Opposing mechanisms underlying differential changes in brain oxygen and temperature induced by intravenous morphine

Abstract

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 morphine at a wide range of doses (0.1-6.4 mg/kg) on changes in brain oxygen levels in freely moving rats. We used 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. We also examined the effects of morphine on NAc, muscle, and skin temperature. 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 the highest dose tested (6.4 mg/kg). Morphine also 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 at high doses, likely to be abused by drug users. NEW & NOTEWORTHY With the use of oxygen sensors coupled with amperometry, we show that morphine induces differential effects on brain oxygen levels, slightly increasing them at low doses and strongly decreasing them at high doses. In contrast, morphine dose dependently decreases oxygen levels in the SC space. Therefore, morphine engages opposing mechanisms affecting brain oxygen levels, enhancing them through neurovascular coupling at low, clinically relevant doses and decreasing them due to dramatic respiratory depression at high doses, likely to be abused.

Keywords: metabolism; neurovascular coupling; nucleus accumbens; opioids; oxygen electrochemistry; rats.

Fig. 1.

Mean (±SE) changes in oxygen levels in the nucleus accumbens (NAc; A) and subcutaneous (SC) space (B) induced by intravenous administration of morphine at a wide range of doses. Closed symbols show values significantly different from preinjection baseline values. Vertical, dotted lines (at 0 min) show the moment of drug injection; n = number of cases averaged to produce mean. Horizontal, dotted lines (at 100%) show preinjection oxygen levels. C: the relationships between changes in NAc and SC oxygen levels. Red symbols show initial values, and purple symbols show values up to the peak of the oxygen response.

Fig. 2.

Original records of changes in electrochemical currents detected in the nucleus accumbens (NAc) and subcutaneous (SC) space by oxygen sensors during intravenous injections of morphine (1.6 and 6.4 mg/kg) in freely moving rats (identified as ES117, -121, and -123). Original data were collected with 1 s time resolution, inverted in polarity, and calibrated in concentration values (in micromolars), based on sensor sensitivity determined in vitro. Note that basal current values and respective oxygen concentrations in the SC space are larger than those in the NAc.

Fig. 3.

Mean (±SE) changes in temperature in the nucleus accumbens (NAc), temporal muscle, and skin (top row), temperature differentials (middle row), and locomotor activity (bottom row) induced by intravenous administration of morphine at a wide range of doses. Closed symbols show values significantly different from preinjection baseline values. Vertical, dotted lines (at 0 min) show the moment of drug injection; n = number of cases averaged to produce mean. Horizontal, dotted lines show baseline values of temperature or locomotion.

Fig. 4.

Time-dependent correlative relationships between changes in nucleus accumbens (NAc) temperature and NAc-muscle and skin-muscle temperature differentials following intravenous morphine administration at 1.6 (A) and 12.8 (B) mg/kg doses. Each graph shows coefficients of correlation and regression lines calculated for different time intervals following the onset of morphine injection (black circles). Closed symbols show values up to the nadir of NAc temperature response.

Fig. 5.

Time-dependent correlative relationships between changes in nucleus accumbens (NAc) oxygen and 3 temperature parameters following intravenous morphine administration at 1.6 and 6.4 mg/kg doses. A and D: NAc temperature; B and E: NAc-muscle differential; C and F: skin-muscle differential. Values up to the peak of the oxygen increase (A–C) or peak of oxygen decrease (D–F) are shown as red symbols. Each graph shows coefficients of correlation and regression lines calculated for different time intervals following the onset of morphine injection. See text for additional explanations.