andersson, T. Hokfelt, V. Mutt, L. Ferland, L. F. Agnati, D. Ganten, S. Said, P. Eneroth and J, A. Gas- tafsson. Localization and possible function of peptidergic neurons and their interactions with central categhohmaine neurons, and the central action of gut hormones. Fedn~ Proc. 38: 2333-2340, 1979.

73. Galeano, C., R. Morcos, R. Cloutier, P. A. Desmarais and P. Beaudry. The immobility reflex: Effect of naioxone. Life Sci. 23: 61-64, 1978.

Page 7: Endorphin III

ROLE OF ENDORPHINS IN STRESS 83

74. Gibson, A., M. Ginsburg, M. Hall and S. L;Hart. The effect of opioid drugs and of lithium on steroidogenesis in rat adrenal cell suspensions. Br. J. Pharmac. 65: 671-676, 1979.

75. Gibson, A., M. Ginsburg, M. Hall and S, L. Hart. The effects of opiate receptor agonists and antagonists on stress-induced secretion of corticosterone in mice. Br. J. Pharmac. 65: 139- 146, 1979.

76. Gibson, A., M. Ginsburg, M. Hall and S. L. Hart. The effect of intracerebroventricular administration of methionine-enkepha- iin on the stress-induced secretion of corticosterone in mice. Br. J. Pharmac. 66: 164-166, 1979.

77. Gibson, A., M. Ginsburg, M. Hall, S. L. Hart and I. Kitchen. Adrenalectomy changes endogenous opioid content in rat hypothalamus. In: Characteristics and Functions o f Opioids, edited by J. M. Van Ree and L. Terenius. Amsterdam: Elsevier North Holland, 1978, pp. 275-276.

78. Gibson, A., M. Ginsburg, M. Hall and S. L. Hall. The influ- ence of naloxone and normorphine on plasma corticosteroid levels in normal and stressed mice. J. Physiol. 270: 28-29, 1977.

79. Gispen, W. H., J. M. Van Ree and D. De Wied. Lipotropin and the central nervous system. Int. Rev. NeurobioL 20: 209-250, 1977.

80. Gispen, W. H. and W. M. Wiegant. Opiate antagonists suppress ACTH~_24-induced excessive grooming in the rat. Neurosci. Lett. 2: 159-164, 1976.

81. Gispen, W. H., J. Buitelaar, V. M. Wiegant, L. Terenius and D. De Wied. Interaction between ACTH fragments, brain opiate receptors and morphine-induced analgesia. Fur. J. Pharmac. 39: 393-397, 1976.

82. Gispen, W. H., V. M. Wiegant, A. F. Bradbury, E. C. Hulme, D. G. Smyth, C. R. Snell and D. De Wied. Induction of exces- sive grooming in the rat by fragments of lipotropin. Nature 264: 794-795, 1976.

83. Gispen, W. H., T. B. Van Wimersma Greidanus, C. Waters- Ezrin, E. Zimmermann, W. A. Krivoy and D. De Wied. Influ- ence of peptides on reduced response of rats to electric foot shock after acute administration of morphine. Eur. J. Phar- mac. 33: 99-105, 1975.

84. Gold, M. S., D. E. Redmond and R. K. Donahedian. The ef- fects of opiate agonist and antagonist on serum prolactin in primates: Possible role for endorphins in prolactin regulation. Endocrinology 105: 284--289, 1979.

85. Goldstein, A. Opioid peptides (Endorphins) in pituitary and brain. Science 193: 1081-1086, 1976.

86. Goldstein, A., G. T. Pryor, C. S. Otis and F. Larsen. On the role of endogenous opioids peptides: Failure of naloxone to influence shock escape threshold in the rat. Life Sci. 18: 599- 604, 1976.

87. Goldstein, A. and E. R. Hilgard. Failure of the opiate an- tagonist naloxone to modify hyphotic analgesia. Proc. hath. Acad. Sci. U. S. A. 72: 2041-2043, 1975.

88. Grandison, L. and A. Guidotti. Regulation of prolactin release by endogenous opiates. Nature 270: 357-359, 1977.

89. Grevert, P. and A. Goldstein. Endorphins: Naloxone fails to alter experimental pain or mood in humans. Science 199: I093-I095, 1978.

90. Grevert, P., E. R. Balaman and A. Goldstein. Naloxone effect on a nociceptive response of hypophysectomized and ad- renalectomized mice. Life Sci. 23: 723-728, 1978.

91. Grevert, P. and A. Goldstein. Effects of naloxone on experi- mentally induced ischemic pain and on mood in human sub- jects. Proc. natn. Acad. Sci. U. S. A. 74: 1291-1294, 1977.

92. Grevert, P. and A. Goldstein. Some effects of naloxone on behavior in the mouse. Psychopharmacology 53: III-I13, 1977.

