Anaphylactic Shock In Mice Research Articles

Inhibitory effect of a new orally active cedrol-loaded nanostructured lipid carrier on compound 48/80-induced mast cell degranulation and anaphylactic shock in mice.

BackgroundType I hypersensitivity is an allergic reaction characterized by the overactivity of the immune system provoked by normally harmless substances. Glucocorticoids, anti-histamines, or mast cell stabilizers are the choices of treatment for type I hypersensitivity. Even though these drugs have the anti-allergic effect, they can have several side effects in prolong use. Cedrol is the main bioactive compound of Cedrus atlantica with anti-tumor, anti-oxidative, and platelet-activating factor inhibiting properties.MethodsIn this study, the preparation and anti-anaphylactic effect of cedrol-loaded nanostructured lipid carriers (NLCs) were evaluated. NLCs were prepared using Compritol® 888 ATO and triolein as lipid phase and vitamin E d-α-tocopherylpolyethyleneglycol 1000 succinate, soya lecithin, and sodium deoxycholate as nanoparticle stabilizers.ResultsThe average diameter of cedrol-NLCs (CR-NLCs) was 71.2 nm (NLC-C1) and 91.93 nm (NLC-C2). The particle had negative zeta potential values of −31.9 mV (NLC-C1) and −44.5 mV (NLC-C2). Type I anaphylactoid reaction in the animal model is significantly reduced by cedrol and cedrol-NLC. This in vivo activity of cedrol resulted that cedrol suppressed compound 48/80-induced peritoneal mast cell degranulation and histamine release from mast cells. Furthermore, compound 48/80-evoked Ca2+ uptake into mast cells was reduced in a dose-dependent manner by cedrol and cedrol-NLC. Studies confirmed that the inhibition of type I anaphylactoid response in vivo in mice and compound 48/80-induced mast cell activation in vitro are greatly enhanced by the loading of cedrol into the NLCs. The safety of cedrol and CR-NLC was evaluated as selectivity index (SI) with prednisolone and cromolyn sodium as positive control. SI of CR-NLC-C2 was found to be 11.5-fold greater than both prednisolone and cromolyn sodium.ConclusionAdministration of CR-NLC 24 hours before the onset of anaphylaxis can prevent an anaphylactoid reaction. NLCs could be a promising vehicle for the oral delivery of cedrol to protect anaphylactic reactions.

Effect of Chlorogenic acid on mast cell-dependent anaphylactic reaction

Chlorogenic acid (CGA), a naturally occurring polyphenol compound, has a number of biological activities. However, roles of CGA in the mast cell-dependent anaphylactic reaction have not been fully examined. In the present study, the effect and mechanism of CGA on mast cell-dependent anaphylactic reaction were investigated using in vivo and in vitro models. CGA inhibited compound 48/80-induced systemic anaphylactic shock in mice and skin vascular permeability in rats. CGA also inhibited anti-dinitrophenyl (DNP) IgE-mediated passive cutaneous anaphylaxis (PCA). Moreover, CGA dose-dependently reduced histamine and TNF-α release from RBL-2H3 cells activated by anti-DNP IgE. Pretreatment with CGA suppressed IgE–antigen complex induced calcium uptake into RBL-2H3 cells. When CGA was added, the level of intracellular cyclic adenosine monophosphate (cAMP) in RBL-2H3 cells was significantly elevated compared with the untreated cells. Decreased calcium uptake and increased cAMP level might be involved in the inhibitory effect of CGA on mast cell activation. These results suggest a possible therapeutic application of CGA in allergic diseases.

