Anaphylactic shock in neuropsychoimmunological research.

Q 1992 Gordon and Brurh Science Publishers S.A. Rinted in the United Srates of Amcrica

Infern. J . Neuroscience, 1992. Vol. 67, pp. 271-284 Reprints available directly from thc publisher photaopyiag permined by license only

ANAPHYLACTIC SHOCK IN NEUROPSYCHOIMMUNOLOGICAL RESEARCH BRANISLAV M. MARKOVIC, MIRJANA DIMITRUEVIC and BRANISLAV D. JANKOVIC

Int J Neurosci Downloaded from informahealthcare.com by Cornell University on 12/27/14 For personal use only.

Immunology Research Center, Belgrade, Yugoslavia (Received December 24. 1991; in final form March 18, 1992)

Anaphylaxis appears to be an excellent experimental model for investigating the intentctions between IK~VOUSsystem (CNS) and immune system. Both afferent and efferent regulatory pathways of anaphylactic response are well characterized. The potent mediators of anaphylactic shock, such as histamine and serotonin, are at the same time neurotransmitters. acting in the CNS, and regulators/modulators of the immune system, since receptors for these substances exist on the membrane of the cells of the immune system. In this article the results of studies on the relationship between anaphylaxis and CNS. performed by both pioneers and contemporary investigators, are briefly reviewed. Recent experiments done in our laboratory are presented, which showed that (a) anaphylactic shock can be induced by intracerebroventricular administration of the shocking dose of antigen; (b) rats can learn to associate the induction of anaphylactic shock with neutral stimuli from the environment; and (c) stress in the form of electric tail-shocks nxluces the intensity of anaphylactic shock.

central

Keywordr: Anaphylactic shock, cerebral anaphylaxis. CNS lesioning. CNS stimulation, conditioned anaphylactic response, w t e aversion, stress. psychoneuroimmunology. neuroimtnummodulation.

Anaphylaxis and bronchial asthma were considered as classic psychosomatic illnesses in humans (Alexander, 1950) since psychosocial factors in general have been implicated to play crucial role in their pathogenesis. In this review article, certain aspects of the CNS activity in relation to anaphylactic response in experimental animals and humans will be considered. It should be noted that attention has been primarily paid to the relationship between CNS and manifestations of anaphylactic shock, which are the result of mast cell degranulation and release of mediators of anaphylaxis, triggered by contact of antigen with mast cell bound antigen-specific IgE, while the issue of regulation of IgE antibody response and the role of effector cells in anaphylaxis has not been considered. CENTRAL NERVOUS SYSTEM AND THE EXPRESSION OF ANAPHYLAXIS In 1907, Besredka suggested that the anaphylactic response has its origin in the CNS and is controlled by the system. The role of the brain function in anaphylaxis has been demonstrated in different experimental models. Thus, decerebration and decapitation were found to suppress the anaphylactic shock (Auer & Lewis, 1910; Schiirer & Strasmann, 1912; Zunz & La Barre, 1926). Decrease of the CNS activity induced by a variety of anesthetic agents (ether, chloral hydrate, urethane, etc.) protected animals and humans from anaphylactic shock. Several reports described the complete This work was supported by Research Foundation of Serbia, Belgrade. Correspwdence to: Dr. Branislav M. Markovid, Immunology Research Center, Vojvode Step 458, 11221 Belgrade, Yugoslavia. 27 I