93. Gruhe, D., K. H. Voigt and E. Weber. Pancreatic glucagon cells contain endorphin-like immunoreactivity. Histochemisto' 59: 75--79, 1978.

94. Guillemin, R., T. M. Vargo, J. Rossier, S. Minick, N. Ling, C. Rivier, W. Vale and F. Bloom. b-Endorphin and adrenocor- ticotrophin are secreted concomitantly by the pituitary gland. Science 197: 1367-1369, 1977.

§51 Gunne, L.-M., L, Lindstrom and L. Terenius. Naloxone- induced reversal of schizophrenic hallucination. J. Neural Trans. 40: 13-19, 1977.

96. Hnddox, M. K. and D. H. Russell. beta-Endorphin is a kidney trophic hormone. Life Sci. 25: 615-620, 1979.

97. Hall, K. R. L. and E. Stride. The varying response to pain in psychiatric disorders. A study in abnormal psychology. Br. J. Med. Psychol. 27: 48--60, 1954.

98. Hambrook, 3. M., B. A. Morgan, M. J. Rance and C. F. C. Smith. Mode of deactivation of the enkephalins by rat and human plasma and rat brain homogenates. Nature 262: 782- 783, 1976.

99. Harris, R. A., H. H. Lob, and E. L. Way. Alterations in the efficacy of naloxone induced by stress, cyclic adenosine monophosphate, and morphine tolerance. Fur. J. Pharmac. 39: 1-10, 1976.

100. Hayes, R. L., G. J. Bennett, P. G. Newlon and D. J. Mayer. Behavioral and physiological studies of non narcotic analgesia in the rat elicited by certain environmental stimuli. Brain Res. 155: 69-90, 1978.

101. Herman, B. H. and J. Panksepp. Effect of morphine and naloxone on separation distress and approach attachment: Evidence for opiate mediation of social affect. Pharmac. Biochem. Behav. 9: 213-220, 1978.

102. Heybach, J. P. and J. Vernikos.Danellis. The effect of pituitary adrenal function on pain sensitivity in the rat. J. Physiol. 283: 331-340, 1978.

103. Hokfelt, T., R. Elde, O. Johansson, L. Terenius and L. Stein. The distribution of enkephalin immunoreactive cell bodies in rat central nervous system. Neurosci. Lett. 5: 25-31, 1977.

104. Holaday, J. W., E. Wei, H. H. Loh and C. H. Li. Endorphin may function in heat adaptation. Proc. natn. Acad. Sci. U. S. A. 7S: 2923-2927, 1978.

105. Hollt, V., O. A. Muller and R. Fahlbusch. b-Endorphin in human plasma: basal and pathologically elevated levels. Life Sci. 25: 37-44, 1979.

106. Hollt, V., R. Przewtocki and A. Herz. beta-Endorphin-like immunoreactivity in plasma, pituitaries and hypothalamus of rats following treatment with opiates. Life Sci. 23: 1057-1066, 1978.

107. Howe, A. and A. J. Thody. The effect of hypothalamic lesions of the pars intermedia of the rat pituitary gland. J. Endocr. 46: 201-208, 1970.

108. Ipp, E., R. Dobbs and R. H. Unger. Morphin and beta endorphin influence the secretion of the endocrine pancreas. Nature 276: 190-191, 1978.

109. Jacob, J. J. C. and K. Ramahadran. Opioid antagonists, endogenous ligands and nociception. Fur. J. Pharmac. 46: 393-394, 1977.

110. Jacquet, Y. F. Opiate effects after adrenocorticotrophin or b-endorphin injection in the periaqueductal gray matter of rats. Science 201: 1032-1034, 1978.

111. Jaffe, J. H. and W. R. Martin. Narcotic analgesics and an- tagonists. In: The Pharmacological Basis o f Therapeutics. edited by L. S. Goodman and A. Gilman. New York: Macmil- lan Co., 1976, pp. 245-283.

112. Janicki, P. and J. Libich. Detection of antagonist activity for narcotic analgesics in mouse hot-plate test. Pharmac. Biochem. Behav. 10: 623-626, 1979.

113. Janowsky, D. S., D. S. Segal, F. Bloom, A. Abrams and R. Guiilemin. Lack of effect on naloxone on schizophrenic symp- toms. Am. J. Psychiat. 134: 926-927, 1977.

114. Jhamandas, K., J. Sawynok and M. Sutak. Enkephalin effects on release of brain acetylcholine. Nature 269: 433--434, 1977.

115. Joiles, J., V. M. Wiegant and W. H. Gispen. Reduced behavioral effectiveness of ACTH~_~4 after a second administration: in- teraction with opiates. Neurosci. Lett. 9: 261-266, 1978.

116. Jones, C. W. and B. T. Picketing. Comparison of the effects of water deprivation and sodium chloride imbibition on the hor- mone content of the neurohypophysis of the rat. J. Physiol. 203: 449--458, 1969.