Sphingosine kinase 1 and sphingosine-1-phosphate receptor 2 are vital to recovery from anaphylactic shock in mice

Sphingosine kinase 1 (SphK1) and SphK2 are ubiquitous enzymes that generate sphingosine-1-phosphate (S1P), a ligand for a family of G protein-coupled receptors (S1PR1-S1PR5) with important functions in the vascular and immune systems. Here we explore the role of these kinases and receptors in recovery from anaphylaxis in mice. We found that Sphk2-/- mice had a rapid recovery from anaphylaxis. In contrast, Sphk1-/- mice showed poor recovery from anaphylaxis and delayed histamine clearance. Injection of S1P into Sphk1-/- mice increased histamine clearance and promoted recovery from anaphylaxis. Adoptive cell transfer experiments demonstrated that SphK1 activity was required in both the hematopoietic and nonhematopoietic compartments for recovery from anaphylaxis. Mice lacking the S1P receptor S1PR2 also showed a delay in plasma histamine clearance and a poor recovery from anaphylaxis. However, S1P did not promote the recovery of S1pr2-/- mice from anaphylaxis, whereas S1pr2+/- mice showed partial recovery. Unlike Sphk2-/- mice, Sphk1-/- and S1pr2-/- mice had severe hypotension during anaphylaxis. Thus, SphK1-produced S1P regulates blood pressure, histamine clearance, and recovery from anaphylaxis in a manner that involves S1PR2. This suggests that specific S1PR2 agonists may serve to counteract the vasodilation associated with anaphylactic shock.

The cytokine interleukin-33 mediates anaphylactic shock.

Anaphylactic shock is characterized by elevated immunoglobulin-E (IgE) antibodies that signal via the high affinity Fc epsilon receptor (Fc epsilonRI) to release inflammatory mediators. Here we report that the novel cytokine interleukin-33 (IL-33) potently induces anaphylactic shock in mice and is associated with the symptom in humans. IL-33 is a new member of the IL-1 family and the ligand for the orphan receptor ST2. In humans, the levels of IL-33 are substantially elevated in the blood of atopic patients during anaphylactic shock, and in inflamed skin tissue of atopic dermatitis patients. In murine experimental atopic models, IL-33 induced antigen-independent passive cutaneous and systemic anaphylaxis, in a T cell-independent, mast cell-dependent manner. In vitro, IL-33 directly induced degranulation, strong eicosanoid and cytokine production in IgE-sensitized mast cells. The molecular mechanisms triggering these responses include the activation of phospholipase D1 and sphingosine kinase1 to mediate calcium mobilization, Nuclear factor-kappaB activation, cytokine and eicosanoid secretion, and degranulation. This report therefore reveals a hitherto unrecognized pathophysiological role of IL-33 and suggests that IL-33 may be a potential therapeutic target for anaphylaxis, a disease of considerable unmet medical need.

Development of a Novel Mouse Anaphylaxis Model Produced by Intermittent Intravenous Injections of Ovalbumin without Adjuvant

This study was performed to develop mouse anaphylaxis model using ovalbumin (OA) as an antigen, with no adjuvant, and an intravenous route of administration. OA at dose levels from 0.5 to 500 mg/kg was injected 3 times into the tail vein of female CD-1 (ICR) mice at 4-day intervals. Clinical signs and extravasation of Evans blue dye (vascular permeability) were observed, serum histamine levels and airway resistance were measured, and histopathological examinations were performed. Furthermore, to detect serum IgE and IgG, heterologous and homologous passive cutaneous anaphylaxis tests were performed. Additionally, strain differences in susceptibility to OA anaphylaxis was examined with 3 mouse strains: ICR, BALB/c and C57BL/6 mice. Shortly after the 3rd injection, most of the animals exhibited systemic anaphylactic signs including death, and this was accompanied by increases in vascular permeability, plasma histamine levels, and airway resistance. Four days after the 2nd injection, anti-OA IgE and IgG were detected in sera of mice injected with 0.5 and 5.0 mg/kg or higher doses of OA, respectively. Histological findings included: congestion in many tissues; detachment of mucosal epithelial cells in the gastrointestinal tract; enhanced death, decreased numbers of lymphocytes, and increased numbers of macrophages in the lymphoid tissues. ICR mice were shown to be most susceptible to the OA anaphylaxis of the 3 mouse strains examined. In conclusion, the results demonstrate that 3 intermittent intravenous injections of OA without adjuvant at 4-day intervals can induce anaphylactic shock in mice, in particular, most effectively in ICR mice, and that the anaphylaxis is characterized by specific IgE and IgG production.