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B . M . MARKOVIC,M. DIMITRIJEVICAND B.D. JANKOVIC

absence of signs of anaphylaxis in experimental animals (Besredka, 1907; Hanzlik & Stockton, 1927; Parish, Barrett & Coombs, 1960) and humans (Quill, 1937; Carron, 1947; Yoda, Yokono & Miyazaki 1980) during general anesthesia. Studies which employed lesioning or stimulation of discrete brain areas have provided evidence on the role of different parts of the CNS in the regulation of anaphylactic response. Thus, lethal anaphylaxis after sensitization of guinea pigs with horse serum was prevented by prior bilateral injuries of the tuber cinereum of the hypothalamus, while lesions placed in several other loci did not produce the effect (Filipp, Szentivanyi & Mess, 1952). In addition, the same group of authors showed that bilateral tuberal damages lowered the mortality rate to passively induced anaphylaxis in guinea pigs (Filipp & Szentivanyi, 1958), and produced inhibition of systemic anaphylaxis, antibody production, and decreased sensitivity to histamine in rabbits (Szentivanyi & Filipp, 1958). Anterior hypothalamic damages afforded significant protection against lethal anaphylaxis in rats sensitized to ovalbumin after intravenous administration of the shocking dose of specific antigen (Luparello, Stein & Park, 1964). In guinea pigs, it seems that anterior hypothalamus plays a central role in regulation of anaphylactic response since lesions in the posterior and medial hypothalamus did not decrease the incidence of lethal anaphylaxis (Macris, Schiavi. Camerino & Stein, 1972a) and passive anaphylaxis (Macris, Schiavi, Camerino & Stein, 1972b). In an early report, Filipp and Szentivanyi (1958) supposed that the protective effect of anterior hypothalamic lesions on lethal anaphylaxis could be due to the decrease in circulating and tissue-fixed antibodies. However, it was shown (Schiavi, Macris, Camerino & Stein, 1975) that antibody titer was not influenced by these lesions. Keller, Shapiro, Schleifer and Stein (1982) described that bilateral anterior hypothalamic lesions placed after immunization did not protect animals from lethal anaphylaxis. Since anterior hypothalamic lesions performed before immunization provided protection against lethal anaphylaxis, the hypothalamic influence appears to be related to the induction of antibody response. The effect of hypothalamic lesions on anaphylaxis could be related to antigen-specific and antigen-nonspecific changes in tissue factors and organ responsivity. It has been shown that anterior hypothalamic lesions resulted in the protection against anaphylactic contractions in respiratory airway hypersensitivity through a decreased reactivity of tracheal smooth muscle to anaphylactic mediators (Van Oosterhout & Nijkamp, 1987). However, the CNS control over anaphylactic responses is not solely restricted to anterior hypothalamic influence, since bilateral lesions of the midbrain reticulum at the level of superior colliculus prevented anaphylactic shock in the guinea pig (Freedman & Fenichel, 1958). Bilateral destruction of medial hypothalamic structures caused more pronounced anaphylactic shock in rabbits (Goldstein, 1976), suggesting that the influence of hypothalamus on anaphylaxis is mediated by complex regulatory pathways. In addition, it was found that electrical stimulation of anterior hypothalamus altered the severity of anaphylactic shock in the guinea pig (Abinder, 1964), but reduced the mortality rate of anaphylactic and histamine shocks (Maslinski & Karczewski, 1957). In spite of the fact that a great deal of experimental work has been devoted to the role of hypothalamus in anaphylaxis, the results are still controversial and the mechanisms not clarified. Long before the "discovery" by contemporary investigators (Brown, Mogutov & Kan, 1970; Besedovsky, Sorkin. Felix & Haas, 1977; Korneva, 1987) that the antibody response is accompanied by encephalographic changes, experiments were performed dealing with the alterations in the activity of the CNS during anaphylactic response. The induction of anaphylactic shock was found to produce transient ab-


