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Clinical Trial
. 2013;8(1):e50169.
doi: 10.1371/journal.pone.0050169. Epub 2013 Jan 8.

Pain facilitation brain regions activated by nalbuphine are revealed by pharmacological fMRI

Robert Gear  1 , Lino Becerra, Jaymin Upadhyay, James Bishop, Diana Wallin, Gautam Pendse, Jon Levine, David Borsook
Affiliations
Clinical Trial

Pain facilitation brain regions activated by nalbuphine are revealed by pharmacological fMRI

Robert Gear et al. PLoS One. 2013.

Abstract

Nalbuphine, an agonist-antagonist kappa-opioid, produces brief analgesia followed by enhanced pain/hyperalgesia in male postsurgical patients. However, it produces profound analgesia without pain enhancement when co-administration with low dose naloxone. To examine the effect of nalbuphine or nalbuphine plus naloxone on activity in brain regions that may explain these differences, we employed pharmacological magnetic resonance imaging (phMRI) in a double blind cross-over study with 13 healthy male volunteers. In separate imaging sessions subjects were administered nalbuphine (5 mg/70 kg) preceded by either saline (Sal-Nalb) or naloxone 0.4 mg (Nalox-Nalb). Blood oxygen level-dependent (BOLD) activation maps followed by contrast and connectivity analyses revealed marked differences. Sal-Nalb produced significantly increased activity in 60 brain regions and decreased activity in 9; in contrast, Nalox-Nalb activated only 14 regions and deactivated only 3. Nalbuphine, like morphine in a previous study, attenuated activity in the inferior orbital cortex, and, like noxious stimulation, increased activity in temporal cortex, insula, pulvinar, caudate, and pons. Co-administration/pretreatment of naloxone selectively blocked activity in pulvinar, pons and posterior insula. Nalbuphine induced functional connectivity between caudate and regions in the frontal, occipital, temporal, insular, middle cingulate cortices, and putamen; naloxone co-admistration reduced all connectivity to non-significant levels, and, like phMRI measures of morphine, increased activation in other areas (e.g., putamen). Naloxone pretreatment to nalbuphine produced changes in brain activity possess characteristics of both analgesia and algesia; naloxone selectively blocks activity in areas associated with algesia. Given these findings, we suggest that nalbuphine interacts with a pain salience system, which can modulate perceived pain intensity.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Drug administration protocol.
After the initial anatomical scans were obtained, either naloxone or saline was infused for Scan 1; for Scan 2 the other drug was infused. Nalbuphine infusion was then started five minutes later. One quarter of the nalbuphine dose was administered every other minute until the full amount was delivered by eight minutes.
Figure 2
Figure 2. Examples of infusion-initiated BOLD signal changes.
Shown is an example in which the Nalb-Sal treatment induced greater activation (i.e., caudate), and an example in which the Nalb-Nalox treatment induced greater activation (i.e., amygdala).
Figure 3
Figure 3. BOLD phMRI activation maps.
Top: BOLD activation maps for Nalb-Sal (see Table 1); middle: BOLD activation maps for Nalb-Nalox infusions (see Table 2). Bottom: Contrast maps for Nalb-Sal>Nalb-Nalox and Nalb-Nalox>Nalb-Sal (see Table 3).
Figure 4
Figure 4. Functional Connectivity Maps.
Caudate functional connectivity induced by Nalb-Sal that was blocked by naloxone (see Table 4). There was no functional significant connectivity induced by the Nalb-Nalox treatment.
See this image and copyright information in PMC

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