Figure 2.

Morphine and M3G pharmacokinetics and pharmacodynamics in CD-1 mice (study 1). (A) Mean morphine plasma concentrations versus time in mice treated with saline followed by morphine (saline/MOR) and mice treated with NTX followed by morphine (NTX/MOR). (B) Mean M3G plasma concentrations versus time in mice treated with saline followed by morphine (saline/MOR) and mice treated with NTX followed by morphine (NTX/MOR). (C) Individual morphine (open circle) and M3G (closed circle) plasma concentrations after saline pretreatment versus effect (TWL). To guide the eye, a sigmoid function is fitted through the two data sets. (D) Individual morphine (open circle) and M3G (closed circle) plasma concentrations after NTX pretreatment versus effect (TWL). To guide the eye, an exponential function is fitted through the two data sets. (E) The ratio of the plasma concentrations morphine and M3G (morphine/M3G) versus TWL for animals treated with saline/MOR. There is a clear positive correlation for ratios <0.03 ( r_p = 0.72). At ratios >0.03, no further increase in TWL was observed because of the preset cutoff value of 30 s. The line through the data is a sigmoid fitted to the whole data set (R² = 0.94). Two outliers (open squares) were not taken into account in the analysis. Each data point is one morphine/M3G measurement obtained in one mouse. PK samples were obtained at t = 30, 60, 90 and 120 min after morphine injection. (F) The ratio of the plasma concentrations morphine and M3G (morphine/M3G) versus TWL for animals treated with NTX/MOR. A negative correlation was present with r_p = −0.65. Each data point is one morphine/M3G measurement obtained in one mouse. PK samples were obtained at t = 30, 60, 90 and 120 min after morphine injection.