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normalities in the electrical activity of certain brain regions. Thus, Gozzano and Colombati (1 950) reported cortical bursts of high potential spikes during generalized anaphylactic shock in rabbits immunized with horse serum and challenged by intravenous route. Similar bioelectrical changes were evoked locally, i.e., only in the brain area where horse serum was directly applied. Brandon (1955) described a variety of electrical phenomena recorded over the cortex and spinal cord of guinea pigs sensitized to horse serum and challenged either by intravenous or intraperitoneal route. In the former, high potential spikes were followed by depression of bioelectrical activity, while in the latter, the spike activity was accompanied by periods of slow wave desynchronization intermixed with periods of generalized depression of electrical activity. Disturbances in electroencephalographic activity during anaphylactic shock were observed even in the absence of any signs of anaphylactic shock (Eriksson & Siiderberg, 1963). In addition to the surface bioelectrical abnormalities in the brain, it was found that deep brain structures, such as dorsal hippocampus, preoptic area and hypothalamus, also exhibited changes consisting of high amplitude spike activity, desynchronization and high amplitude slow waves during anaphylaxis in guinea pigs (Heimlich, Dunlop & Smith, 1960). The increase in hypothalamic electrical activity appeared concomitantly with antibody production and changes in acetylcholinesterase activity in intraperitoneally challenged rats sensitized to pollen allergen (Sharma, Thakur, Maurya, Garg & Singh, 1987). Alterations of the electrical activity were found in vitro in the phrenic nerve taken from immunized guinea pigs upon exposure to the specific antigen (Ninomiya, Gijdn & Alonso-deFlorida, 1972). This finding is consistent with the observations that antibodies bound to the surface membrane antigens of neurons can modulate in vivo and in vitro functions of the neurons (Jankovid, 1985). CENTRAL NERVOUS SYSTEM AS A ROUTE OF ANTIGEN ADMINISTRATION The brain may serve as a route for the induction of immune response. It has been shown that injections of heterologous erythrocytes (JankoviC, DraSkoci & IsakoviC, 1961) and human gamma-globulin (MitroviC, Drdkoci & JankoviC, 1964) into the lateral ventricles of the rabbit brain induce significant antibody production. Moreover, intravenous and subarachnoid routes of immunization have been found to be equally effective in the induction of antibody synthesis in rabbits (Sherwin, O’Brien, Richter, Cosgrove & Rose, 1963). Intracerebroventricular (Hochwald, Zarudsky, Bell & Thorbecke, 1985) and intracerebral (Widner, Moller & Johansson, 1988) application of antigen resulted in high plaque-forming cell response of deep cervical lymph nodes and spleen. Intracerebroventricular route of immunization was used for the induction of anaphylactic type hypersensitivity in the cat (JankoviC, RakiC, Veskov & Horvat, 1969). These results suggest that particulate and protein antigens can cross the brain-blood banier and enter the systemic circulation. Intracerebroventricularly injected antigens can reach irnmunocornpetent cells by leptomeningovascular, perineuro-lymphatic and ependymal routes. In this respect, mesothelial cells of subarachnoid space were found to have an important role in the transfer of intracisternally injected erythrocytes and colloidal gold from cerebrospinal fluid to blood (Dupont, Van Wart & Kraintz, 1961). In support to the idea that the CNS has important role in the development and course of anaphylaxis are the findings that the administration of the shocking dose of antigen into the brain of sensitized animal can elicit anaphylactic shock. Besredka


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MARKOW, M. DIMITRUEVIC AND B.D.

