Pharmacological FMRI: Measuring Opioid Effects on the BOLD Response to Hypercapnia

Abstract

Opioid binding to the cerebral blood vessels may affect vascular responsiveness and hence confound interpretation of blood oxygen level-dependent (BOLD) responses, which are usually interpreted as neuronal in origin. Opioid binding varies in different brain regions. It is unclear whether opioids alter neurovascular coupling, or whether their effects are purely neuronal. This study used BOLD functional magnetic resonance imaging (FMRI) to investigate the effect of a lopioid agonist remifentanil, on cerebrovascular CO 2 reactivity (being one component of neurovascular coupling). Hypercapnic challenges were delivered to human volunteers, while controlling potential opioid-induced respiratory depression. The BOLD signal increase to hypercapnia was compared before and during remifentanil administration. Remifentanil was shown not to have a generalised effect on CO 2 responsiveness in the cerebral vasculature. However, it caused a significant reduction in the positive BOLD response to hypercapnia in the bilateral primary sensorimotor cortices, bilateral extrastriate visual areas, left insula, left caudate nucleus, and left inferior temporal gyrus. We conclude that remifentanil does not modulate cerebrovascular CO 2 reactivity, as we saw no difference in BOLD response to hypercapnia in areas with high opioid receptor densities. We did however see a focal reduction in areas related to motor control and putative task activation, which we conclude to be related to changes in neuronal activity related to the sedative effects of remifentanil. Our method of controlling CO 2 levels effectively mitigated the potential confound of respiratory depression and allowed comparison over a similar range of CO 2 levels. We suggest that similar methodology should be used when investigating other potentially vasoactive compounds with FMRI.

Finding a way in: A review and practical evaluation of fMRI and EEG for detection and assessment in disorders of consciousness

“…A growing body of evidence shows that many diseases and pathologies -including brain injuries -alter neurovascular coupling and change BOLD signal without necessarily affecting neuronal function Gsell et al, 2000;Krainik et al, 2005;Lindauer et al, 2010;Sakatani et al, 2003Sakatani et al, , 2007. In the same vein, we must also consider that patients with severe brain injuries are usually on several medications, which can also influence neurovascular coupling (Bruhn et al, 2001;Luchtmann et al, 2010;Pattinson et al, 2007;Reinhard et al, 2010). We can attribute changes in BOLD signal to changes in neural activity if and only if signalling and vascular reactivity are not altered; and we can compare between groups (e.g., patients and controls) only if these properties are the same in both groups.…”

Hypercapnia-Induced Cerebral Hyperperfusion: An Underrecognized Clinical Entity

“…4,7,[11][12][13][14][15][16][17][18][19][20][21][22] Most experimental studies of hypercapnia increase pCO 2 through rebreathing techniques or 5% CO 2 air mixtures. These methods result in a mild increase in pCO 2 of approximately 5 to 8 mm Hg.…”

“…However, the opioid influence on the hypercapnic response was evaluated by Pattinson et al, 19 who found that opioids did not modulate the vascular reactivity with regard to blood oxygen level-dependent functional MR imaging signal intensity changes.…”

“…3,4,[7][8][9][10][11][12][13] Techniques such as transcranial Doppler, nuclear medicine positronemission tomography (PET) and single-photon emission CT, angiography, phase-contrast MR imaging, and arterial spinlabeled (ASL) MR perfusion have been used to evaluate the experimental hypercapnic effect on cerebral perfusion. 4,7,[11][12][13][14][15][16][17][18][19][20][21][22][23] It is not uncommon that hospitalized patients can have marked increases in pCO 2 in excess of 30 mm Hg from baseline, both on an acute or on a chronic basis. In a similar fashion, hyperventilation may produce marked hypocapnia.…”

Role of Neuroimaging in Analgesic Drug Development

“…One method of identifying the effects of pharmacologic agents on the properties of vasodilation is a breath holding task. Pattinson et al [52] employed a breath holding task to demonstrate that the hemodynamic response observed was not a global effect and was in fact localized to target regions and were related to neural activity.…”