Page 8: Endorphin III

84 AMIR, BROWN AND AMIT

t17. Jouhaneau-Bowers, M. and J. Le Magnen. ACTH self- administration in rats. Pharmac. Biochem. Behav. 10: 325--328, 1979.

118, Kaplan, R. and S. D. Glick. Prior exposure to footshock in- duced naloxone hyperaigesia. Life Sci. 24: 2309-2312, 1979.

119. Kastin, A. J., R. D. Olson, A. V. Schally and D. H. Coy. CNS effects of peripherally administered brain peptides. Life Sci. 25: 401--414, 1979.

120. Katz, R. J. ACTH4-t0 antagonism of morphine-induced behav- ioral activation in the mouse. Eur. J. Pharmac. 53: 393--395, 1979.

121. Katz, R. J. Naltrexone antagonism of exploration in the rat. Int. J. Neurosci. 9: 49-51, 1979.

122. Katz, R. J. and K. A. Roth. Stress-induced grooming in the rat -an endorphin mediated syndrome. Neurosci. Lett. 13: 209-- 212, 1979.

123. Katz, R. J. and J. Gelbart. Endogenous opiates and behavioral responses to environmental novelty. Behav. Biol. 24: 338-348, 1978.

124. Keim, K. L. and B. S. Ernest. Physiological and biochemical concomitants of restraint stress in rats. Pharmac. Biochem. Behav. 4: 289-297, 1976.

125. Kelly, D. D. and R. J. Bodnar. Stress induced analgesia: A behavioral analysis. Neurosci. Biocbehav. Res., in press.

126. Kobayashi, R. M., M. Palkovits, R. J. Miller, K. J. Chang and P. Cvatrecasas. Brain enkephalin distribution is unaltered by hypophysectomy. Ltfe Sci. 22: 527-530, 1978.

127. Kokka, N. and A. S. Fairhurst. Naloxone enhancement of acetic acid-induced writhing in rats. L(fe Sci. 21: 975-980, 1977.

128. Kosterlitz, H. W. Endogenous opioid peptides and the control of pain. Psychol. Med. 9: 1-4, 1979.

129. Krieger, D. T., A. S. Liotta, H. Hauser and M. J. Brownstein. Effect of stress, adrenocorticotropin or corticosteroid treat- ment, adrenalectomy, or hypophysectomy on hypothalamic immunoreaetive adrenocorticotropin concentrations. Endocri- nology 165: 737-742, 1979.

130. Krieger, D. T. and A. S. Liotta. Pituitary hormones in brain: Where, how and why. Science 205: 366-372, 1979.

131. Krieger, D. T., A. S. Liotta, G. Nicholsen and J. S. Kizer. Brain ACTH and endorphin reduced in rats with monosodium glutamate-induced arcuate nuclear lesions. Nature 278: 562- 563, 1979.

132. Krieger, D. T., A. Liotta and C. H. Li. Human plasma im- munoreactive b-lipotropin: correlation with basal and stimu- lated plasma ACTH concentrations. Life Sci. 21: 1771-1778, 1977.

133. Krieger, D. T., A. Liotta and M. J. Brownstein. Presence of conicotropin in brain of normal and hypophysectomized rats. Proc. hath. Acad. Sci. U. S. A. 74: 648-652, 1977.

134. Krivoy, W. A., D. C. Kroeger and E. Zimmermann. Neuro- peptides: influence on acute and chronic effects of opiates. Psychoneuroendocrinology 2: 43-51, 1977.

135. Krivoy, W., D. Kroeger, A. Taylor and E. Zimmermann. An- tagonism of morphine by b-melanocyte stimulating hormone and by tetracosactin. Eur. J. Pharmac. 27: 339-345, 1974.

136. Kuhar, M. J., C. B. Pert and S. H. Snyder. Regional distribu- tion of opiate receptor binding in monkey and human brain. Nature 245: 447-450, 1973.

137. Kurland, A. A., L. Mccabe, T. E. Hanlon and D. Sullivan. The treatment of perceptual disturbances in schizophrenia with naloxone hydrochloride. Am. J. Psychiat. 134: I408-1410, 1977.

138. Kvemansky, R. Transsynaptic and humoral regulation of ad- renal eathecolamine synthesis in stress. Biochem. Pharmac. 23: Suppl. 1, 160-166, 1974.

139. Kvemansky, R., V. K. Weise and I. J. Kopin. Elevation of adrenal tyrosine hydroxylase and pbenylethanolamine-N- methyl transferase by repeated immobilization of rats. Endocrinology if'/: 744-749, 1970.

140. Labella, F., G. Queen and J. Senyshyn. Lipotropin: localiza- tion by radioimmunoassay of endorphin precursor in pituitary and brain. Biochem. biophys. Res. Commun. 75: 350-351, 1977.

