Septic shock I is one of the leading cause of death in hospitalized patients and mortality rates of up to 50% have been reported. Despite all efforts, no regimen today seems to be successful in the treatment of septic shock. The endogenous opioid
system
(EOS) includes three major families of peptides: dynorphins, endorphins and enkephalins. Several lines of evidence indicate that EOS is implicated in the pathophysilogy of anaphylactic and endotoxic shock. An opioid receptor blocker naloxone has
been
used extensively in studies for the role of EOS or endogenous opiod peptides (EOP). However, there have been few, if any, detailed investigative studies regardingthe effect of naloxone on TNF-α production and the lethality in response to
endotoxin, and
tumorigenesis. The aim of this study was to evaluate the involvement of EOP in the endotoxic shock as well as anaphylactic shock, and tumorigenesis by i.p administration anloxone 50 ㎍ per mouse prior to and/or after the administration of
Klebsiella
pneumoniae O3 lipopolysaccharide (KO3 LPS). The ICR mice were injected i.v. with KO3 LPS 250 ㎍ or 300 ㎍ per mouse. In addition, since it has been proposed that the production of platelet activating factor (PAF) and nitric oxide (NO)in response
to
LPS
regulates an important aspects of septic shock, effects of both a PAF antagonist, BN 50739 and an inhibitor of NO production, NG-monomethyl-L-arginine(NGMMA) on endotoxin induced shock were also investigated. A single i.p. administration of
naloxone 25
㎍ or 50 ㎍ per mouse 15 min prior to KO3 LPS challenge protected significantly from endotoxic shock and the protective effect of 50 ㎍ naloxone was much more pronounced than 25 ㎍ naloxone administration. Naloxone when given 50 ㎍ 15 min, 30 min
or 60
min prior to or after KO3 LPS challenge protected significantly from LPS-induced shock and the protective affect of naloxone given 15 min before or after KO3 LPS challenge was again much more pronounced than that of naloxone given 30 min before
or
after
LPS challenge. Interestingly, a sigle i.p. administration of 50 ㎍ naloxone 15 min of 30 min before KO3 LPS challenge caused significant inhibition of serum TNF-α production. It is also confirmedthat a single intraperitoneal administration of 50
㎍
naloxne 15 min or 30 min before shock induction with ovalbuin suppressed fatal active systemic anaphylaxis. Surprisingly, naloxone administration (50㎍ or 100㎍ per mouse) into mice at various time before and after i.v. injection of B16 melanoma
cells(5×10E5) caused the inhibition of growth of melanoma in the lungs. A single intravenous injection of a PAF receptor antagonist BN 50739 (200 ㎍ per mouse) 30 min or 60 min before KO3 LPS challenge greatly improved the survival rate of mice
and had
a long duration (48 hr) of action. A single i.v. administration of 600㎍ of NGMMA 60 min before KO3 LPS injectio significantly increased the survival rate. The present restults regarding PAF antagonist and NO production suggest that PAF and NO
may
play
an important role in LPS-induced shock and that BN 50739 and NGMMA may be an effective preventive drug for endotoxic shock. The pathogenic mechanism of septic shock appears to be vary complex and factors other than EOP are also important in
pathology of
septic shock. Taken together, the present studies demonstrated that naloxone inhibited TNF-α production and protected mice from KO3 LPS-induced shock as well as OVA-induced active systemic anaphylaxis. Naloxone also surprisingly inhibitedthe
growth o
B16 melanoma. BN 50739 and NGMMA significantly protected mice from KO3LPS-induced shock. These observations implied that EOP, TNF-α, PAF and NO may play critical role in the pathophysiology of endotoxic shock, and that naloxone, BN 50739 and
NGMMA
may
be useful in the prevention and treatment of lifetheratning septic shock andtumorigenesis.
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