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Antianaphylactic effect of naloxone in mice is mediated by increased central sympathetic outflow to sympathetic nerve endings and adrenal medulla
180
Brain Research, 274 (1983) 180-183
Elsevier
Antianaphylactic effect of naloxone in mice is mediated by increased central sympathetic outflow to sympathetic nerve endings and adrenal medulla SHIMON AMIR Department of Isotope Research, Weizmann Institute of Science, 76 100 Rehovot (Israel)
(Accepted May 3rd, 1983) Key words: anaphylactic shock - - naloxone - - endorphin - - sympathetic nervous system - - mice
Intravenous naloxone, 1 or 10 mg/kg, protects sensitized mice from lethal anaphylaxis. The protective effect is reversed by pretreatment with the ganglionic blocker, chlorisondamine chloride, peripheral chemical sympathectomy with 6-hydroxydopamine or bilateral adrenal gland denervation. The possible involvement of the sympathetic nervous system in naloxone's antianaphylactic action, suggested by these findings, is discussed. We have recently shown that the opiate antagonist, naloxone, improves survival in experimental anaphylaxis in mice, apparently by blocking opiate receptors in the central nervous system (CNS) 2,3. This effect may be secondary to naioxone's ability to attenuate the cardiovascular depression of anaphylactic shock z4. Studies in endotoxic ]3 and hemorrhagic shock 9 indicated that the cardiovascular protective effects of naloxone involve CNS actions 14,~7 which are peripherally mediated by sympathetic nervous system (SNS) stimulation 7,8,15,16.28.29. We have now examined the involvement of the SNS in naloxone's antianaphylactic action and report that this effect could result from increased central sympathetic outflow to sympathetic nerve endings and the adrenal medulla. Male ICR mice were immunized intraperitoneally (i.p.) with 2 mg bovine serum albumin (BSA) in 0.2 ml aluminium hydroxide gel. Ten days later they were challenged intravenously (i.v.) with 25/~g BSA or 25 ~g BSA plus 1 or 10 mg/kg naloxone or 1 or 10 mg/kg naltrexone methyl bromide (MRZ 2663-BR), a selective peripherally acting opiate antagonist, and the mortality rate was determined. The involvement of the SNS in the response to naloxone was evaluated by comparing the effect of 25/~g BSA and 25/~g BSA plus 10 mg/kg naloxone in groups of mice subjected to one of the following treatments: (i) inhibition of sympathetic transmission by the ganglionic blocker, 0006-8993/83/$03.00 © 1983 Elsevier Science Publishers B.V.
chlorisondamine chloride, 3 mg/kg i.p., 2 h prior to challenge; (ii) peripheral chemical sympathectomy by the catecholamine neurotoxin, 6-hydroxydopamine (6-OHDA), 50 mg/kg i.v. in 0.2 ml saline containing 1% ascorbic acid, 4 days prior to challenge; or (iii) bilateral adrenal-medullary gland denervation. Denervation was performed under ether anesthesia by removing the glands from the body and immediately replacing them in the adrenal beds where they were allowed to revascularize for 4 weeks. The viability of the adrenal cortex in these animals was demonstrated by their ability to survive and gain weight without having to be maintained on saline. Sham operations consisted of exposing the adrenal glands bilaterally. The adrenal denervated and sham-operated mice were immunized 18 days following surgery and challenged with 25/~g BSA or 25/~g BSA plus 10 mg/kg naloxone 10 days later. The results are shown in Figs. 1 and 2. Between 80 and 90% of the challenged mice died of anaphylactic shock. The fatally shocked mice exhibited laboured respiration ,became cyanosed, developed convulsions and died usually within 30 min after injection of the antigen. The surviving animals exhibited marked lack of activity which lasted for 1-3 h after challenge; 6 h later these animals seemed normal. Administration of naloxone, 1 or 10 mg/kg, together with the challenge dose of BSA significantly decreased the mortality rate (Fig. 1). Treatment with naltrexone
181
I00
m
CONTROL NALOXONE
MRZ
I._1 In- 50 O
0
125~] I I | I I0
25 25 I I0
DOSE ( m g / k g ) Fig, 1. The effect of different doses of naloxone or the selective peripherally acting opiate antagonist, naltrexone methyl bromide (MRZ), on anaphylactic mortality in mice. The drugs were administered i.v. concomitantly with the challenge dose of BSA (25 pg). The numbers inside the bars indicate the number of animals in each group. Asterisks indicate significant differences from BSA alone (control) (P < 0.05; Z2 test for two independent samples).