JANKOVIC

(1907) observed typical anaphylactic shock after intracerebral injection of horse serum to guinea pigs immunized with horse serum. Similarly, injection of ovalbumin into the cortex of the monkey sensitized to that antigen produced convulsions similar to those seen in anaphylactic syndrome (Kopeloff, Davidoff & Kopeloff, 1936). It was recently demonstrated (MarkoviC, SporEiC, LazareviC & JankoviC, 1990) that anaphylactic shock can be elicited after administration of antigen into the cerebrospinal fluid of rats immunized with ovalbumin. In this case, intracerebroventricular injection of antigen (Table 1) induced rapid development of typical signs of anaphylactic shock: adynamia, atonia, cyanosis and dyspnea. A dose-response relationship was observed between the amount of antigen used for shock induction and the severity of shock determined by clinical signs, hematocrit rise and drop in rectal temperature. The results presented in Table 2 indicate that anaphylactic shock induced by intracerebroventricular injection of antigen was less pronounced than that induced by intravenous injection of antigen, but more pronounced than intraperitoneally induced shock. These results suggest the active involvement of CNS in the development of anaphylactic shock. The application of the shocking dose of antigen via cannulae permanently inserted into the lateral ventricles of the rat brain, as employed in the above study, excluded the possibility for antigen to enter the blood circulation. CENTRAL NERVOUS SYSTEM COGNITIVE FUNCTION MODULATES ANAPHYLACTIC RESPONSES Pavlovian conditioning has been used as an experimental approach to provide evidence in support to the view that anaphylactic response is controlled by the CNS activity. The idea that anaphylaxis could be provoked by neutral stimuli in the absence of antigen was advanced even before pioneer experiments of Metalnikov and Chorine ( 1926) of conditioning of immunological responses which showed that immune response can be induced by a stimulus which has been previously presented to the sensitized subject together with the specific antigen. There are numerous reports based on clinical observations that placing a patient in an environment in which he has been previously exposed to antigen induced typical asthmatic attack. In patients sensitized to rose pollen, asthmatic attack could be provoked by an artificial rose (MacKenzie, 1886). Hill (1930) reported that hay fever attack could be induced in subjects sensitive to pollen by a picture of hay field. These findings suggested that stimuli from the environment act as conditioned stimuli and induce conditioned anaphylactic response. One of the first studies which employed pairing of environmental stimuli and antigen, as the unconditioned stimulus, was performed by Dekker, Pelser and Groen (1957). They found that after several pairings of specific antigen with the procedure of antigen administration, inhalation of pure oxygen or even the application of mouthpiece was sufficient to provoke an asthmatic attack with typical clinical signs and reduced vital capacity. The finding that asthmatic attacks observed after exposure to neutral stimuli in the absence of specific antigen could not be distinguished from those that appeared after antigen administration, pointed out that the observed phenomenon is related to the brain (mind) and the principles of classical conditioning. Well controlled studies with experimental animals provided further evidence that anaphylactic response could be conditioned. Ottenberg, Stein, Lewis and Hamilton (1958) administered the shocking dose of sprayed ovalbumin (the unconditioned stimulus) in a box (the conditioned stimulus) to guinea pigs sensitized to ovalbumin. Thirteen daily trials were performed in which the inhalation of antigen in the box

12

11

11

Saline

10 10 24

2 mg ovalbumin 3 mg ovalbumin

1 mg ovalbumin 2 mg ovalbumin 3 mg ovalbumin

n

0 0 0

90 92 0 0 0

(%)

Mortality Rate

10 10 12

70

(46)

Incidence of Shock

0

0

0

1.3 f 1.5 2.2 f 1.4 2.3 2 1.4

Shock Score' (Mean f SD)

3.0 f 1.7 4.2 f 1.8 5.2 f 1.6 .4 f .7 .6 f .7 .8 f .6

47.1 f 2.2 49.0 f 2.4 46.8 f 1.6

Drop in Rectal Temperature (Mean f SD)

51.3 f 2.6 52.9 f 3.4 52.0 f 3.9

Hematocrit (Mean f SD)

'Mean score, an arithmetic score reflecting the overall intensity of anaphylactic shock, defined as follows: 0 , no signs of shock; 1, mild shock, adynamia, atonia, ruffled hair, hypersensitivity to tactile stimuli; 2, moderate shock, crawling on stomach, cyanosis, rapid respiration; 3, Severe shock, marked cyanosis; 4, very Severe shock, prostration; and 5 , fatal shock.

