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Morphine remains widely used in clinical settings due to its potent analgesic properties. However, one of the gravest risks of all opioids is their ability to induce respiratory depression and subsequent brain hypoxia that can lead to coma and death. Due to these life-threatening effects, our goal was to examine the effects of intravenous (iv) morphine at a wide range of doses (0.1-12.8 mg/kg) on changes in brain oxygen levels in freely-moving rats. We employed oxygen sensors coupled with high-speed amperometry and conducted measurements in the nucleus accumbens (NAc) and subcutaneous (SC) space, the latter serving as a proxy for blood oxygen levels that depend on respiratory activity. Morphine induced dose-dependent decreases in SC oxygen levels, suggesting respiratory depression, but differential effects on NAc oxygen: increases at low and moderate doses (0.1-1.6 mg/kg) and decreases at high doses (6.4 mg/kg). We also examined the effects of morphine on NAc, muscle, and skin temperature. Morphine increased brain temperature at low and moderate doses but induced a biphasic, down-up change at high doses. The oxygen increases appear to result from a neurovascular coupling mechanism via local vasodilation and enhanced oxygen entry into brain tissue to compensate for blood oxygen drops caused by modest respiratory depression. At high morphine doses, this adaptive mechanism is unable to compensate for the enhanced respiratory depression, resulting in brain hypoxia. Hence, morphine appears to be safe when used as an analgesic at clinically relevant doses, but poses great risks when abused at high doses.

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