Central and Peripheral Mechanisms Underlying Physiological and Drug-Induced Fluctuations in Brain Oxygen in Freely-Moving Rats.

Eugene A Kiyatkin

doi:10.3389/fnint.2018.00044

Abstract

The goal of this work is to consider physiological fluctuations in brain oxygen levels and its changes induced by opioid drugs. This review article presents, as a comprehensive story, the most important findings obtained in our laboratory by using high-speed amperometry with oxygen sensors in awake, freely moving rats; most of these findings were separately published elsewhere. First, we show that oxygen levels in the nucleus accumbens (NAc) phasically increase following exposure to natural arousing stimuli. Since accumbal neurons are excited by arousing stimuli and NAc oxygen levels increase following glutamate (GLU) microinjections in the NAc, local neural activation with subsequent cerebral vasodilation appears to mediate the rapid oxygen increases induced by arousing stimuli. While it is established that intra-cerebral entry of oxygen depends on brain metabolism, physiological increases in NAc oxygen occurred more rapidly than increases in metabolic activity as assessed by intra-brain heat production. Therefore, due to neural activation and the subsequent rise in local cerebral blood flow (CBF), the brain receives more oxygen in advance of its metabolic requirement, thus preventing potential metabolic deficits. In contrast to arousing stimuli, three opioid drugs tested (heroin, fentanyl and oxycodone) decrease oxygen levels. As confirmed by our recordings in the subcutaneous space, a densely vascularized location with no metabolic activity of its own, these decreases result from respiratory depression with subsequent fall in blood oxygen levels. While respiratory depression was evident for all tested drugs, heroin was ~6-fold more potent than oxycodone, and fentanyl was 10-20-fold more potent than heroin. Changes in brain oxygen induced by respiratory depression appear to be independent of local vascular and blood flow responses, which are triggered, via neuro-vascular coupling, by the neuronal effects of opioid drugs.

Highlights

The brain is one of the heaviest consumers of oxygen in the body (Siesjo, 1978; Rolfe and Brown, 1997) and oxygen consumption increases during neuronal activation (Fox and Raichle, 1986; Fellows and Boutelle, 1993; Attwell et al, 2010)
Due to the critical role of respiratory depression in mediating acute life-threatening effects of opioid drugs, we examined changes in brain oxygen induced by three representative opioids: oxycodone, heroin and fentanyl (Solis et al, 2017b,c, 2018a,b)
Due to fentanyl’s increased potency in terms of inducing respiratory depression (Yeadon and Kitchen, 1990; Dahan et al, 2005; Pattinson, 2008), intake of heroinfentanyl mixtures may result in serious health complications, including comatose state and lethality (Compton et al, 2016; Suzuki and El-Haddad, 2017). To mirror such a real-world scenario, in which an individual believing that he or she is consuming a standard dose of heroin is consuming a heroin sample laced with a smaller amount of fentanyl, we examined changes in nucleus accumbens (NAc) oxygen induced by heroin (0.4 mg/kg) contaminated with 10% fentanyl (0.04 mg/kg)

Summary

Introduction

The brain is one of the heaviest consumers of oxygen in the body (Siesjo, 1978; Rolfe and Brown, 1997) and oxygen consumption increases during neuronal activation (Fox and Raichle, 1986; Fellows and Boutelle, 1993; Attwell et al, 2010). Oxygen entry into brain tissue depends on oxygenation of arterial blood, which is determined by respiratory activity, a highly variable physiological parameter that is affected by activity state, behavior and different drugs. All these dynamic changes in metabolic oxygen consumption and its entry from arterial blood affect extracellular oxygen levels in brain tissue, an important homeostatic parameter critical for maintaining proper neuronal activity and neural functions. Due to these dynamic and potentially opposing influences, it remains unclear how the balance between oxygen consumption and its entry from arterial blood is maintained under physiologically relevant conditions, how it is changed during neural activation elicited by natural arousing stimuli, and how it is affected by drugs which directly affect the CNS and respiration

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Findings

Conclusion