methyl bromide, 1 or 10 mg/kg was not effective. Prior treatment with chlorisondamine chloride (Fig. 2A) or with 6-OHDA, which selectively destroys sympathetic nerve terminals while sparing adrenal medullary catecholamine-containing cells 19 (Fig. 2B) reversed the protective effect of naloxone, 10 mg/kg. Denervation of the adrenal glands blocked the protective effect of 10 mg/kg naloxone as well as increased shock susceptibility (from 80% mortality in sham-operated mice to 100% mortality in adrenal denervated mice) (Fig. 2C). In previous studies we implicated CNS receptors in naloxone's protective effect in anaphylactic shock in mice, since treatment with the selective, peripherally acting antagonist, naltrexone methyl bromide, was ineffective in improving survival 2.3. The present resuits are consistent with this observation (see Fig. 1). Additionally the results indicate that treatments which compromise SNS function diminish the antianaphylactic effect of naloxone. Collectively, these findings suggest that naloxone's antianaphylactic effect depends on CNS actions which are peripherally mediated by SNS activation. Both the sympathetic
nerve endings and the adrenal medulla are functionally implicated in the protective action since selective destruction of either one of these effectors blocked the response to naloxone. Anaphylactic shock in the mouse results from circulatory collapse which is brought about by loss of effective blood volume into the extravascular space due to dilation of blood vessels and increased capillary permeability z3. This reaction is mediated by histamine, 5-hydroxytryptamine, bradykinin and a slow-reacting substance of anaphylaxis (SRS-A) released from IgE-sensitized mast cells24, and it is accompanied by marked SNS stimulation 1.12.27. The increased sympathetic tone during anaphylaxis may be effective in physiologically opposing the immunological vascular reactions, including the vasodilation and loss of intravascular fluid, produced particularly b y low doses of antigen by increasing cardiac contractility and rate and peripheral vasoconstriction. In recent studies it has been demonstrated that endogenous opiate (endorphin) systems are functionally activated in shock states5,n, 20 and that centrally administrated opiates, including endorphins decrease the sympathetic tone 6,21,26as well as blunt baroreflex responses to physiological stimuli such as acute changes in blood pressure 25. Thus, the natural protection against the immunological vascular reactions and consequent circulatory collapse in anaphylaxis attended by the compensatory increments in sympathetic activity may normally be limited by negative input via released endorphins, which act through CNS sites to decrease sympathetic outflow. Naloxone can reverse the inhibitory effects of endorphins at central sympathetic centers by blocking CNS receptors thus facilitating sympathetic outflow to peripheral sympathetic effectors and improving the physiological compensatory processes in shock. This interpretation is consistent with the finding that i.v. naloxone, either 5 min before or 30 min after induction of systemic anaphylaxis in rats, significantly inhibited the fall in blood pressure associated with shock 24. Two additional points need to be made about the results obtained for naloxone in anaphylactic shock. First, naloxone improves survival in mouse anaphylaxis not only when administered concomitantly with the challenge dose of antigen but also when injected at different times after challenge, i.e. naloxone can
182
A
B
