Central effects of mu, delta, and kappa receptor agonists in hemorrhagic shock

We have recently shown that selective mu-opiate receptor agonists increase blood pressure and heart rate when injected into the anteroventral hypothalamus (AV3V) of the conscious rat, and that lesions of this area may worsen the effects of hypovolemia. These experiments suggested the possibility that mu-agonists might enhance cardiovascular recuperation following acute hemorrhagic shock. Sprague-Dawley rats (250-300 g) were prepared with indwelling polyethylene catheters (under halothane anesthesia) in both femoral arteries, and a guide cannula to allow intrahypothalamic injections. Twenty-four hours after surgery, animals were made hypovolemic by withdrawing arterial blood (8.5 ml/300 g) over a 5 min period. After the bleeding, 0.9% NaCl or D-Ala2-D-Leu5-enkephalin (DADL; delta-agonist), D-Ala2-MePhe4-Gly-ol-enkephalin (DAGO; mu-agonist) and U-50488H (trans(+)-dichloro-N-methyl-N-(2-[1-pryodynyl])-benzene-acetami ne, methane-sulfate hydrate) (kappa-agonist) were injected in 1 microliter volume into the AV3V. Hemodynamic parameters were followed for 2 hr. Neither DADL nor U-50488H affected the blood pressure and heart rate responses to hemorrhage. In contrast, the mu-opiate receptor agonist, DAGO, enhanced the recovery of blood pressure and stimulated the heart rate. These data suggest that specific mu-opiate receptor agonists might possess beneficial effects in shock and trauma by enhancing cardiovascular recuperation through centrally-mediated mechanisms.