Paeonol inhibits anaphylactic reaction by regulating histamine and TNF-α

Paeonol, a major phenolic component of Moutan Cortex, was known to have antiaggregatory, antioxidant and antiinflammatory activities. In the present study, we tried to elucidate the effects of paeonol on anaphylactic reaction and its mode of action. Paeonol significantly inhibited histamine release from the rat peritoneal mast cells (RPMCs) treated with compound 48/80, a mast cell degranulator. The release of tumor necrosis factor (TNF)-α mast cell activating cytokine was significantly suppressed in RBL-2H3 mast cells pretreated with anti-dinitrophenyl (DNP) immunoglobulin E (IgE) in a dose–dependent manner. Paeonol significantly inhibited IgE production in B cells activated by anti-CD40 mAb, recombinant interleukin-4 (rIL-4) and recombinant histamine releasing factor (rHRF). Paeonol effectively downregulated the expression of IL-4 in the activated B cells by reverse transcription–polymerase chain reaction (RT–PCR). We also confirmed that paeonol effectively inhibited anaphylactic shock in mice by 90% at a dose of 0.5 mg/mouse versus PBS treated control 2 h after the i.p. injection of compound 48/80. These results suggest that paeonol has antianaphylatic activity by regulating histamine and TNF-α.

Suppressive effects of antihistaminic and/or anti-PAF agents on passive anaphylactic shock in mice sensitized with allogeneic monoclonal IgE and IgG1 antibodies and hyperimmune serum

For the immunopharmacological characterization of murine passive anaphylactic shock, the effects of antihistaminics and/or anti-platelet-activating factor (anti-PAF) agents were studied on the shock mediated by allogeneic monoclonal IgE and IgG1 antibodies and hyperimmune serum. IgE antibody-mediated shock was strongly suppressed by cyproheptadine (10 mg/kg, ip) in every strain regardless of the age and sex of the mice and the presence or absence of a shock potentiator. As far as tested with CTS, DS, and B6D2F1 mice, IgE antibody-mediated shock was also suppressed by the other two antihistamines, triprolidine (10 mg/kg, ip) and oxatomide (100 mg/kg, Po). This type of shock was not suppressed by an anti-PAF agent, CV-6209 (3.3 mg/kg, iv), when tested on aged CTS mice given no shock potentiator and young DS mice given a potentiator such as Bordetella pertussis organisms or DL-propranolol. IgG1 antibody-mediated shock was also suppressed by cyproheptadine in general except for CTS mice. Suppression in the DL-propranolol-treated DS and C3H/He mice was not very marked on sensitization with undiluted or slightly diluted IgG1 ascites but quite striking on sensitization with properly diluted ascites. In contrast with the effect of cyproheptadine, suppression by CV-6209 was obvious in aged CTS mice but not in young DL-propranolol-treated DS mice. The shock in DL-propranolol-treated DS mice sensitized with undiluted or slightly diluted ascites was completely abolished by the combined use of these two agents. These results suggest that histamine and/or PAF play a major role in IgE antibody- and IgG1 antibody-mediated shock. However, so far as tested in young DS mice, the shock mediated by serum differed in drug susceptibility from that mediated by the monoclonal antibodies. In the absence of shock potentiators, prevention was produced by cyproheptadine in the males which had been sensitized with the 1:4 or 1:8 dilution of the immune serum. In the presence of DL-propranolol, prevention was not produced even by the combined treatment with cyproheptadine and CV-6209. Therefore, it is likely that some mediators other than histamine and PAF, whose release is triggered by antibody isotypes other than IgE and IgG1, play a greater role for the shock mediated by hyperimmune serum than for the shock mediated by IgE or IgG1 antibody, especially in the presence of shock potentiators.

