Interactions of benzodiazepines with heroin: Respiratory depression, temperature effects, and behavior

Abstract

Benzodiazepines are important therapeutic drugs, but they are often abused and co-abused with opioids. Clinical evidence suggests that benzodiazepines can inhibit respiration, and when combined with the respiratory-depressive effects of opioids, may increase likelihood of death. In this study we used oxygen sensors coupled with high-speed amperometry and multi-site thermorecording to examine how intravenous (iv) midazolam, a potent benzodiazepine, modulates the brain hypoxic and temperature effects of iv heroin in freely-moving rats. Oxygen levels and brain temperature were assessed with high temporal resolution in the nucleus accumbens (NAc), an important structure in the motivational-reinforcement circuit. When administered alone, midazolam (2 mg/kg) modestly decreased NAc temperature but had no evident effects on oxygen levels in this structure. In contrast, heroin (0.4 mg/kg) induced a strong decrease in NAc oxygen that was followed by a weaker, rebound-like oxygen increase. Midazolam pretreatment did not affect heroin-induced brain hypoxia but potentiated the initial hypothermia induced by heroin. However, co-administration of these drugs potentiated the heroin-induced oxygen decrease and enhanced heroin-induced brain hypothermia. Co-administration of heroin and midazolam also resulted in enhanced locomotor inhibition and loss of motor control. This effect caused some rats to collapse, resulting in nose and mouth occlusion, which caused a secondary hypoxic phase. These results could have important implications for human drug users, as the combined use of benzodiazepines with potent opioids not only results in sustained brain hypoxia but creates conditions of loss of motor control which could result in asphyxia and death. This article is part of the Special Issue entitled 'New Vistas in Opioid Pharmacology'.

Keywords: Brain hypoxia; Midazolam; Nucleus accumbens; Opiates; Rats; Vasoconstriction/vasodilation.

Figure 1

Mean (±SEM) changes in NAc oxygen levels (in percent vs. pre-injection baseline=100%) induced by iv administration of midazolam or saline (A) and heroin injected one hour after midazolam or saline (B). Filled symbols indicate values significantly different from pre-injection baseline (time=0) shown as black horizontal dotted lines. Vertical black lines indicate the moment of injection. C shows differences in the initial oxygen decreases (0–16 min) and subsequent increases (16–40 min) induced by heroin in the two treatment groups. These data were calculated as mean (±SEM) area under the curve in each treatment group and compared using Student’s t-test.

Figure 2

Mean (±SEM) changes in temperature, temperature differentials, and locomotion induced by iv administration of midazolam (A-C) and heroin injected one hour after saline (D-F) or midazolam pretreatment (G-I). Filled symbols indicate values significantly different from pre-injection baseline (time=0), shown as black horizontal dotted lines. Vertical black lines indicate the moment of injection. Red dotted line (G) shows the pre-heroin baseline established after midazolam injection. Horizontal dotted lines in the locomotion graphs show mean locomotion for 10 min preceding drug injection.

Figure 3

Mean (±SEM) changes in temperature, temperature differentials, and locomotion induced by co-administration of midazolam and heroin. Filled symbols indicate values significantly different from pre-injection baseline (time=0) shown as black horizontal dotted lines. Horizontal dotted line in bottom graph shows mean locomotion for 10 min preceding drug injection.

Figure 4

Mean (±SEM) changes in NAc oxygen levels (in percent vs. pre-injection baseline=100%) induced by iv administration of heroin and its co-administration with midazolam (A). Filled symbols indicate values significantly different from the pre-injection baseline and the bold horizontal line shows significant between-treatment differences. C shows differences in the initial oxygen decreases (0–12 min) and subsequent increases (12–40 min) induced by heroin in the two treatment groups. These data were calculated as mean (±SEM) area under the curve in each treatment group and compared using Student’s t-test. Asterisk shows significant between-treatment differences assessed in the areas under the curves (p<0.05).

Figure 5

Original records of changes in Nac oxygen levels (A-C; shown in μM) and temperature parameters (D, E) induced by co-administration of midazolam and heroin (black arrow). A and B show two examples of oxygen changes, with the appearance of spontaneous, secondary oxygen decreases (blue arrow). C shows a similar example, when the rat was manually touched (grey arrow) when oxygen levels spontaneously decreased to very low levels. D and E show changes in temperatures in three recording locations and changes in brain-muscle and skin-muscle temperature differentials in the rat (DP8), which was injected with midazolam + heroin and died during the recording. Red asterisk in D and E shows the moment of full cessation of breathing.