141. Lahti, R. A. and R. J. Collins. Chronic naloxone results in prolonged increases in opiate binding sites in brain. Eur. .1 Pharmac. 2: 263-264, 1978.

142. Lal, S., N. P. V. Nair, P. Cervantes, J. Pulman and H. Guyda. Effect of naloxone or levallorphan on serum prolactin concen- trations and apomorphine-induced growth hormone secretion. Acad. psychiat, neurol, scand. 59: 173-179. 1979.

143. LaMotte, C. C., A. Snowman, C. B. Pert and S. H. Snyder. Opiate receptor binding in rhesus monkey brain: Association with limbic structure. Brain Res. 155: 374-379. 1978.

144. Lazarus, L. H., L. Ling and R. Guillemin. Beta lipotropin as a prohormone for the morphinomimetic peptides endorphins and enkephalins. Proc. natn. Acad. Sci. U. S. A. 73: 2156--2159. 1976.

145. Lebmann, H., N. P. Vasavan Nair and N. S. Kline. beta- Endorphin and naioxone in psychiatric patients: Clinical and biological effects. Am. J. Psychiat. 136: 762-766, 1979.

146. Levine, J. D., N. C. Gordon, R. T. Jones and H. L. Fields. The narcotic antagonist naloxone enhances clinical pain. Nature 272: 826--827, 1978,

147. Lewis, R. V., A. S. Stern, J. Rossier, S. Stein and S. Uden- friend. Putative enkephalin precursor in bovine adrenal medulla. Biochem. biophys. Res. Commun. 89: 822--829, 1979.

148. Li, C. H., L. Barnafi, M. Chretien and D. Chung. Identification and amino acid sequence of/3-LPH from sheep pituitary glands. Nature 208: 1093-1094, 1965.

149. Lien, E. L., R. L. Finichel, V. Garsky, D. Sarantakis and N. H. Gant. Enkephalin-stimulated prolactin release. L~fe Sei. 19: 837-840, 1976.

150. Lindstrom, L. H., E. Widerlov. L. M. Gunne, A. Wahtstrom and L. Terenius. Endorphins in human cerebrospinal fluid: Clinical correlations to some psychotic states. Acta psychiat. neurol, scand. 57: 153-164, 1978.

151. Liotta, A. S., D. Gildersleeve, M. Brownstein and D. T. Krieger. In vitro biosynthesis of 31k ACTH/beta endorphin- like activity by bovine hypothalamus. Proc. nam. Acad. SoL U. S. A. 76: 1448-1452, 1979.

152. Liotta, A. S., T. Suda and D. T. Krieger. beta-Lipotropin is the major opioid-like peptide of human pituitary and rat pars dis- talis: Lack of significant beta-endorphin. Proc. hath. Acad. Sci. U. S. A. 75: 2950-2954, 1978.

153. Loh, H. H., D. A. Brase, S. Sampath-Khannas, J. B. Mar and E. L. Way./3-endorphin in vitro inhibition of striatal dopamine release. Nature 264: 567-568, 1976.

154. Lundberg, J. M., B. Hamberger, M. Schultzberg, T. Hokfelt, P. O. Granberg, S. Efendic, L. Terenius, M. Golstein and R. Luft. Enkephalin- and somatostalin-like immunoreactivities in human adrenal medulla and pheochromocytoma. Proc. hath. Acad. Sci. U. S. A. 76: 4079--4083, 1979.

155. Madden, J., H. Akil, R. L. Patrick and J. D. Barchas. Stress- induced parallel changes in central opioid levels and =pain re- sponsiveness in the rat. Nature 265: 350-360, 1977.

156. Mains, R. E., B. A. Eipper and M. Ling. Common precursor to corticotropins and endorphins. Proc. hath. Acad. Sci. U. SI A. 74: 3014-3018, 1977.

157. Martin, J. B., G. Tolls, 1. Woods and H, Guyda. Failure of naloxone to influence physiological growth hormone and pro- lactin secretion. Brain Res. 168: 210-215, 1979.

158. Mata, M. M., H. Gainer und W. A. Kiee. Effect of dehydration on the endogenous opiate content of the rat neuro-intermediate lobe. Life Sci. 21:1 I59--i 162, 1977.

159. Mayer, D. J., D. P. Price, J. Barber and A. Rafii. Acupuncture analgesia: Evidence for activation of a pain inhibitory system as a mechanism of action. In: Pain Research and Therapy, Vol. I., edited by J. J. Bonita and D. C. albe-Fessard. New York: Raven Press, 1976, pp. 751-755.

160. Mckelvey, G. W. A. The role of the pituitary-adrenal system in the development of behavioral arousal. Irish J. Med~ Sci. 147: Suppl. 1, 49-52, 1978.