Anti-allergic effects and oedema inhibition caused by the extract of Drymis winteri.

To study the acute anti-inflammatory and anti-allergic properties of an extract of D. winteri. Paw oedema induced in rats with various stimuli and anaphylactic shock in mice. The hydroalcoholic extract (HE) of D. winteri (Winteraceae) (30 to 100 mg/kg, p.o., 1 h prior) inhibited carrageenan (300 micrograms/paw) and dextran (100 micrograms/paw)-induced paw oedema formation in a dose-dependent manner, with mean ID50 values of 49 and < 30 mg/kg, respectively. The HE of D. winteri (30 to 100 mg/kg) also inhibited paw oedema induced by bradykinin (BK) (3 nmol), substance P (SP) (10 nmol) and PAF-acether (PAF) (10 nmol), in a dose-dependent manner, with mean ID50 values of 56, 63, and 58 mg/kg, respectively. However, the HE inhibited the rat paw oedema induced by prostaglandin E2 (PGE2) (10 nmol) (29 +/- 7 and 33 +/- 2% at 60 and 240 min) to a smaller extent, and had no effect on oedema elicited by histamine (100 nmol). In adrenalectomized animals, the inhibition by the HE of D. winteri (100 mg/kg, p.o., 1 h prior) of BK-elicited oedema (3 nmol/paw) was significantly smaller when compared with that observed in control animals. When assessed in rats actively sensitised to ovalbumin (OVO), the oedema caused by OVO (6 micrograms/paw) was significantly inhibited by HE of D. winteri (30 to 100 mg/kg, p.o.), with a mean ID50 of about 65 mg/kg. The HE of D. winteri (100 and 200 mg/kg, p.o.) significantly increased survival rate when assessed in anaphylactic shock in mice actively sensitised to the antigen. The protective effect was long-lasting, being observed for up to 15 h. Dexamethasone, used as positive control (0.5, 1 and 2 mg/kg) produced a long-lasting (up to 24 h) increase in the survival rate of the animals. These results confirm and extend our previous studies, and demonstrate the clear oral anti-inflammatory and anti-allergic properties of the active principle(s) present in the barks of D. winteri, thus confirming its reported medicinal use in folk medicine for the management of airway diseases.

Recombinant soluble form of the human high-affinity receptor for IgE prevents anaphylactic shock in mice

The ectodomain of the alpha subunit of the human high-affinity receptor for IgE (Fc epsilon RI) has been engineered as a recombinant soluble protein (sFc epsilon RI alpha) and purified in large quantity from the supernatant of transfected mammalian cells. The sFc epsilon RI alpha was apparently heterogeneous in terms of molecular weight (40 to 60 kd), and this heterogeneity was largely due to N-linked carbohydrates on the molecule. The amino terminal sequence was homogeneous and identical to the sequence predicted from the complementary DNA sequence. The amino acid composition of the sFc epsilon RI alpha was in agreement with the values expected from the cDNA sequence. The sFc epsilon RI alpha formed a complex with IgE, and gel filtration analyses of the complex of the sFc epsilon RI alpha and human IgE supported the idea that the stoichiometry of the IgE binding was 1:1. Passive anaphylactic shock in mice was suppressed when the sFc epsilon RI alpha was intravenously injected after sensitization with anti-trinitrophenyl IgE and challenged with the appropriate antigen. In this model the sFc epsilon RI alpha was effective when administered 48 hours before the antigen challenge, but not 24 hours before the challenge. These results suggest that the sFc epsilon RI alpha facilitated the dissociation of IgE from Fc epsilon RI on mast cells in vivo and suppressed type I allergic reactions.

