Functional magnetic resonance imaging studies of opioid receptor-mediated modulation of noxious-evoked BOLD contrast in rats

Shah, Yasmene B.; Haynes, L.E; Prior, M. J. W.; Marsden, C.A.; Morris, Peter G.; Chapman, Victoria

doi:10.1007/s00213-005-2214-6

Cited by 47 publications

(45 citation statements)

References 52 publications

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“…Our results for morphine appear to contradict those obtained in a recent study using BOLD signal (Shah et al, 2005), but it is more difficult to relate our results to patterns of heroininduced brain stimulation. IV heroin is metabolized to both morphine and 6-acetylmorphine, and the latter acts more like a high-efficacy MOR agonist of the fentanyl class than like morphine (Selley et al, 2001).…”

Section: Spatial Distribution Of Fcbv Changescontrasting

confidence: 57%

“…Functional MRI in rats using restricted brain coverage has produced disparate results for this class of drugs. Morphine has been reported to induce positive changes in BOLD signal (Shah et al, 2005), in apparent contradiction with decreased glucose metabolism observed in another study (Cohen et al, 1991). Heroin produced predominantly negative changes in BOLD signal, with some positively responding voxels in cortex (Xi et al, 2002).…”

Section: Introductionmentioning

confidence: 43%

“…These studies employed mechanical ventilation to minimize changes in PaCO2, because opiates are known to depress respiration, which would produce non-specific increases of blood flow, blood volume, and BOLD signal in free-breathing animals due to elevated levels of arterial carbon dioxide. A recent study in free-breathing rodents found that intraperitoneal injection of 5 mg/ kg morphine induced positive changes in BOLD signal (Shah et al, 2005), which could result from respiratory depression. BOLD signal is particular susceptible to contamination by changes in arterial CO2 concentration, because hypercarbia does not affect oxygen utilization; hypercarbia-induced increases in BOLD signal are roughly twice as large as those due to neuronal activation for matched changes in blood flow (Hoge et al, 1999).…”

Section: Systemic Physiologymentioning

confidence: 99%

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Remifentanil administration reveals biphasic phMRI temporal responses in rat consistent with dynamic receptor regulation

et al. 2007

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Many pharmacological stimuli influence multiple neurotransmitter systems in the brain, and the dynamics of the functional brain response can vary regionally. In this study, the temporal response of cerebral blood volume (CBV) was employed to spatially segment cerebral effects due to infusion of a potent mu-opioid receptor agonist. Repeated intravenous injection of 10 ug/kg remifentanil in rats caused reproducible regional positive, negative, and biphasic changes in CBV. Three temporal processes were identified in the cerebral response and analyzed within the framework of the general linear model. Firstly, a slow component identified CBV changes that were almost exclusively negative, and the spatial distribution was similar to the inhibition produced by morphine (200 ug/ kg). The largest CBV reductions occurred in caudate, accumbens, ventral hippocampus, cingulate, and piriform cortex. Secondly, a more rapid temporal component corresponded primarily with a regional distribution of positive changes in CBV consistent with GABAergic inhibition of hippocampal interneurons and associated projections. Thirdly, a response with the dynamics of mean arterial blood pressure correlated positively with CBV changes in hypothalamus, consistent with a central mechanism for control of blood pressure. We propose that the dominant source of the temporal variance in signal is dynamic modulation of drug targets by receptor endocytosis, an established effect in vitro. These results suggest that the temporal response of fMRI signal reflects underlying neurobiological processes, so that temporal decomposition strategies may aid interpretation of pharmacological mechanisms by identifying interconnected regions or those associated with common neural targets and processes.

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Section: Spatial Distribution Of Fcbv Changescontrasting

confidence: 57%

Section: Introductionmentioning

confidence: 43%

Section: Systemic Physiologymentioning

confidence: 99%

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Remifentanil administration reveals biphasic phMRI temporal responses in rat consistent with dynamic receptor regulation

et al. 2007

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“…One parameter that may affect the magnitude of BOLD responses is abrupt changes of blood pressure (Kalisch et al, 2001;Tuor et al, 2002). Gradual changes that remain within the range of effective cerebral autoregulation are less likely to be associated with BOLD signal alterations (Zaharchuk et al, 1999;Shah et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

Blood Oxygenation Level-Dependent Visualization of Synaptic Relay Stations of Sensory Pathways along the Neuroaxis in Response to Graded Sensory Stimulation of a Limb