161. Meites, J., J. F. Bruni, D. A. Van Vugt and A. F. Smith. Relation of endogenous opioid peptides and mortflaine to neuro- endocrine functions. Life Sci. 24:1325-1335, 1979.

Page 9: Endorphin III

ROLE OF ENDORPHINS IN STRESS 85

162. Mendelson, J. H., J. Ellingboe, J. C. Keuhnle and N. K. Mello. Effects of naltrexone on mood and neuroendocrine function in normal adult males. Psychoneuroendocrinology 3: 231-236, 1979.

163. Merskey, H, and F. G. Spear. Pain: Psychological and Psy- chiatric Aspects. London: BaUiere, Tindall and Cox, 1967.

164. Mezey, E., M. Palkovits, E. R. Dekloet, J. Verhoef and D. De Wied. Evidence for pituitary-brain transport of a behaviorally potent ACTH analog. Life Sci. 22: 831--838, 1978.

165. Minneman, K. P. and L. L. Iversen. Enkephalin and opiate narcotics increase cyclic GMP accumulation in slices of the neostriatum. Nature 268: 313-314, 1976.

166. Moroni, F., D. L. Cbeney and E. Costa. Inhibition of acetyl- choline turnover in rat hippocampus by intra-septal injections of beta endorphin and morphine. Naunyn-Schmiedebergs Arch. Pharmac. 299: 149-153, 1977.

167. Murphree, H. B. Introduction to psychotropic drugs. In: Drill's Pharmacology in Medicine, edited by J. R. DiPalma. New York: McGraw Hill Co. Inc., 1971, pp. 324-349.

168. Nemeroff, C. B. and A. J. Prange Jr. Peptides and psychoneuroendocrinoiogy. Archs gen. Psychiat. Chicago 35: 999-1010, 1978.

169. Nicoll, R. A., G. R. Siggins, N. Ling, F. E. Bloom and R. Guillemin. Neuronal actions of endophins and enkephalins among brain regions: A comparative microiontophoretic study. Proc. hath. Acad. Sci. U. S. A. 74: 2584-2588, 1977.

170. North, R. A. Opiates, opioid peptides and single neurons. Life Sci. 24: 1527-1546, 1979.

171. North, M. A. Naloxone reversal or morphine analgesia but failure to alter reactivity to pain in the formalin test. Life Sci. 22: 295-302, 1978.

172. Oliver, C., R. S. Michal and J. C. Porter. Hypothalamic, pituitary vasculature: Evidence for retrograde blood flow in the pituitary stalk. Endocrinology 101: 598--604, 1977.

173. Orwoll, E., J. W. Kendall, L. Lamorena and R-. McGilvra. Adrenocorticotropin and melanocyte--stimulating hormone in the brain. Endocrinology 104: 1845-1852, 1979.

174. Panksepp, J., B. Herman, R. Conner, P. Bishop and J. P. Scott. The biology of social attachment: Opiates alleviate sep- aration distress. Biol. Psychiat. 13: 607-618, 1978.

175. Panksepp, J., T. Vilberg, N. J. Bean, D. Coy and A. J. Kastin. Reduction of distress vocalization in chiks by opiate-like pep- tides. Brain Res. Bull. 3: 663--667, 1978.

176. Patrick, R. L. and N. Kirshner. Effect of stimulation on the levels of tyrosine hydroxylase, dopamine beta hydroxylase, and catecholamines in intact and denervated rat adrenal glands. Molec. Pharmac. 7: 87-96, 1971.

177. Pelletier, G. and R. Leclerc. Immunohistochemical localization of adrenocorticotropin in the rat brain. Endocrinology 104: 1426-1433, 1979.

178. Pelletier, G., R. Leclerc, F. Labrie, J. Cote, M. Chretien and M. Lis. Immunohistochemical localization of b-lipotropic hor- mone in the pituitary gland. Endocrinology 100: 770--776, 1977.

179. Pert, C. B., M. J. Kuhar and S. N. Snyder. Autoradiographic localization of the opiate receptor in rat brain. Life Sci. 16: 1849-1854, 1975.

180. Pezalla, P. D., M. Lis, N. G. Seidah and M. Chretien. Lipo- tropin, melanotropin and endorphin: In vivo catabolism and entry into cerebrospinal fluid. Can. J. Neurol. Sci. $: 183-188, 1978.

181. Plomp, G. J. J. and J. M. Van Ree. Adrenocorticotrophic hor- mone fragments mimic the effect of morphine in vitro. Br. J. Pharmac. 64: 223-227, 1978.

182. Polak, J. M., S. N. Sullivan, S. R. Bloom, P. Facer and A. G. E. Pearse. Enkephalin-like immunoreactivity in human gas- trointestinal tract. Lancet 1: 972-974, 1977.

