Vol. 297, Issue 2, 612-619, May 2001

Blockade of Delta Opioid Receptors in the Ventrolateral Periaqueductal Gray Region Inhibits the Fall in Arterial Pressure Evoked by Hemorrhage

Sinan Cavun, Garth E. Resch, Adam D. Evec, Michelle M. Rapacon-Baker and William R. Millington

Department of Basic and Pharmaceutical Sciences, Albany College of Pharmacy, Albany, New York (S.C., W.R.M.); and School of Biological Sciences (G.E.R.) and Medicine (A.D.E., M.M.R.-B.), University of Missouri, Kansas City, Missouri

Severe hemorrhage lowers arterial pressure by suppressing sympathetic activity. The central mechanism that initially triggers the fall in arterial pressure evoked by hemorrhage is not well understood, although opioid neurons are thought to play a role. This study tested the hypothesis that hemorrhagic hypotension is mediated by delta opioid receptors in the ventrolateral periaqueductal gray (vlPAG), a region importantly involved in opioid analgesia. Depressor sites were first identified by microinjecting DL-homocysteic acid (20 nmol/0.1 µl) or -endorphin (0.5 nmol/0.1 µl) into the vlPAG of halothane-anesthetized rats. Consistent with earlier reports, DL-homocysteic acid injection into the caudal vlPAG lowered arterial pressure and heart rate; -endorphin evoked a comparable depressor response, but did not affect heart rate. Naloxone or selective opioid receptor antagonists were subsequently injected into the vlPAG 5 min before hemorrhage (1.9 or 2.5 ml/100 g of body weight over 20 min) was initiated using the same stereotaxic coordinates. Naloxone injection into the caudal vlPAG completely prevented the fall in arterial pressure evoked by hemorrhage. The response was dose-dependent and evident with both fixed volume and fixed pressure hemorrhage. The delta opioid receptor antagonist naltrindole inhibited hemorrhagic hypotension significantly in both conscious and anesthetized rats but mu and kappa receptor antagonists were ineffective. -Endorphin_1-27, an endogenous opioid receptor antagonist, was also significantly inhibitory. Naltrindole was ineffective when injected into the dorsolateral periaqueductal gray and did not influence cardiovascular function in nonhemorrhaged animals. These data support the hypothesis that hemorrhagic hypotension is mediated by delta opioid receptors in the vlPAG.