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.

Earlier reports indicate that morphine provokes cognitive and circulatory defects caused by sepsis. Pharmacologic, histopathologic, and molecular studies were employed in this communication to implicate inflammatory pathways of the hippocampus in this clinically relevant sepsis‐morphine interaction. Sepsis was induced with cecal ligation and puncture and behavioral studies were undertaken 24 hr later. The data showed that the subcutaneous treatment of septic rats with morphine (7 mg/kg, 6 and 24 hr prior to sepsis) caused significant (i) decreases in systolic blood pressure measured by the tail‐cuff plethysmography, and (ii) impairment in cognitive function as revealed by Morris water maze test, new object recognition test, and Y maze test. Such hemodynamic and behavioral anomalies were substantially obliterated after blockade of opioid receptors or inhibition of TNFα with naloxone (0.5 mg/kg) and infliximab (6 mg/kg), respectively. The improvement in cognitive function caused by naloxone or infliximab was paralleled with dramatic falls in serum IL‐1β and diminution in neuronal degeneration and necrosis seen in hippocampal tissues. Immunohistochemical studies revealed that the heightened hippocampal expression of MAPKERK and NFκB observed in the sepsis/morphine‐challenged rats was remarkably reduced upon treatment with naloxone or infliximab. These findings incriminate opioid receptors in the amplified hemodynamic and behavioral sequalae of sepsis and suggest a therapeutic potential for the downregulation of hippocampal MAPKERK/NFκB cascade in offsetting the exaggerated responsiveness to the sepsis/morphine insult.