Activation of peripheral
cannabinoid CB(1) receptors contributes to hemorrhagic
hypotension, and
endocannabinoids produced by macrophages and platelets may be mediators of this effect. A number of studies have provided evidence that functional links exist in the mechanisms of action of
cannabinoids and
opioid peptides; and
opioids too play an important role in the pathophysiology of hemorrhagic
hypotension and
shock. On the other hand,
melanocortin peptides, which are the main endogenous functional antagonists of
opioid peptides, have an antishock effect in animals and humans. Thus, we investigated whether an interaction exists between
endocannabinoids and the endogenous
opioid/antiopioid system also in a condition of
hemorrhagic shock and, particularly, whether the blockade of
cannabinoid CB(1) receptors potentiates the antishock effect of
melanocortins.
Urethane-anesthetized rats were stepwise bled until mean arterial pressure decreased to, and stabilized at, 21-23 mm Hg. In this model of
hemorrhagic shock, which caused the death of all control rats within 30 min after vehicle (
tween 80, 5% in saline) injection, the intravenous (i.v.) bolus injection of the
cannabinoid CB(1) receptor antagonist N-piperidino-5-[4-chlorophenyl]-1-[2,4 dichlorophenyl]-4-methyl-3-pyrazolecarboxamide (
SR141716A) increased mean arterial pressure, pulse pressure, respiratory rate and survival rate in a dose-related manner (0.1-3 mg/kg), an almost complete recovery of mean arterial pressure, pulse pressure and respiratory rate, and 100% survival at the end of the observation period (2 h), occurring with the dose of 3 mg/kg. The
melanocortin ACTH-(1-24) (
adrenocorticotropin) also produced in a dose-related manner (0.02-0.16 mg/kg i.v.) a restoration of cardiovascular and respiratory functions, and increased survival rate, an almost complete recovery and 100% survival at the end of the observation period (2 h) occurring with the dose of 0.16 mg/kg. When a subactive dose of
SR141716A (0.2 mg/kg; 30% survival) was associated with a subactive dose of ACTH-(1-24) (0.02 mg/kg; 12% survival), a complete reversal of the
shock condition was obtained with 100% survival at the end of the 2-h observation period. The present results show that the concurrent inhibition of both endogenous
opioid and
cannabinoid systems produces a reversal of
hemorrhagic shock more effective than that produced by the inhibition of either of them. These data suggest that functional interactions between
endocannabinoids and
opioid/antiopioid are at work also in the pathophysiology of
hemorrhagic shock.