CONTROL
C
CONTROL
CHLORISONOAMINE
SHAM 6-OHDA
ADRENAL DENERVAT ION
>- I 0 0 I--
m
50
0 -
NX
-
NX
-
NX
-
NX
-
NX
-
NX
Fig. 2. The effect of 10 mg/kg naloxone (NX) on anaphylactic mortality in mice pretreated with chlorisondamine chloride (3 mg/kg i.p.) (A); 6-OHDA (50 mg/kg i.v.) (B); or subjected to bilateral adrenal gland denervation (C). Control mice were pretreated with saline (A) or 6-OHDA vehicle (B) or were subjected to a sham operation (C). Naloxone was administered i.v. concomitantly with the challenge dose of BSA (25/~g). The numbers inside the bars indicate the number of animals in each group. Asterisks indicate significant difference from BSA alone (P < 0.05; X2 test for two independent samples). reverse the progression of shock 3. Second, only the effects of low doses of antigen ( < 5 0 ~g) are blocked by naloxone. With higher doses of antigen the protective effect of naloxone (1-10 mg/kg) in mouse anaphylaxis is destroyed (unpublished observations). This further supports the thesis that naloxone's antianaphylactic effect occurs primarily by improving an ongoing physiological (sympathetic) c o m p e n s a t o r y process initiated by the challenging dose of antigen12, 27. Preliminary results suggest that naloxone may facilitate sympathetic outflow by antagonizing an endorphin interaction at sympathetic centers at the hypothalamus since depletion of hypothalamic pools of endorphins (enkephalins, /3-endorphin) by 1 Alho, A., Jaattela, A., Lahdensuu, M., Rokkanen, P., Avikainen, V., Karaharju, E., Tervo, T. and Lepisto, P., Catecholamines in shock, Ann. Clin. Res.. 9 (1977) 157-163. 2 Amir, S., Opiate antagonists improve survival in anaphy-
the neonatal administration of m o n o s o d i u m glutamate protects mice from lethal anaphylaxis 4 as well as blocks the response to naloxone. The possibility that naloxone's beneficial action also involves blockade of the central p a r a s y m p a t h e t i c outflow l0 or alteration in the release of chemical mediators of anaphylaxis from sensitized mast cells ~8.30 is currently under investigation. I would like to thank M. Harel for technical assistance, Dr. E. T h o m a s for helpful comments on the manuscript, E n d o L a b o r a t o r i e s for the gift of natoxone and C I B A - G e i g y for the gift of chlorisondamine chloride. lactic shock, Europ. J. Pharmacol., 80 (1982) 161-162. 3 Amir, S. and Harel, M., Involvement of endorphins in anaphylactic shock in mice, Soc. Neurosci. Abstr., 8 (1982) 227. 4 Amir, S. and Davis, L., Protective effect of neonatal MSG-
183
5
6
7
8 9 10 11 12 13 14
15
16 17
induced arcuate nuclear lesions in anaphylactic shock, Europ. J. Pharmacol., 84 (1982) 237-238. Carr, D. B., Bergland, R., Hamilton, A., Blume, H., Kasting, N., Arnold, M., Martin, J. B. and Rosenblatt, M., Endotoxin-stimulated opioid peptide secretion: two secretory pools and feedback control in vivo, Science, 217 (1982) 845--848. Daskaiopoulos, N. Th., Laubie, M. and Schmitt, H., Localization of the central sympatho-inhibitory effect of a narcotic analgesic agent, fentanyl, in cats, Europ. J. Pharmacol., 33 (1975) 91-97. Dashwood, M. R. and Feldberg, W., Central inhibitory effect of released opiate peptides on adrenal medulla, revealed by naloxone in the cat, J. Physiol. (Lond.), 300 (1979) 22P-23P. Dirksen, R., Wood, G. J. and Nijhuis, G. M. M., Mechanism of naloxone therapy in the treatment of shock: a hypothesis, Lancet, i (1981) 607-608. Faden, A. I. and Holaday, J. W., Opiate antagonists: a role in the treatment of hypovolemic shock, Science, 205 (1979) 317-318. Faden, A. I., Jacobs, T. P. and Holaday, J. W., Endorphin-parasympathetic interaction in spinal shock, J. autonomic Nerv. Syst., 2 (1980) 295-304. Faden, A. I., Jacobs, T. P., Mougey, E. and Holaday, J. W., Endorphins in experimental spinal injury: therapeutic effect of naloxone, Ann. Neurol., 10 (1981) 326-332. Hamberger, B., Fredholm, B. B. and Farnebo, L. O., Anaphylaxis and plasma catechotamines, Life Sci., 26 (1980) 1465-1471. Holaday, J. W. and Faden, A. I., Naloxone reversal of endotoxin hypotension suggests role of endorphins in shock, Nature (Lond.), 275 (1978) 450-451. Holaday, J. W., O'Hara, M. and Faden, A. I., Hypophysectomy alters cardiorespiratory variables: central effects of pituitary endorphins in shock, Amer. J. Physiol., 241 (1981) H479-H485. Holaday, J. W., D'Amato, R. J., Ruvio, B. A. and Faden, A. I., Action of naloxone and TRH on the autonomic regulation of circulation, Advanc. Biochem. Psychopharmacol., 33 (1982) 353-361. Holaday, J. W., Cardiovascular consequences of endogenous opiate antagonism, Biochem. Pharmacol., 32 (1983) 573-585. Janssen, H. F. and Lutherer, L. O., Ventriculocisternal administration of naloxone protects against severe hypotension during endotoxin shock, Brain Research, 194 (1980) 608--612.
18 Johnson, A. R. and Morgan, N. C., Inhibition of the release of histamine from rat mast cells: the effect of cold and adrenergic drugs on release of histamine by 48/80 and antigen, J. Pharmacol. exp. Ther., 175 (1970) 632-640. 19 Kostrzewa, R. M. and Jacobowit, D. M., Pharmacological actions of 6-hydroxydopamine, Pharmacol. Rev., 26 (1974) 199-288. 20 Lang, R. E., Bruckner, U. B., Hermann, K., Kempf, B., Rascher, W., Sturm, V., Unger, Th. and Ganten, D., Effect of hemorrhagic shock on the concomitant release of endorphin and enkephalin-like peptides from the pituitary and adrenal gland in the dog, Advanc. Biochem. Psychopharmacol., 33 (1982) 363-368. 21 Laubie, M., Schmitt, H., Vincent, M. and Remond, G., Central cardiovascular effects of morphinomimetic peptides in dogs, Europ. J. Pharmacol., 46 (1977) 67-71. 22 Lima, A. O., Pharmacologically active substances released during anaphylactic shock in the mouse, Int. Arch. Allergy, 32 (1967) 46-54. 23 Munoz, J. and Bergman, R. K., Mechanism of anaphylactic death in the mouse, Nature (Lond.), 205 (1965) 199-200. 24 Paciorek, P. M. and Todd, M. H., A comparison of the cardiovascular effects of meptazimol and naloxone following anaphylactic shock in anaesthetised rats, Brit. J. Pharma-" col., 76 (1982) 245 p. 25 Petty, M. A. and Reid, J. L., The effect of opiates on arterial baroreceptor reflex function in the rabbit, NaunynSchmiedeberg's Arch. Pharmacol., 319 (1982) 206-211. 26 Petty, M. A., de Jong, A. and de Wied, D., An inhibitory role of fl-endorphin in central cardiovascular regulation, Life Sci., 30 (1982) 1835-1840. 27 Piper, P. J., Collier, H. O. J. and Vane, J. R., Release of catecholamines in the guinea-pig by substances involved in anaphylaxis, Nature (Lond.), 213(1967) 838-840. 28 Schadt, J. C. and York, D. H., The effects of autonomic blockade on the response to naloxone in conscious rabbits made hypotensive by hemorrhage, Fed. Proc., 40 (1981) 522. 29 Wright, D. J. P., The fall in circulating leucocyte and platelet counts after endotoxin: an adrenergic opioid interaction, Neuropeptide, 1 (1981) 181-202. 30 Yamasaki, Y., Shimamura, O., Kizu, A., Nakagawa, M. and Ijichi, H., IgE-mediated 14C-serotonin release from rat mast cells modulated by morphine and endorphins, Life Sci., 31 (1982) 471-478.
