Acute opioid effects on human brain as revealed by functional magnetic resonance imaging
Introduction
Exogenous opioids are used as analgesics. Their main adverse effects include sedation, respiratory depression, euphoria or dysphoria, nausea, and impaired cognitive function. The opioid system is also involved in the modulation of emotions, anxiety, reward, stress, learning, and memory acquisition. The physiological effects of opioids are mediated by activation of mu, delta, and kappa opioid receptors throughout the central and peripheral nervous systems. Post-mortem auto-radiographic and positron emission tomography (PET) studies in humans have shown that the highest densities of mu-opioid receptors are found in the cingulate cortex, thalamus, periaqueductal gray, and caudate nucleus (Cross et al., 1987, Frost et al., 1985). The stimulation of opioid receptors further activates cholinergic, adrenergic, and dopaminergic neurotransmitter systems (Chiang and Zhuo, 1989, Hagelberg et al., 2004, Jackisch et al., 1986).
Modulation of neuronal activation by opioids has previously been studied with PET. The effects of a single intravenous fentanyl bolus (Firestone et al., 1996), fentanyl analgesia (Adler et al., 1997), remifentanil infusions of different doses (Wagner et al., 2001), and remifentanil analgesia (Petrovic et al., 2002) have caused significant changes in regional cerebral blood flow particularly in the anterior cingulate and orbitofrontal cortices. These areas have also been activated by pain, modulation of pain by hypnosis, and placebo analgesia (Baron et al., 1999, Iadarola et al., 1998, Petrovic et al., 2002, Rainville et al., 1997, Tölle et al., 1999).
Functional magnetic resonance imaging (fMRI) has been widely used to study brain activation induced either by specific sensory stimulation or motor or cognitive task performance. Recently, fMRI has also been used to analyze local changes in human brain activity resulting from drug administration. The term pharmacological MRI (phMRI) has been introduced (Honey and Bullmore, 2004). Most of the phMRI studies have combined the administration of a drug with cognitive task performance or sensory stimulation (Jokeit et al., 2001, Wise et al., 2004). The actual effects of a drug on brain activation in the absence of other modulating factors have been investigated only in a couple of phMRI studies. All such studies have been conducted in addicts using psychoactive drugs, e.g. cocaine (Breiter et al., 1997) and nicotine (Stein et al., 1998).
Pharmacokinetics present a particular challenge to fMRI studies of drug-induced changes in neuronal activation. Remifentanil is a potent ultra-short acting mu-opioid receptor agonist (Rosow, 1999) that can be administered as repetitive intravenous boluses during one imaging period. In the present study, we used fMRI to assess the magnitude and distribution of brain activation caused by remifentanil. The specific aim was to analyze the time course of the drug-induced blood oxygen level dependent (BOLD) signal intensity changes. The study was conducted in healthy, non-addict subjects in the absence of sensory stimuli such as pain or abstinence symptoms and craving of drugs that may activate the same brain areas as opioids. We anticipated that remifentanil modulates the activation of brain areas that are known to have a high density of opioid receptors. We also expected to see some effects in brain areas that have been implicated to have a role in the processing of pain.
Section snippets
Materials and methods
The study protocol was approved by the ethics committee of the Department of Surgery at the Helsinki University Central Hospital and by the Finnish National Agency for Medicines.
Behavioral pretests
In two of the eight subjects, remifentanil injections caused a short lasting and transient respiratory depression both in the behavioral pretest and in the fMRI. During fMRI, the blood oxygen saturation (SpO2) decreased to the lowest level of 88% in these subjects. Excessive head movement (over 2 mm) during the fMRI of these two subjects leads to their exclusion from the analysis.
In the remaining six subjects, changes in the arterial blood pressure and SpO2 were negligible during the behavioral
Discussion
Pharmacological fMRI is becoming an exciting method to study the effects of psychoactive drugs in different patient groups. The opioid system is particularly interesting as it modulates several physiologic functions including mood, learning, reward, and analgesia. It has been suggested to play a role in several disorders such as depression, anxiety, chronic pain, and addictive behavior. The function of the opioid system is affected by gender and several genetic polymorphisms, the polymorphism
Conclusion
For the first time, we have used fMRI to report spatially and temporally detailed information after opioid administration in the absence of behavioral tasks or experimentally induced sensory or motor stimulation. This study sets basis for further research exploring functional changes in the opioid system resulting from genetic differences and/or disease or treatment.
Acknowledgments
The study was supported by grants from The Helsinki University Hospital Research Funds (TYH 2232), The Sigrid Jusélius Foundation, and The Academy of Finland (grant no. 201955).
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