Experimental: Immunized Immunized Immunized Control: Immunized Nonimmunized Nonimmunized

Group

IntracerebroVentricular Injection

TABLE 1 Anaphylactic Shock in Rats Given Shocking Dose of Ovalbumin Intracerebroventricularlyon Day 21 after Immunization


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MARKOW, M . DIMITRIJEVIC AND B . D . JANKOVIC



211

provoked the unconditioned response which consisted of respiratory distress similar to asthmatic attack in humans. On the following 13 days, animals were subjected to test trials in the same box. In the absence of antigen spray, animals developed conditioned asthmatic attacks which did not progress into convulsions. However, the conditioning paradigm used in this experiment was incomplete, since control groups were missing, the unconditioned response was not clearly defined and measured, and the possibility that certain amount of antigen remained in the box during test trials was not excluded. More recently, in a series of well designed studies, it was shown that guinea pigs can associate olfactory stimulus with the presentation of specific antigen (Russell, Dark, Cummins, Ellman, Callaway & Peeke, 1984; Dark, Peeke, Ellman & Salfi, 1987; Peeke, Ellman, Dark, Salfi & Reus, 1987). The unconditioned response measured in these experiments was antigen-induced increase in blood histamine level in guinea pigs immunized with bovine serum albumin. Using the classical discrimination conditioning procedure, it was demonstrated that olfactory stimulus, which was previously paired with the administration of antigen, functioned as the conditioned stimulus and induced the conditioned response: increase in blood histamine level in the absence of specific antigen. MacQueen, Marshall, Perdue, Siege1 and Bienenstock (1989) reported that the association between environmental stimuli and the presentation of specific antigen may be established using the Pavlovian conditioning procedure. In this study, the unconditioned response was antigen-induced increase of the rat mast cell protease I1 in the serum of immunized animals. Following pairing of audiovisual stimuli (the conditioned stimuli) and the injection of specific antigen (the unconditioned stimulus), the conditioned response, i.e., increase in the blood level of mast cell specific enzyme, was recorded in response to the presentation of conditioned stimuli alone. A series of experiments was performed in an attempt to provide evidence that rats can associate the presentation of specific antigen with gustatory stimulus (MarkoviC, DjuriC & JankoviC, 1986; DjuriC, MarkoviC, LazareviC & JankoviC, 1987; MarkoviC, DjuriC, LazareviC & JankoviC, 1988; DjuriC, MarkoviC, LazareviC & JankoviC, 1988) and environmental stimuli (DjuriC, MarkoviC, LazareviC, Sobrian & JankoviC, 1987; DjuriC, MarkoviC, LazareviC & JankoviC, 1989). To determine whether rats would associate gustatory stimulus (taste of saccharin as the conditioned stimulus, CS) with the injection of the shocking dose of antigen (the unconditioned stimulus, US) eliciting sublethal anaphylactic shock, the classical conditioning taste aversion paradigm was employed (Garcia, Kimmeldorf & Kaelling, 1955). Rats sensitized to ovalbumin were subjected to single-trial conditioning using three modes of CS-US presentation: (a) CS perorally, US intravenously; (b) CS perorally, US intraperitoneally; and (c) CS intravenously, US intravenously (MarkoviC et al., 1988). In subsequent twobottle preference test, rats given saccharin prior to the induction of anaphylactic shock avoided the otherwise preferred saccharin solution, thus exhibiting conditioned taste aversion (Figure 1). The associative nature of this phenomenon was supported by the finding that immunized rats given the shocking dose of antigen but not exposed to saccharin (US-only control), and immunized rats exposed to saccharin but not given the shocking dose of antigen (CS-only control), as well as nonimmunized rats given a CS-US pairing, did not develop an aversion to saccharin solution. Furthermore, excellent retention of CS-US association was found 8 weeks after the conditioning trial, and unreinforced preexposure to saccharin weakened subsequent conditioned taste aversion (DjuriC et al., 1987). These results clearly demonstrated that rats can associate gustatory stimulus with the presentation of specific antigen leading to anaphylactic shock. A dose-response relationship between the amount of antigen

B.M.MARKOVIC, M. DMITRIJEVIC AND B.D. JANKOVIC

278

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G r o u p s FIGURE 1 Saccharin preference ratio (saccharin intake/saccharin intake + tap water intake, mean 2 SD) in rats after three modes of CS-US presentation: (a) CS perorally, US intravenously; (b) CS perorally, US intraperitoneally; and (c) CS intravenously, U S intravenously. Group I , nonimmunized rats presented with a CS-US pairing; Group 2, CS-only group: immunized rats exposed to CS but not given the US; Group 3, US-only group; immunized rats not exposed to CS before the US presentation; and Group 4, immunized rats presented with a CS-US pairing.

