Central Inflammatory and Oxidative Signals Contribute to the Morphine Exacerbation of Cardiovascular Hallmarks of Sepsis in Rats

Abstract ID 95481 Poster Board 073 Sepsis remains one of the most serious and possibly fatal complications encountered in intensive care units. Considering the frequent use of narcotic analgesics in this setting, we investigated whether cardiovascular and inflammatory features of sepsis could be modified by morphine. One day prior to cardiovascular assessment, rats were instrumented with femoral and intracisternal (i.c.) indwelling catheters and sepsis was induced by cecal ligation and puncture (CLP). The i.v. administration of morphine (3 and 10 mg/kg) significantly and dose-dependently aggravated septic manifestations of hypotension and cardiac autonomic neuropathy reflected by the reductions in time- and spectral indices of heart rate variability (HRV). The maximal rate of rise of left ventricular pressure (dP/dtmax, a measure of left ventricular contractility) was also reduced by morphine. Such morphine effects were mostly eliminated following (i) blockade of μ-opioid receptors by i.v. naloxone and (ii) inhibition of central PI3K, MAPK-ERK, MAPK-JNK, NADPH oxidase, or Rho-kinase by i.c. wortmannin, PD98059, SP600125, diphenyleneiodonium, and fasudil, respectively. Further, immunohistochemical studies demonstrated that the CLP-evoked upregulation of myocardial expression of toll-like receptor 4 (TLR4) and monocyte chemoattractant protein-1 (MCP1) were accentuated by morphine in a naloxone-sensitive manner. Overall, the worsening effect of morphine on cardiovascular and autonomic derangements caused by sepsis are μ-opioid receptor-dependent and are prompted by inflammatory, chemotactic, and oxidative signals in cardiac and central tissues. Clinical studies are warranted to re-affirm the injurious interaction between narcotic analgesics and the septic challenge.