183. Przewlocki, R., V. Hollt, K. H. Goigt and A. Herz. Modulation of in vitro release of b-endorphin from the separate lobes of the rat pituitary. Life Sci. 24: 1601-1608, 1979.

184. Rangel, L. Psychiatric aspects of pain. Psychosom. Med. 15: 22-37, 1953.

155. Riley~ A. L., D. A, Zellner and H. J. Duncan. The role of endorphin in animal learning and behavior. Neurosci. Biobehav. Rev. 4: 69-76, 1980.

186. Roberts, J. L. and G. Herbert. Characterization of a common precursor to corticotropin and b-lipotropin: Cell-free synthesis of the precursor and identification of corticotropin peptides in the molecule. Proc. natn. Acad. Sci. U. S. A. 74: 4826--4830, 1977.

187. Ross, M., P. A. Berger and A. Goldstein. Plasma beta endorphin immunoreactivity in schizophrenia. Science 205: 1163-1164, 1979.

188. Ross, M., R. Dingledine, B. M. Cox and A. Gulstein. Distribu- tion of endorphins (peptides with morphine-like pharmacologi- cal activity) in pituitary. Brain Res. 124: 523-532, 1977.

189. Rossier, J., E. Battenberg, Q. Pittman, A. Bayon, L. Koda, R. Miller, R. Guillemin and F. Bloom. Hypothalamic enkephalin neurones may regulate the neurohypophysis. Nature 227: 653--655, 1979.

190. Rossier, J., R. Gnillemin and F. Bloom. Foot-shock induced stress decreases LeuS-enkephalin immunoreactivity in rat hypothalamus. Fur. J. Pharmac. 48: 465--466, 1978.

191. Rossier, J., T. M. Vargo, S. Minick, N. Ling, F. G. Bloom and R. Guillemin. Regional distribution of b-endorphin and enkephalin content in rat brain and pituitary. Proc. natn. Acad. Sci. U. S. A. 74: 5162-5165, 1977.

192. Rossier, J., E. D. French, C. Rivier, N. Ling, R. Guillemin and F. Bloom. Foot-shock induced stress increases b-endorphin levels in blood but not brain. Nature 270: 618-.620, 1977.

193. Rubinstein, M., S. Stein and S. Udenfriend. Characterization of pro-opiocortin, a precursor to opioid peptides and cortico- tropin. Proc. natn. Acad. Sci. U.S.A. 75: 669-671, 1978.

194. Rubin, P., S. Swezey and T. Blaschke. Naloxone lowers plasma prolacting in brain. Lancet 1: 1293, 1979.

195. Rubinstein, M., S. Stein, L. D. Gerber and S. Udenfriend. Isolation and characterization of the opioid peptides from rat pituitary: b-lipotropin. Proc. natn. Acad. Sci. U. S. A. 74: 3052-3055, 1977.

196. Rudman, D. and J. W. Issacs. Effect of intratbecal injections of melanotropic-lipolytic peptides on the concentration of 3'5'- cyclic adenosine monophosphate in cerebrospinal fluid. Endocrinology 97: 1476-1480, 1975.

197. Saffran, M. and A. V. Schally. The status of the corticotropin releasing factor (CRF). Neuroendocrinology 24: 359-375, 1977.

198. Santagustino, A., D. Cocchi, E. Giagnoni, E. Gori, E. Muller and S. Ferri. Some relationships between endorphins and pituitary hormones. In: Advances in Biochemical pharmacol- ogy, Vol. 18, edited by E. Costa and M. Trabucchi. New York: Raven Press, 1978, pp. 175-181.

199. Schultzberg, M., T. Hokfelt, L. Terenius, L. G. Elfvin, J. M. Lundberg, J. Brandt, R. Elde and M. Goidstein. Enkephalin immunoreactive nerve fibers and cell bodies in sympathetic ganglia of the guinea-pig and rat. Neuroscience 4: 249-270, 1979. Schultzberg, M., C. F. Dreyfus, M. D. Gershon, T. Hokfelt, R. Eide, G. Niison, S. Said and M. Goldstein. VIP-, enkephalin-, substance P-, and somatostatin-like immunoreactivity in neurons intrinsic to the intestine: Immunohistochemical evi- dence from organotypic tissue cultures. Brain Res. 155: 239- 248, 1978. Schultzberg, M., J. M. Lundberg, T. Hokfelt, L. Terenius, J. Brandt, R. P. Elde and M. Goidstein. Enkephalin-like im- munoreactivity in gland cells and nerve terminals of the adrenal medulla. Neuroscience 3:1169-1186, 1978. Schultzberg, M., T. Hokfelt, J. M. Lundberg, L. Terenius, L.-G. Elfvin and R. EIde. Enkephalin-like immunoreactivity in nerve terminals in sympathetic gangiia and adrenal medulla and in adrenal medullary gland cells. Acta physiol, scand. 103: 475-477, 1978. Selye, H. The story of the adaptation syndrome. Acta Med. Montreal, 1952. Selye, H. Stress. The physiology and pathology of exposure to stress. Acta Med. Montreal, 1950.