used for shock induction and the conditioned taste aversion was demonstrated (DjuriC et al., 1988): sensitized animals receiving higher doses of antigen and experiencing stronger anaphylactic shock showed more pronounced taste aversion. In another series of experiments, we investigated whether rats would learn to associate the environmental stimuli with the presentation of specific antigen. For this purpose, immunized rats were subjected to the second anaphylactic shock in an environment different from that in which the first anaphylactic shock was induced: It was found (Figure 2) that rats who experienced both shocks in the same environment (groups C/C and NC/NC) had significantly smaller drop in rectal temperature than rats subjected to the second shock in different environment (groups C/NC and NC/ C). The observed increased resistance to the induction of the second anaphylactic shock could be explained by the association of antigen administration procedure and systemic effects of antigen, i.e., by the conditioning of compensatory response (Siegel, 1975) which opposed the effects of the unconditioned response. The finding that repeated unreinforced presentations of the antigen administration procedure prior to its pairing with the ,induction of the first anaphylactic shock attenuated the conditioned response (group PE NC/NC, Figure 3) points further to the associative nature of this phenomenon. Finally, stressful stimuli from the environment could be related to the development of anaphylactic shock. In spite of the abundance of data concerning the effect of stress on various parameters of immune response, there are only few reports dealing

279


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G r o u p s FIGURE 2 Drop in rectal temperature (mean f SD) after induction of the first and second anaphylactic shock in NC (noncolony mom marked by a low intensity buzzing noise) and C (colony mom in which the rats were housed).

with the influence of stress on anaphylaxis. Rasmussen, Spencer and Marsh (1959) and Treadwell and Rasmussen (1%1) found that mice subjected to acute or chronic shuttle-box stress showed increased resistance to the induction of anaphylactic shock. It should be noted that these authors used the procedure of passive anaphylaxis which involved the injection of a mixture of homologous antibody and antigen into non-

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G r o u p s FIGURE 3 Drop in rectal temperature(mean 2 SD) after induction of the first and second anaphylactic shock in NC/NC p u p (rats subjected to both shocks in the new environment) and PE NC/NC grwp (rats preexposed to the new environment prior to the induction of the first shock).

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16 8 17

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"Statistically significant difference, p < .05 (tail-shocked rats 1's both controls) 'Statistically significant difference, p i.05 (tail-shccked rats I'S home cage controls) 'Statistically significant difference. p. < .OS (sound-stressed rats \'s non stressed rats)

Acute stress Tail-shocked rats Apparatus-controls Home cage controls Chronic stress Tail-shocked rats AppardtUS-controk Home cage controls Sound-stressed rats Non stressed rats

Group

Shock Score (Mean _C SD)