Protection against anaphylactic shock by gadolinium chloride-induced Kupffer cell blockade

Data in the literature concerning the role of Kupffer cells in anaphylaxis are contradictory. In the present study the effect of Kupffer cell blockade induced by gadolinium chloride (GdCl 3) on anaphylactic shock was investigated. Our observations show that GdCl 3 prevents lethal anaphylactic shock in mice sensitized to ovalbumin. Gadolinium chloride given i.v. in a dose of 1 mg (100 g) −1 body weight 24 or 48 h before the elicitation of anaphylactic shock resulted in 80% survival, compared with the 43% survival in the control group. The same dose of gadolinium chlorde and also other rare earth metal salts, like lanthanum-, praseodymium-, neodymium-, and european chlorides given i.v., one day before the elicitation of anaphylactic shock, greatly reduced the mortality in mice sensitized with ovalbumin and Bordatella pertussis vaccine. However, gadolinium chloride given, per os, in a dose of 2 mg (100 g) −1 body weight, one or two days before the elicitation of anaphylactic shock were ineffective. Gadolinum chloride similarly abrogated the symptoms of anaphylaxis, including the accumulation of serotonin and histamine in the liver. The results suggest that Kupffer cells play an important role in mouse anaphylaxis.

Inhibition of anaphylactic shock by gadolinium chloride-induced Kupffer cell blockade: Agents actions 1994; 41/SPEC. ISS: C97–C98

Data in the literature concerning the role of macrophages in anaphylaxis are contradictory. In the present study, the effect of macrophage blockade induced by gadolinium chloride (GdCl3) on anaphylactic shock is investigated. Our observations show that GdCl3 prevents lethal anaphylactic shock in mice sensitized to ovalbumin. Gadolinium chloride given i.v. in a dose of 1 mg/100 g body weight 24 or 48 h before the elicitation of anaphylactic shock resulted in 80% survival, compared with the 43% survival in the control group. The same dose of this rare-earth metal salt also greatly reduced the mortality in mice sensitized with ovalbumin containingBordetella pertussis vaccine, and similarly abrogated the symptoms of anaphylaxis, including the accumulation of serotonin and histamine in the liver. The results suggest that macrophages play an important role in mouse anaphylaxis.

A High α-Linolenate Diet Suppresses Antigen-Induced Immunoglobulin E Response and Anaphylactic Shock in Mice

Mice were fed for 2 mo diets having ratios of alpha-linolenate [18:3 (n-3)] to linoleate [18:2(n-6)] of < 0.01, 0.36, 1.0 and 3.9. Proportions of safflower seed oil and perilla seed oil were adjusted to obtain these ratios. The dietary alpha-linolenate to linoleate balance was reflected in the proportion of (n-3) and (n-6) highly unsaturated fatty acids with 20- and 22-carbon chains in spleen phospholipids, but the ratio did not affect the proportion of T lymphocyte subsets expressing CD4 and CD8 antigens in splenic leukocytes. The immunoglobulin (Ig) G and IgM responses against sheep red blood cells when estimated as plaque-forming cells present in spleen, were not affected significantly by the diets. However, the serum hemagglutinin titer was slightly but significantly higher in the high alpha-linolenate diet group [18:3(n-3)/18:2(n-6) = 3.9] than in the dietary group with 18:3(n-3) to 18:2(n-6) ratios of 0.36 and < 0.01. In contrast, the IgE antibody response against egg albumin, as well as the mortality from anaphylactic shock induced by a second challenge with antigen, was significantly lower in the high alpha-linolenate diet group [18:3(n-3)/18:2(n-6) = 3.9] than in the high linoleate diet [18:3(n-3)/18:2(n-6) < 0.01] group. These results, together with the reported suppressive effects of a high alpha-linolenate diet on the formation of lipid-derived allergic mediators, support the hypothesis that raising the (n-3) to (n-6) ratios of diets would be effective in reducing the severity of immediate-type allergic hypersensitivity.