200.

201.

202.

203.

204.

Page 10: Endorphin III

86 AM1R, B R O W N A N D AMI ' I

205. Shaar, C. J., R. C. A. Frederickson, N. B. Dininger and L. Jackson. Enkephalin analogues and naloxone modulate the re- lease of growth hormone and prolactin-evidence for regulation by an endogenous opioid peptide in brain. Life Sci. 21: 853- 860, 1977.

206. Shanker, G. and R. K. Sharma. b-Endorphin stimulates cor- ticosterone synthesis. Biochem. biophys. Res. Commun. 86: 1-5, 1979.

207. Simantov, R. and S. H. Snyder. Opiate receptor binding in the pituitary gland. Brain Res. 124: 178-184, 1977.

208. Simantov, R., M. J. Juhar, G. R. Uhl and S. H. Snyder. Opioid peptide enkephalin: Immunohistochemical mapping in rat cen- tral nervous system. Proc. natn. Acad. Sci. U. S. A. 74: 2167- 2171, 1977.

209. Singer, G. Psychological or physiological analgesics: A recon- ciliation. Biobehav. Rev. 1: 13%139, 1977.

210. Stewart, J. and R. Eikelboom. Stress masks the hypothermic effect of naloxone in rats. Life Sci. 25: 1165-1172, 1979.

211. Sullivan, S. N., S. R. Bloom and J. M. Polak. Enkephalin in peripheral neuroendocrine tumors. Lancet 1: 986-987, 1978.

212. Tang, A. H. and R. J. Collins. Enhanced analgesic effects of morphine after chronic administration of naioxone in the rat. Eur. J. Pharmac. 47: 473--474, 1978.

213. Taube, H. D., E. Borowski, T. Endo and K. Starke. Enkephalin: a potential modulator of noradrenaline release in rat brain. Eur. J. Pharmac. 38: 377-380, 1976.

214. Terenius, L., A. Wahlstrom and H. Agren. Naloxone (Narcan) treatment in depression: Clinical observation and effects on CSF endorphins and monoamine metabolites. Psychophar- macology 54: 31-33, 1977.

215. Terenius, L. Somatostatin and ACTH are peptides with partial antagonist-like selectivity for opiate receptors. Eur. J. Phar- mac. 38: 211-213, 1976.

216. Terenius, L., A. Wahlstrom, L. Lindstrom and E. Widerlov. Increased CSF levels of endorphins in chronic psychosis. Neurosic. Lett. 3: 157-162, 1976.

217. Terenius, L. Effect of peptides and amino acids on dihy- dromorphine binding to the opiate receptor. J. Pharm. Phar- mac. 27: 450-452, 1975.

218. Terenius, L., W, H. Gispen and D. De Wied. ACTH-iike pep- tides and opiate receptors in the rat brain: Structure activity studies. Eur. J. Pharmac. 33: 395-399, 1975.

219. Teschemacher, H. J., K. E. Opheim, B. M. Cox and A. Gold- stein. A peptide-like substance from pituitary that acts like mor- phine I. isolation. Life Sci. 16: 1771-1776, 1975.

220. Thoenen, H. Induction of tyrosine hydroxylase in peripheral and central adrenerglc neurons by cold exposure of rats. Na- ture 228: 861-862, 1970.

221. Torda, C. Effects of recurrent postnatal pain-related stressful events on opiate receptor-endogenous ligand system. Psychoneu_roend?crinology 3: 85-91, 1978.

222. Tseng, L. F., H. H. Loh and C. H. Li. b-Endorphin as a potent analgesic by intravenous injection. Nature 263: 239-240, 1976.

223. Vale, W., J. Rivier, R. Guillemin and C. Rivier. Effect of purified CRF and other substances on the secretion of ACTH and b-endorphin-like immunoactivities by cultured anterior or neurointermediate pituitary cells. In: Central Nervous System Effects o f Hypothalamic Hormones and other Peptides, edited by Collu et al. New York: Raven Press, 1979.

224. Vale, W., C. Rivier, L. Yang, S. Minick and R. Guillemin. Effects of purified hypothaiamic corticotropin releasing factor and other substances on the secretion of adrenocorticotropin and b-endorphin-like immunoactivities in vitro. Endocrinology 103: 1910-1915, 1978.

225. Van Loon, G. R. and E. B. Souza. Development of tolerance to the ACTH releasing effects of beta endorphin. Res. Commun. Chem. Pathol. Pharmac. 22: 203-204, 1978.

226. Van Vugt, D. A., J. F. Bruni and J. MeRes. Naloxone inhibi- tion of stress-induced increase in prolactin secretion. Life Sci. 22: 85-90, 1978.

