Morphine Aggravates Inflammatory, Behavioral, and Hippocampal Structural Deficits in Septic Rats.

Although pain and sepsis are standard comorbidities of intensive care units, reported data on whether pain control by opioid analgesics could alter inflammatory and end-organ damage caused by sepsis remain contradictory and inconclusive. Here, we tested the hypothesis that morphine, the gold standard narcotic analgesic, modifies behavioral and hippocampal structural defects induced by sepsis in rats. Sepsis was induced with cecal ligation and puncture (CLP) and behavioral studies were undertaken 24 hr later in septic and/or morphine-treated animals. The induction of sepsis or exposure to morphine (7 mg/kg) elicited similar: (i) falls in systolic blood pressure, (ii) alterations in spatial memory and learning tested by the Morris water maze (increases in escape latency, and decreases in time spent on quadrant plate, distance travelled, and number of crossings), and (iii) depression of exploratory behavior measured by the new object recognition test. These hemodynamic and cognitive defects were significantly exaggerated in septic rats treated with morphine compared with individual interventions. Similar patterns of amplified inflammatory (IL-1β) and histopathological signs of hippocampal damage (neuronal degeneration, satellitosis, and neuronophagia) were noted in morphine-treated septic rats. We also show that the presence of intact opioid receptors is mandatory for the elicitation of behavioral and hemodynamic effects of morphine because no such effects were observed after simultaneous blockade of these receptors by naloxone. Together, these findings suggest that morphine acts probably via opioid receptors to provoke sepsis manifestations of inflammation, and behavioral and hippocampal deficits.