Inhibition of anaphylactic shock by gadolinium chloride-induced Kupffer cell blockade

Data in the literature concerning the role of macrophages in anaphylaxis are contradictory. In the present study, the effect of macrophage blockade induced by gadolinium chloride (GdCl3) on anaphylactic shock is investigated. Our observations show that GdCl3 prevents lethal anaphylactic shock in mice sensitized to ovalbumin. Gadolinium chloride given i.v. in a dose of 1 mg/100 g body weight 24 or 48 h before the elicitation of anaphylactic shock resulted in 80% survival, compared with the 43% survival in the control group. The same dose of this rare-earth metal salt also greatly reduced the mortality in mice sensitized with ovalbumin containing Bordetella pertussis vaccine, and similarly abrogated the symptoms of anaphylaxis, including the accumulation of serotonin and histamine in the liver. The results suggest that macrophages play an important role in mouse anaphylaxis.

Differential effect of a PAF antagonist CV‐3988 on active and passive anaphylactic shock in various mouse strains

To define the role of platelet-activating factor (PAF) in anaphylactic shock in the mouse, the suppressive effect of CV-3988, a PAF antagonist, on active and passive anaphylactic shock was studied. Various mouse strains treated or not treated with Bordetella pertussis (B. pertussis) were used. We found that the effect of CV-3988 on anaphylactic shock in the mice that were actively sensitized with bovine serum albumin plus B. pertussis differed markedly according to mouse strain. CV-3988 suppressed the anaphylactic shock in C3H/He and CBA/JN mice at a low dose of 3 mg/kg, whereas antagonists to other mediators such as histamine, serotonin, thromboxane A2 and leukotrienes did not show a suppressive effect. This suggests that PAF plays a major role in anaphylactic shock in these strains. On the other hand, CV-3988 did not suppress active anaphylactic shock in cataract Shionogi (CTS), NOD and DS strains even at a high dose of 30 mg/kg, which could be interpreted to suggest that PAF is not active in these strains. However, this possibility was ruled out based on the similar results obtained in passive anaphylactic shock and PAF-induced shock in these mice. Passive anaphylactic shock in CTS mice mediated by IgG1 antibody was markedly suppressed by CV-3988 but not at all by antagonists to other mediators. Furthermore, the suppressive action of CV-3988 against passive anaphylactic shock, and PAF-induced shock was greatly attenuated when the mice were pretreated with B. pertussis. From these results, the conclusion can be drawn that PAF is the main mediator of active and passive anaphylactic shock in the mouse in general, even though the effect of CV-3988 differs depending on the mouse strain and on whether or not B. pertussis treatment is used.

An inhibitor of nitric oxide production, N Gnitro-L-arginine-methyl ester, improves survival in anaphylactic shock

Induction of anaphylactic shock in mice by i.v. antigen challenge (bovine serum albumin, 100 mg) or i.v. treatment with the mast cell degranulator compound 48/80 resulted in 80 and 90% mortality rate, respectively. Inhibition of nitric oxide (NO) synthesis from L-arginine by co-injection of the L-arginine analog N Gnitro-L-arginine methyl ester (L-NAME, 30 mg/kg) reduced the mortality rate by 40 and 20% in the antigen- and compound 48/80-induced shock models. Treatment with 60 mg/kg L-NAME reduced the mortality rate by 60% in these shock models. This beneficial effect was reversed by addition of L-arginine (120 mg/kg) but not D-arginine (120 mg/kg). These results suggest NO production as a possible mechanism involved in the pathophysiology of anaphylactic shock.

Age-Dependent Difference in Susceptibility to IgE Antibody- and IgG1Antibody-Mediated Passive Anaphylactic Shock in the Mouse

The age dependence of the susceptibility to passive anaphylactic shock was studied in the mouse. Anti-BPO IgE monoclonal antibody produced potent systemic sensitization sufficient for provocation of lethal shock in most aged (6 to 10 months) CTS, DS and C57BL/6J mice but only in a very few young (1.5 to 2.5 months) mice. A similar trend was found in the NOD strain, though it was not as definite as in the above three strains. Age-dependent potentiation of the IgE antibody-mediated anaphylactic shock was not found in both sexes of five other strains, C3H/He, DBA/2, NON, BALB/c and B6D2F1. However, the potentiation became obvious even in these strains, when they were treated with Bordetella pertussis before the antigen challenge. Age-dependent potentiation was also clear with IgG1 antibody-mediated anaphylactic shock in DS females and NON males. In contrast, no age-dependent difference was seen for the shock induced by PAF which is estimated to be the main mediator for anaphylactic shock in the mouse. This suggests that the age-dependent potentiation of anaphylactic shock does not seem to be due to elevated susceptibility to the mediator but to its increased release. The sex-dependent differences was also studied and found to be particularly clear in the case of IgG1 antibody-mediated anaphylactic shock in young DS and aged NON mice.