227. Verhoef, J., M. Paikovits and A. Witter. Distribution of a be- haviorally highly potent ACTH4_9 analog in rat brain after intraventricular administration. Brain Res. 126: 89-104, 1979.

228. Verebey, K., J. Volavka and D. Clouet. Endorphins in psy- chiatry. Archs gen. Psychiat. Chicago 35: 877-888, 1978.

229. Vernmikos-Danellis, J. Estimation of corticotropin releasing activity of rat hypothalamus and neurohypophysis before and after stress. Endocrinology 75: 514--520. 1964.

230. Volavka, J., A. Mallya, S. Baig and J. Perez-CrueL Naloxone in chronic schizophrenia. Science 196: 1227-1228, 1977.

231. Wardlaw, S. L. and A. G. Frantz. Measurement of b-endorphin in human plasma. J. ctin. Endocr. 18: 176-180. 1979.

232. Watson, S. J. and H. Akil. b-endorphin and b-MSH: Common cells of origin and binding properties. Soc. neurosci. Abstr. 5: 1840, 1979.

233. Watson, S. J., H. Akil, P. A. Berger and J. D, Barchas. Some observations on the opiate peptides and schizophrenia. Archs gen. Psychiat. Chicago 36: 35-41, 1979.

234. Watson, S. J., P. A. Berger, H. Akil, M. J. Mills and J. D. Barchas. Effects of naloxone on schizophrenia: Reduction in hallucination in subpopulation of subjects. Science 201: 73-76, 1979.

235. Watson, S. J., H. Akil, C. W. Richard Ill and J. D. Barchas. Evidence for two separate opiate peptide neuronal systems. Nature 275: 226-228, 1978.

236. Watson, S. J., C. W. Richard IIl and J. D. Barchas. Ad- renocorticotropin in rat brain: lmmunocytochemical localiza- tion in cells and axons. Science 200: 1180-1182, 1978.

237. Watson, S. J., H. Akil, S. O. Sullivan and J. D. Barchas. Im- munocytochemical localization of methionine enkephalin. Life Sci. 21: 733-738, 1977.

238. Weber, E., K. H. Voigt and R. Martin. Concomitant storage of ACTH- and endorphin-like immunoreactivity in secretory granules of anterior pituitary corticotrophs. Brain Res. 157: 385-390, 1978.

239. Waitzman, R. E., D. A. Fisher, S. Minick, N. Ling and R. Guillemin. b-Endorphin stimulates secretion of arginine vaso- pressin in vivo. Endocrinology 101: 1643-1646, 1977.

240. Wesche, D. L. and R. C. A. Frederickson. Diurnal differences in opioid peptide levels correlated with nociceptive sensitivity. Life Sci. 24: 1861-1868, 1979.

241. Wiedemann, E., T, Satio, J. A, Linfoot and C. H. Li. Specific radioimmunoassay of human beta-endorphin in unextracted plasma. J. olin. Endocr. Metab. 49: 478-480, 1979.

242. Wiegant, V. M., W. H. Gispen, L. Terenius and D. De Wied. ACTH-iike peptides and morphine: interaction at the level of the CNS. Psychoneuroendocrinology 2: 63--69, t977.

243. Wiegant, V. M., A. J. Dunn, P. S. Schotman and H. Gispen. ACTH-like neurotropic peptides: Possible regulators of rat brain cyclic AMP. Brain Res. 168: 565-584, 1979.

244. Winter, C. A. and L. Flataker. The effect of corticosterone, desoxycorticosterone and adrenal-corticotrophic hormone upon the responses of animals to analgesic drugs. J. Pharmac. exp. Ther. 103: 93-105, 1951.

245. Wong, C.-L. and G. A. Bentley. The effect of stress and ad- renalectomy on morphine analgesia and naloxone potency in mice. Eur. J. Pharmac. 56: 197-205, 1979.

246. Wood, P. L., D. Malthe-Sorenssen, D. L. Cheney and G. Costa. Increase of hippocampal acetylcholine turnover rate and stretching yawning syndrome elicited by alpha-MSH and ACTH. Lift, Sci. 22: 673-678, 1978.

247. Yasukawa, N., H. Mouder, S. D. Michael and J. J. Christian. Opiate antagonist counteracts reproductive inhibition by por- cine ACTH extract. Life Sci. 22: 1381-1390, t978.

248. Yoshizaki, T. Effect of histamine, bradykinin and morphine on adrenalin release from rat adrenal gland..lap. J. Pharmac. 23: 695-699, 1973.

249. Zimmermann, E. and W. Krivoy. Antagonism helwecn mor- phine and the polypeptides ACTH, ACTHI-24 and b-MSH in the nervous system. Prog. Brain Res. 39: 383--392, t973.