Abstract
While it is known that opioid receptors (ORs) are densely expressed in both the brain and periphery, it is widely accepted that hypoxic effects of opioids result solely from their direct action in the CNS. To examine the role of peripheral ORs in triggering brain hypoxia, we used oxygen sensors in freely moving rats to examine how naloxone-HCl and naloxone-methiodide, the latter which is commonly believed to be peripherally restricted, affect brain oxygen responses induced by intravenous heroin at low, human-relevant doses. Similar to naloxone-HCl, naloxone-methiodide at a relatively low dose (2 mg/kg) fully blocked heroin-induced decreases in brain oxygen levels. As measured by mass spectrometry, naloxone-methiodide was found to be ~40-fold less permeable than naloxone-HCl across the blood-brain barrier, thus acting as a selective blocker of peripheral ORs. Despite this selectivity, a low but detectable amount of naloxone was found in brain tissue after naloxone-methiodide administration, potentially influencing our results. Therefore, we examined the effects of naloxone-methiodide at a very low dose (0.2 mg/kg; at which naloxone was undetectable in brain tissue) and found that this drug still powerfully attenuates heroin-induced brain oxygen responses. These data demonstrate the role of peripheral ORs in triggering heroin-induced respiratory depression and subsequent brain hypoxia.
Highlights
Respiratory depression that leads to brain hypoxia appears to be the most dangerous effect of opioid drugs[1,2,3,4,5]
Since our liquid chromatography-mass spectrometry (LC-MS) experiment revealed no detectable amounts of naloxone or methyl-naloxone after the injection of naloxone-MET at a low dose, we conducted an additional experiment, in which we examined whether heroin-induced nucleus accumbens (NAc) oxygen responses (0.1 mg/kg) would be affected by sc administration of naloxone-MET at a lower dose (0.24 mg/kg), the molar equivalent to naloxone HCl at 0.2 mg/kg
In contrast to most studies focused on ventilation aspects of respiration or changes in O2 in peripheral blood, the use of oxygen sensors coupled with high-speed amperometry allowed us to directly monitor heroin-induced changes in brain oxygen levels and quantitatively assess brain hypoxia—the functional output of respiratory activity and a clinically relevant parameter
Summary
Respiratory depression that leads to brain hypoxia appears to be the most dangerous effect of opioid drugs[1,2,3,4,5]. It is generally believed that respiratory depression results from the direct interaction of opioid drugs with opioid (mainly μ) receptors (ORs) expressed on brainstem neurons of the breathing center as well as other central neurons[6,7,8,9] This basic mechanism has solid experimental support: respiratory activity has been shown to rapidly decrease following intracerebral, intercisternal, and local intra-brain microinjections of various opioid agonists[10,11,12]. Naloxone-HCl, a highly potent non-selective opioid antagonist that crosses the BBB and interacts with both centrally and peripherally located ORs, fully blocks respiratory depression as well as other physiological and behavioral effects of morphine, heroin and fentanyl[7]. This three-point temperature-recording paradigm makes it possible to evaluate the effects of drugs on brain metabolic activity and peripheral vascular tone[32]
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