Lilja

Endo

Hofstetter

et al. 2006

Journal of Neuroscience

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Blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging (fMRI) was used to test at which levels of the neuroaxis signals are elicited when different modalities of sensory information from the limbs ascend to cortex cerebri. We applied graded electric stimuli to the rat hindlimbs and used echo-planar imaging to monitor activity changes in the lumbar spinal cord and medulla oblongata, where primary afferents of painful and nonpainful sensation synapse, respectively. BOLD signals were detected in ipsilateral lumbar spinal cord gray matter using sufficiently strong stimuli. Using stimuli well below the threshold needed for signals to be elicited in the spinal cord, we found BOLD responses in dorsal medulla oblongata. The distribution of these signals is compatible with the neuroanatomy of the respective synaptic relay stations of the corresponding sensory pathways. Hence, the sensory pathways conducting painful and nonpainful information were successfully distinguished. The fMRI signals in the spinal cord were markedly decreased by morphine, and these effects were counteracted by naloxone. We conclude that fMRI can be used as a reliable and valid method to monitor neuronal activity in the rat spinal cord and medulla oblongata in response to sensory stimuli. Previously, we also documented BOLD signals from thalamus and cortex. Thus, BOLD responses can be elicited at all principal synaptic relay stations along the neuroaxis from lumbar spinal cord to sensory cortex. Rat spinal cord fMRI should become a useful tool in experimental spinal cord injury and pain research.

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“…fMRI studies in animals are also being used to examine effects of analgesics. For example, treatment of the paw with formalin produced bilateral increases in cerebral blood flow in somatosensory cortex, cingulate, and the periaqueductal gray area in rats, and pretreatment with morphine attenuated these formalin-induced fMRI effects (Shah et al, 2005). Morphine also blocked pain-associated fMRI responses to electrical stimulation and injection of capsaicin (Tuor et al, 2000;Malisza and Docherty, 2001).…”

Section: Downloaded Frommentioning

confidence: 99%

Preclinical Assessment of Candidate Analgesic Drugs: Recent Advances and Future Challenges

Negus

Vanderah²,

Brandt

et al. 2006

J Pharmacol Exp Ther

219

201

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In analgesic drug development, preclinical procedures are widely used to assess drug effects on pain-related behaviors. These procedures share two principal components: 1) a manipulation intended to produce a pain-like state in the experimental subject and 2) measurement of behaviors presumably indicative of that pain state. Drugs can then be evaluated for their ability to attenuate pain-related behaviors. In the simplest procedures, the pain state is produced by delivery of an acute noxious stimulus (e.g., a warm thermal stimulus), and the primary dependent measures focus on withdrawal responses or other nocifensive behaviors that increase in rate, frequency, or intensity in response to the noxious stimulus. This approach has been refined in two ways. First, new methods have been developed to induce more clinically relevant pain states. In particular, pain requiring clinical intervention is often associated with inflammation or neuropathy, and novel procedures have emerged to model these conditions and their ability to produce hypersensitive pain states, such as allodynia and hyperalgesia. Second, studies are incorporating a broader array of painrelated behaviors as dependent measures. For example, pain not only stimulates nocifensive behaviors but also suppresses many adaptive behaviors, such as feeding or locomotion. Measures of pain-suppressed behaviors can provide new insights into the behavioral consequences of pain and the effects of candidate analgesics. In addition, functional magnetic resonance imaging has emerged as a noninvasive tool for investigating changes in neural activity associated with pain and analgesia. Integration of these complementary approaches may improve the predictive validity of analgesic drug development.

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Functional magnetic resonance imaging studies of opioid receptor-mediated modulation of noxious-evoked BOLD contrast in rats

Abstract: Our data demonstrate that morphine modulates noxious-evoked changes in signal intensity in discrete brain regions. fMRI studies in rats are able to identify specific brain regions involved in the pharmacological modification of physiologically evoked changes in regional brain activation.

Cited by 47 publications

References 52 publications

Remifentanil administration reveals biphasic phMRI temporal responses in rat consistent with dynamic receptor regulation

Remifentanil administration reveals biphasic phMRI temporal responses in rat consistent with dynamic receptor regulation

Blood Oxygenation Level-Dependent Visualization of Synaptic Relay Stations of Sensory Pathways along the Neuroaxis in Response to Graded Sensory Stimulation of a Limb

Preclinical Assessment of Candidate Analgesic Drugs: Recent Advances and Future Challenges

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