Brain Research, 274 (1983) 180-183
Elsevier
Antianaphylactic effect of naloxone in mice is mediated by increased central sympathetic outflow to sympathetic nerve endings and adrenal medulla SHIMON AMIR Department of Isotope Research, Weizmann Institute of Science, 76 100 Rehovot (Israel)
(Accepted May 3rd, 1983) Key words: anaphylactic shock - - naloxone - - endorphin - - sympathetic nervous system - - mice
Intravenous naloxone, 1 or 10 mg/kg, protects sensitized mice from lethal anaphylaxis. The protective effect is reversed by pretreatment with the ganglionic blocker, chlorisondamine chloride, peripheral chemical sympathectomy with 6-hydroxydopamine or bilateral adrenal gland denervation. The possible involvement of the sympathetic nervous system in naloxone's antianaphylactic action, suggested by these findings, is discussed. We have recently shown that the opiate antagonist, naloxone, improves survival in experimental anaphylaxis in mice, apparently by blocking opiate receptors in the central nervous system (CNS) 2,3. This effect may be secondary to naioxone's ability to attenuate the cardiovascular depression of anaphylactic shock z4. Studies in endotoxic ]3 and hemorrhagic shock 9 indicated that the cardiovascular protective effects of naloxone involve CNS actions 14,~7 which are peripherally mediated by sympathetic nervous system (SNS) stimulation 7,8,15,16.28.29. We have now examined the involvement of the SNS in naloxone's antianaphylactic action and report that this effect could result from increased central sympathetic outflow to sympathetic nerve endings and the adrenal medulla. Male ICR mice were immunized intraperitoneally (i.p.) with 2 mg bovine serum albumin (BSA) in 0.2 ml aluminium hydroxide gel. Ten days later they were challenged intravenously (i.v.) with 25/~g BSA or 25 ~g BSA plus 1 or 10 mg/kg naloxone or 1 or 10 mg/kg naltrexone methyl bromide (MRZ 2663-BR), a selective peripherally acting opiate antagonist, and the mortality rate was determined. The involvement of the SNS in the response to naloxone was evaluated by comparing the effect of 25/~g BSA and 25/~g BSA plus 10 mg/kg naloxone in groups of mice subjected to one of the following treatments: (i) inhibition of sympathetic transmission by the ganglionic blocker, 0006-8993/83/$03.00 © 1983 Elsevier Science Publishers B.V.
chlorisondamine chloride, 3 mg/kg i.p., 2 h prior to challenge; (ii) peripheral chemical sympathectomy by the catecholamine neurotoxin, 6-hydroxydopamine (6-OHDA), 50 mg/kg i.v. in 0.2 ml saline containing 1% ascorbic acid, 4 days prior to challenge; or (iii) bilateral adrenal-medullary gland denervation. Denervation was performed under ether anesthesia by removing the glands from the body and immediately replacing them in the adrenal beds where they were allowed to revascularize for 4 weeks. The viability of the adrenal cortex in these animals was demonstrated by their ability to survive and gain weight without having to be maintained on saline. Sham operations consisted of exposing the adrenal glands bilaterally. The adrenal denervated and sham-operated mice were immunized 18 days following surgery and challenged with 25/~g BSA or 25/~g BSA plus 10 mg/kg naloxone 10 days later. The results are shown in Figs. 1 and 2. Between 80 and 90% of the challenged mice died of anaphylactic shock. The fatally shocked mice exhibited laboured respiration ,became cyanosed, developed convulsions and died usually within 30 min after injection of the antigen. The surviving animals exhibited marked lack of activity which lasted for 1-3 h after challenge; 6 h later these animals seemed normal. Administration of naloxone, 1 or 10 mg/kg, together with the challenge dose of BSA significantly decreased the mortality rate (Fig. 1). Treatment with naltrexone
181
I00
m
CONTROL NALOXONE
MRZ
I._1 In- 50 O
0
125~] I I | I I0
25 25 I I0
DOSE ( m g / k g ) Fig, 1. The effect of different doses of naloxone or the selective peripherally acting opiate antagonist, naltrexone methyl bromide (MRZ), on anaphylactic mortality in mice. The drugs were administered i.v. concomitantly with the challenge dose of BSA (25 pg). The numbers inside the bars indicate the number of animals in each group. Asterisks indicate significant differences from BSA alone (control) (P < 0.05; Z2 test for two independent samples).
