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ANESTHETIC PHARMACOLOGY

Morphine Attenuates Microvascular Hyperpermeability via a Protein Kinase A-Dependent Pathway

Rudolph Puana, MD^*, Russell K. McAllister, MD^*, Felicia A. Hunter, BS, Julie Warden, MD^*, and Ed W. Childs, MD

From the Departments *Anesthesiology and Surgery, Scott and White Clinic and Memorial Hospital, Scott, Sherwood and Brindley Foundation, Texas A&M Health Science Center College of Medicine, Temple, Texas.

Address correspondence and reprint requests to Ed Childs, MD, Associate Professor of Surgery, Scott and White Memorial Hospital, 2401 S. 31st St., Temple, TX 76508. Address e-mail to echilds{at}swmail.sw.org.

BACKGROUND: A recently published study from our laboratory demonstrated that morphine sulfate (MS) attenuates microvascular hyperpermeability after hemorrhagic shock in rats.

MS binds to the µ receptors located on the surface of endothelial cells. Activation of the endothelial cell µ receptors has been shown by several investigators to stimulate adenylate cyclase. We hypothesize that MS binding to the µ receptor on endothelial cells increases cyclic adenosine monophosphate via adenylate cyclase activation. Cyclic adenosine monophosphate inhibits the phosphoinositide/MAP kinase hyperpermeability pathway via the protein kinase A (PKA)-dependent inhibition of Raf-1.

METHODS: Studies were conducted in five groups of urethane-anesthetized Sprague-Dawley rats: Group 1—control group, Group 2—a non–receptor-blocking adenylate cyclase inhibitor: SQ22536, at 100 µg/kg (n = 5), Group 3—a PKA inhibitor: H89, at 10 µg/kg, Group 4—a morphine sulfate (10 µg/kg) and PKA inhibitor group, and Group 5—an adenylate cyclase inhibited and morphine (10 µg/kg) group. Intravital microscopy in mesenteric postcapillary venules and rat lung microvascular endothelial cell monolayers were used to measure permeability.

RESULTS: Adenylate cyclase and PKA inhibition resulted in vascular hyperpermeability.

CONCLUSION: Our data demonstrated an increase in vascular hyperpermeability after inhibition of adenylate cyclase via SQ22536, a nonreceptor inhibitor. This increase in hyperpermeability was attenuated when treated with MS. Morphine did not attenuate hyperpermeability after blockage following PKA with H89 suggesting the action of MS is upstream of PKA and PKA dependent.