TABLE 3 The Effect ol' Stress on Anaphylactic Shock in the Rat


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immunized mice. The use of this model of shock induction overcomes the problem of individual variations in antibody response and subsequent diversities in the intensity of anaphylactic shock, but still has some limitations and disadvantages. In order to examine the effect of stress on the development and course of anaphylactic shock, a series of experiments was performed in which immunized rats were subjected to acute (DjordjeviC, MarkoviC, LazareviC, Bukilica, DjuriC & JankoviC, 1990) or chronic (MarkoviC, DjordjeviC, LazareviC, SporeiC, DjuriC & JankoviC, 1990; MariC, DjuriC, DimitrijeviC, Bukilica, DjordjeviC, Markovid & JankoviC, 1991) stress procedures which involved the use of inescapable electric shock delivered through tail electrodes (MarkoviC, de Mello Loureiro, DjordjeviE, Lazarevid, DjuriC & JankoviC, 1989). The effect of chronic audiogenic stress on the manifestations of anaphylactic shock was also investigated (DjuriC, DjordjeviC, LazareviC, Markovic' & JankoviC, 1990). Following the respective stress session, immunized rats were injected with the shocking dose of antigen and the intensity of anaphylactic shock was evaluated. The effects of stress on anaphylactic shock in rats given 3 mg of ovalbumin intraperitoneally are presented in Table 3. The results indicate that rats subjected to either acute or chronic stress procedures showed increased resistance to the induction of anaphylactic shock. Although further experiments are needed to clarify the mechanisms of the observed stress-induced protection against anaphylaxis, it appears that opioid peptides may play an important role. It has been demonstrated that inescapable tail-shock procedure used in these experiments induced rise in the level of endogenous opioids (Grau, Hyson, Maier, Madden & Barchas, 1985). In addition, it has been shown that endorphins (Amir & van Ree, 1985) and enkephalins (JankoviC & Marie, 1987) are involved in the development of anaphylactic shock.

CONCLUDING REMARKS Anaphylactic shock was the first experimental model which suggested the interrelationship between the immune system and CNS. From the beginning of this century, the efferent and afferent pathways of CNS-immune system correlation associated with anaphylaxis were the subject of numerous studies. CNS regulatory efferent pathways have been demonstrated, indicating that brain functions have crucial role in the development of anaphylactic response. Experiments using lesioning and stimulation of various brain structures showed that the hypothalamus plays a central role in the regulation of anaphylaxis. It was also reported that general anesthesia suppressed the appearance of anaphylactic shock. The afferent pathways of CNS-imrnune system relationship were demonstrated by pronounced disturbances of bioelectrical neural activity during anaphylactic response. The brain was used both as a route for the production of anaphylactic type hypersensitivity and the induction of anaphylactic shock. Evidence that the CNS higher activity exerts control over anaphylaxis is provided by studies in which conditioning techniques were employed. Several reports demonstrated that anaphylactic response could be elicited by a neutral stimulus which has been previously presented together with the specific antigen. Further, it has been shown that stress has a profound protective effect on anaphylaxis. The experiments described clearly indicate that CNS function regulates and modulates the development and course of anaphylactic shock. However, the role of neurohumoral factors in the interactions between the CNS and anaphylactic response remains to be elucidated.

B.M.

282

MARKOVIC, M.

DIMITRIJEVIC

AND B.D. JANKOVIC

KEFERENCES


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Anaphylactic Shock.

[Anaphylactic shock lasting 4 days].

Anaphylactic shock induced by mephenesin.

Anaphylactic shock produced by latex.

Metabolic changes in dogs during anaphylactic shock.

Myocardial substrate utilization in anaphylactic shock.

Anaphylactic shock secondary to rattlesnake bite.

Anaphylactic Shock at the Beginning of Hemodialysis.

A Case of Pranlukast-Induced Anaphylactic Shock.

Anaphylactic shock during pulmonary hydatid cyst surgery.

Anaphylactic shock induced by intravenous gadopentetate dimeglumine.

Anaphylactic Shock at the End of Hemodialysis.

[Electrocardiogramme in anaphylactic shock in humans (author's transl)].

Fluconazole administration leading to anaphylactic shock in a preterm newborn.

The effect of anaphylactic shock on laryngeal calibre in rabbits.

Myocardial damage during protracted anaphylactic shock in guinea pigs.

Endotracheal epinephrine in a canine anaphylactic shock model.

Metabolism of histamine during anaphylactic shock in guinea-pigs [proceedings].

Diabetic foot due to anaphylactic shock: a case report.

High risk of anaphylactic shock during surgery for spina bifida.

Anaphylactic Shock Following Nonionic Contrast Medium during Caudal Epidural Injection.

[Anesthetics responsible for anaphylactic shock. A French multicenter study].

Anaphylactic shock after retreatment with OKT3 monoclonal antibody.

Anaphylactic shock caused by ingestion of polyethylene glycol.