methyl bromide, 1 or 10 mg/kg was not effective. Prior treatment with chlorisondamine chloride (Fig. 2A) or with 6-OHDA, which selectively destroys sympathetic nerve terminals while sparing adrenal medullary catecholamine-containing cells 19 (Fig. 2B) reversed the protective effect of naloxone, 10 mg/kg. Denervation of the adrenal glands blocked the protective effect of 10 mg/kg naloxone as well as increased shock susceptibility (from 80% mortality in sham-operated mice to 100% mortality in adrenal denervated mice) (Fig. 2C). In previous studies we implicated CNS receptors in naloxone's protective effect in anaphylactic shock in mice, since treatment with the selective, peripherally acting antagonist, naltrexone methyl bromide, was ineffective in improving survival 2.3. The present resuits are consistent with this observation (see Fig. 1). Additionally the results indicate that treatments which compromise SNS function diminish the antianaphylactic effect of naloxone. Collectively, these findings suggest that naloxone's antianaphylactic effect depends on CNS actions which are peripherally mediated by SNS activation. Both the sympathetic
nerve endings and the adrenal medulla are functionally implicated in the protective action since selective destruction of either one of these effectors blocked the response to naloxone. Anaphylactic shock in the mouse results from circulatory collapse which is brought about by loss of effective blood volume into the extravascular space due to dilation of blood vessels and increased capillary permeability z3. This reaction is mediated by histamine, 5-hydroxytryptamine, bradykinin and a slow-reacting substance of anaphylaxis (SRS-A) released from IgE-sensitized mast cells24, and it is accompanied by marked SNS stimulation 1.12.27. The increased sympathetic tone during anaphylaxis may be effective in physiologically opposing the immunological vascular reactions, including the vasodilation and loss of intravascular fluid, produced particularly b y low doses of antigen by increasing cardiac contractility and rate and peripheral vasoconstriction. In recent studies it has been demonstrated that endogenous opiate (endorphin) systems are functionally activated in shock states5,n, 20 and that centrally administrated opiates, including endorphins decrease the sympathetic tone 6,21,26as well as blunt baroreflex responses to physiological stimuli such as acute changes in blood pressure 25. Thus, the natural protection against the immunological vascular reactions and consequent circulatory collapse in anaphylaxis attended by the compensatory increments in sympathetic activity may normally be limited by negative input via released endorphins, which act through CNS sites to decrease sympathetic outflow. Naloxone can reverse the inhibitory effects of endorphins at central sympathetic centers by blocking CNS receptors thus facilitating sympathetic outflow to peripheral sympathetic effectors and improving the physiological compensatory processes in shock. This interpretation is consistent with the finding that i.v. naloxone, either 5 min before or 30 min after induction of systemic anaphylaxis in rats, significantly inhibited the fall in blood pressure associated with shock 24. Two additional points need to be made about the results obtained for naloxone in anaphylactic shock. First, naloxone improves survival in mouse anaphylaxis not only when administered concomitantly with the challenge dose of antigen but also when injected at different times after challenge, i.e. naloxone can
182
A
B