Production of active and passive anaphylactic shock in the WBB6F1 mouse, a mast cell-deficient strain

The role of mast cells in active and passive anaphylactic shock was examined using the WBB6F1 mouse, a genetically mast cell-deficient strain. Lethal anaphylactic shock occurred at high incidence rates in mice actively sensitized to bovine serum albumin (BSA). The reaction was specific to BSA since the shock could not be elicited by human or guinea pig serum albumin in these animals. Lethal shock could be prevented by CV-3988 but not by cyproheptadine, which suggests that the shock is mediated by PAF but not by histamine and serotonin. Similarly, lethal shock was provoked by homologous antigens in mice which had been passively sensitized with allogeneic anti-benzylpenicilloyl (BPO) IgG1 monoclonal antibody or with allogeneic or xenogeneic anti-BSA antiserum, but not in those sensitized with allogeneic anti-BPO IgE monoclonal antibody. These findings suggest that mast cells are not necessarily required for anaphylactic shock in the mouse.

Effect of non-steroidal anti-inflammatory drugs on alkyl-acetyl-glycerol-phosphorylcholine-induced anaphylactic shock in mice

Effect of non-steroidal anti-inflammatory drugs on alkyl-acetyl-glycerol-phosphorylcholine-induced anaphylactic shock in mice

Beneficial effect of γ-endorphin-type peptides in anaphylactic shock

γ-Endorphin-type peptides (i.e. γ-endorphin, des-tyr′-γ-endorphin [DTγE]) result from the processing of the opioid peptide, β-endorphin. Previous studies have implicated the involvement of β-endorphin in various types of shock, including anaphylactic shock. In the present experiments the intracerebroventricular (i.c.v.) administration of γ-endorphin (10 μg) or DTγE (3.3–10 μg) significantly improved survival in anaphylactic shock in mice. Moreover, DTγE (10 μg) reversed the effect of i.c.v. β-endorphin (3.3 μg) to exacerbate shock. A similar dose of DTγE was ineffective in antagonizing β-endorphin-induced analgesia. The anti-anaphylactic action of DTγE as well as its effect to block the pro-anaphylactic action of β-endorphin were prevented by pretreatment with the sympathetic ganglionic blocker, chlorisondamine chloride. The results suggest that γ-endorphin-type peptides may act in the central nervous system (CNS) to physiologically oppose the autonomic pathophysiologic influences of β-endorphin.

Morphine exacerbates anaphylactic shock in mice by stimulating central opiate receptors

Intravenous (i.v.) administration of 25 mg/kg morphine significantly increased mortality following induction of systemic anaphylaxis in mice. This effect was blocked by pretreatment with the opiate antagonist naltrexone but not by the selective peripherally acting antagonist naltrexone methyl bromide. Additionally, the effect of i.v. morphine was blocked by the opiate antagonist Win 44,441-3, but not by its inactive (+)-isomer Win 44,441-2. Furthermore, intracerebroventricular (i.c.v.) administration of 25 μg morphine increased anaphylactic mortality. This effect was blocked by i.v. naloxone. Finally, the effect of i.v. morphine, 25 mg/kg, on anaphylactic mortality was reversed by i.c.v. naloxone. Collectively, these findings demonstrate that morphine can exacerbate anaphylactic shock reactivity by stimulating specific CNS opiate receptors. The role of endogenous opiate mechanisms in the pathogenic sequence of circulatory shock is discussed.