CONTROL
C
CONTROL
CHLORISONOAMINE
SHAM 6-OHDA
ADRENAL DENERVAT ION
>- I 0 0 I--
m
50
0 -
NX
-
NX
-
NX
-
NX
-
NX
-
NX
Fig. 2. The effect of 10 mg/kg naloxone (NX) on anaphylactic mortality in mice pretreated with chlorisondamine chloride (3 mg/kg i.p.) (A); 6-OHDA (50 mg/kg i.v.) (B); or subjected to bilateral adrenal gland denervation (C). Control mice were pretreated with saline (A) or 6-OHDA vehicle (B) or were subjected to a sham operation (C). Naloxone was administered i.v. concomitantly with the challenge dose of BSA (25/~g). The numbers inside the bars indicate the number of animals in each group. Asterisks indicate significant difference from BSA alone (P < 0.05; X2 test for two independent samples). reverse the progression of shock 3. Second, only the effects of low doses of antigen ( < 5 0 ~g) are blocked by naloxone. With higher doses of antigen the protective effect of naloxone (1-10 mg/kg) in mouse anaphylaxis is destroyed (unpublished observations). This further supports the thesis that naloxone's antianaphylactic effect occurs primarily by improving an ongoing physiological (sympathetic) c o m p e n s a t o r y process initiated by the challenging dose of antigen12, 27. Preliminary results suggest that naloxone may facilitate sympathetic outflow by antagonizing an endorphin interaction at sympathetic centers at the hypothalamus since depletion of hypothalamic pools of endorphins (enkephalins, /3-endorphin) by 1 Alho, A., Jaattela, A., Lahdensuu, M., Rokkanen, P., Avikainen, V., Karaharju, E., Tervo, T. and Lepisto, P., Catecholamines in shock, Ann. Clin. Res.. 9 (1977) 157-163. 2 Amir, S., Opiate antagonists improve survival in anaphy-
the neonatal administration of m o n o s o d i u m glutamate protects mice from lethal anaphylaxis 4 as well as blocks the response to naloxone. The possibility that naloxone's beneficial action also involves blockade of the central p a r a s y m p a t h e t i c outflow l0 or alteration in the release of chemical mediators of anaphylaxis from sensitized mast cells ~8.30 is currently under investigation. I would like to thank M. Harel for technical assistance, Dr. E. T h o m a s for helpful comments on the manuscript, E n d o L a b o r a t o r i e s for the gift of natoxone and C I B A - G e i g y for the gift of chlorisondamine chloride. lactic shock, Europ. J. Pharmacol., 80 (1982) 161-162. 3 Amir, S. and Harel, M., Involvement of endorphins in anaphylactic shock in mice, Soc. Neurosci. Abstr., 8 (1982) 227. 4 Amir, S. and Davis, L., Protective effect of neonatal MSG-
183
5
6
7
8 9 10 11 12 13 14
15
16 17
induced arcuate nuclear lesions in anaphylactic shock, Europ. J. Pharmacol., 84 (1982) 237-238. Carr, D. B., Bergland, R., Hamilton, A., Blume, H., Kasting, N., Arnold, M., Martin, J. B. and Rosenblatt, M., Endotoxin-stimulated opioid peptide secretion: two secretory pools and feedback control in vivo, Science, 217 (1982) 845--848. Daskaiopoulos, N. Th., Laubie, M. and Schmitt, H., Localization of the central sympatho-inhibitory effect of a narcotic analgesic agent, fentanyl, in cats, Europ. J. Pharmacol., 33 (1975) 91-97. Dashwood, M. R. and Feldberg, W., Central inhibitory effect of released opiate peptides on adrenal medulla, revealed by naloxone in the cat, J. Physiol. (Lond.), 300 (1979) 22P-23P. Dirksen, R., Wood, G. J. and Nijhuis, G. M. M., Mechanism of naloxone therapy in the treatment of shock: a hypothesis, Lancet, i (1981) 607-608. Faden, A. I. and Holaday, J. W., Opiate antagonists: a role in the treatment of hypovolemic shock, Science, 205 (1979) 317-318. Faden, A. I., Jacobs, T. P. and Holaday, J. W., Endorphin-parasympathetic interaction in spinal shock, J. autonomic Nerv. Syst., 2 (1980) 295-304. Faden, A. I., Jacobs, T. P., Mougey, E. and Holaday, J. W., Endorphins in experimental spinal injury: therapeutic effect of naloxone, Ann. Neurol., 10 (1981) 326-332. Hamberger, B., Fredholm, B. B. and Farnebo, L. O., Anaphylaxis and plasma catechotamines, Life Sci., 26 (1980) 1465-1471. Holaday, J. W. and Faden, A. I., Naloxone reversal of endotoxin hypotension suggests role of endorphins in shock, Nature (Lond.), 275 (1978) 450-451. Holaday, J. W., O'Hara, M. and Faden, A. I., Hypophysectomy alters cardiorespiratory variables: central effects of pituitary endorphins in shock, Amer. J. Physiol., 241 (1981) H479-H485. Holaday, J. W., D'Amato, R. J., Ruvio, B. A. and Faden, A. I., Action of naloxone and TRH on the autonomic regulation of circulation, Advanc. Biochem. Psychopharmacol., 33 (1982) 353-361. Holaday, J. W., Cardiovascular consequences of endogenous opiate antagonism, Biochem. Pharmacol., 32 (1983) 573-585. Janssen, H. F. and Lutherer, L. O., Ventriculocisternal administration of naloxone protects against severe hypotension during endotoxin shock, Brain Research, 194 (1980) 608--612.
18 Johnson, A. R. and Morgan, N. C., Inhibition of the release of histamine from rat mast cells: the effect of cold and adrenergic drugs on release of histamine by 48/80 and antigen, J. Pharmacol. exp. Ther., 175 (1970) 632-640. 19 Kostrzewa, R. M. and Jacobowit, D. M., Pharmacological actions of 6-hydroxydopamine, Pharmacol. Rev., 26 (1974) 199-288. 20 Lang, R. E., Bruckner, U. B., Hermann, K., Kempf, B., Rascher, W., Sturm, V., Unger, Th. and Ganten, D., Effect of hemorrhagic shock on the concomitant release of endorphin and enkephalin-like peptides from the pituitary and adrenal gland in the dog, Advanc. Biochem. Psychopharmacol., 33 (1982) 363-368. 21 Laubie, M., Schmitt, H., Vincent, M. and Remond, G., Central cardiovascular effects of morphinomimetic peptides in dogs, Europ. J. Pharmacol., 46 (1977) 67-71. 22 Lima, A. O., Pharmacologically active substances released during anaphylactic shock in the mouse, Int. Arch. Allergy, 32 (1967) 46-54. 23 Munoz, J. and Bergman, R. K., Mechanism of anaphylactic death in the mouse, Nature (Lond.), 205 (1965) 199-200. 24 Paciorek, P. M. and Todd, M. H., A comparison of the cardiovascular effects of meptazimol and naloxone following anaphylactic shock in anaesthetised rats, Brit. J. Pharma-" col., 76 (1982) 245 p. 25 Petty, M. A. and Reid, J. L., The effect of opiates on arterial baroreceptor reflex function in the rabbit, NaunynSchmiedeberg's Arch. Pharmacol., 319 (1982) 206-211. 26 Petty, M. A., de Jong, A. and de Wied, D., An inhibitory role of fl-endorphin in central cardiovascular regulation, Life Sci., 30 (1982) 1835-1840. 27 Piper, P. J., Collier, H. O. J. and Vane, J. R., Release of catecholamines in the guinea-pig by substances involved in anaphylaxis, Nature (Lond.), 213(1967) 838-840. 28 Schadt, J. C. and York, D. H., The effects of autonomic blockade on the response to naloxone in conscious rabbits made hypotensive by hemorrhage, Fed. Proc., 40 (1981) 522. 29 Wright, D. J. P., The fall in circulating leucocyte and platelet counts after endotoxin: an adrenergic opioid interaction, Neuropeptide, 1 (1981) 181-202. 30 Yamasaki, Y., Shimamura, O., Kizu, A., Nakagawa, M. and Ijichi, H., IgE-mediated 14C-serotonin release from rat mast cells modulated by morphine and endorphins, Life Sci., 31 (1982) 471-478.