FMRI Measurement of CNS Responses to Naloxone Infusion and Subsequent Mild Noxious Thermal Stimuli in Healthy Volunteers

Borras, M. C.; Becerra, Lino; Ploghaus, Alexander; Gostic, J. M.; DaSilva, Alexandre F.; González, Ramón; Borsook, David

doi:10.1152/jn.00249.2003

Cited by 105 publications

(96 citation statements)

References 68 publications

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“…Although this was not directly investigated in the present report, substantial baseline endogenous opioid tone has been described in the rodent basal ganglia (Zangen et al, 1999) and amygdala (Kraus et al, 1996;Gestreau and Besson, 2000). Consistent with the presence of this tone in human subjects, the opioid receptor antagonist naloxone increased the activity of a number of cortical (eg anterior cingulate, prefrontal and insular, entorhinal and parahippocampal cortices) and subcortical (eg basal ganglia, hippocampus) regions in a recent fMRI study (Borras et al, 2004).…”

Section: Discussionsupporting

confidence: 68%

Smoking Modulation of μ-Opioid and Dopamine D2 Receptor-Mediated Neurotransmission in Humans

Scott

Domino

Heitzeg

et al. 2006

Neuropsychopharmacol

112

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This is a pilot examination of the hypothesis that some of the effects of smoking cigarettes in humans are mediated through nicotine activation of opioid and dopamine (DA) neurotransmission. Neuroimaging was performed using positron emission tomography and the radiotracers [11 C]carfentanil and [ 11 C]raclopride, labeling m-opioid and DA D2 receptors, respectively. Six healthy male smokers were abstinent overnight. After radiotracer administration, subjects smoked two denicotinized cigarettes, followed 45 min later by two average nicotine cigarettes. Dynamic data were acquired over 90 min, and transformed into parametric maps of receptor availability in vivo (binding potential, BP), corresponding to low and high nicotine smoking periods and analyzed on a voxel-by-voxel basis using SPM'99 and correction for multiple comparisons. Significant activation of m-opioid receptor-mediated neurotransmission from denicotinized to average nicotine conditions was observed in the right anterior cingulate cortex. DA D2 neurotransmission was activated in the ventral basal ganglia, correlating with Fagerströ m scale nicotine dependence scores. Lower m-opioid receptor BP was also detected during the denicotinized smoking condition in the smoker group, compared to baseline scans in non-smokers, in the cingulate cortex, thalamus, ventral basal ganglia, and amygdala. These reductions were reversed during the average nicotine condition in the thalamus, ventral basal ganglia and amygdala. These data point to both the feasibility of simultaneously examining opioid and DA neurotransmission responses to smoking in humans, as well as to the need to examine non-nicotine aspects of smoking to more fully understand the behavioral effects of this drug.

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Section: Discussionsupporting

confidence: 68%

Smoking Modulation of μ-Opioid and Dopamine D2 Receptor-Mediated Neurotransmission in Humans

Scott

Domino

Heitzeg

et al. 2006

Neuropsychopharmacol

112

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“…The effects of µ-opioid receptor blockade on experimental pain are inconsistent, with reports of pain increasing after naloxone administration (Buchsbaum et al, 1983;Borras et al, 2004), not changing (El-Sobky et al, 1976;Grevert and Goldstein, 1978), or decreasing (Stacher et al, 1988;Al'Absi et al, 2004). This inconsistency may be due to individual differences in pain sensitivity (Buchsbaum et al, 1983) or could be dose-related.…”

Section: Discussionmentioning

confidence: 99%

“…In particular, opioid release in cortical regions involved in emotional processing appears to suppress the emotive element of pain (Zubieta et al, 2001) and affective states such as sadness (Zubieta et al, 2003), whereas blocking µ-opioid receptors with naloxone increases activity in these regions (Borras et al, 2004). Thus, activation of the endogenous opioid system during psychological stress could suppress the affective and sensory components of pain independently.…”

Section: Introductionmentioning

confidence: 99%

Negative affect, pain and sex: The role of endogenous opioids

Frew

Drummond

2007

Pain

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Opioid neurotransmission modulates pain and negative affect during psychological stress.To determine whether these effects differ between men and women, the opioid receptor antagonist naltrexone or placebo was administered double-blind to 21 men and 22 women before they completed 30 minutes of difficult mental arithmetic. To heighten negative affect, participants received seven moderately noxious electric shocks during the math task, which were believed to be contingent upon performance. Before and after the math task, participants rated pain intensity and unpleasantness while their left hand was immersed in 2 o C water for up to 4 minutes. Anxiety, discouragement and anger were also rated before, during and after the math task. Tolerance of cold-induced pain was greater in men, whereas discouragement during the math task was greater in women. Opioid blockade did not influence ratings of negative affect, which increased in line with the intensity and unpleasantness of shock-induced pain. The intensity and unpleasantness of cold-induced pain increased after the math task only in women administered naltrexone.Within the naltrexone condition, pain ratings increased most in the most discouraged subjects. However, this relationship was absent in placebo recipients, implying that the hyperalgesic effect of psychological distress was tempered by opioid release. Greater stress-evoked discouragement in women than men may explain why cold-induced pain increased after the math task only in women administered naltrexone.

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“…Recently, we reported on the central, dose-dependent pharmacodynamic effects of buprenorphine in humans with use of functional imaging methodology, in part, to further understand the neurobiological mechanisms underlying its analgesic properties (Borras et al, 2004;Becerra et al, 2006;Leppa et al, 2006;Upadhyay et al, 2011). Although buprenorphine is an opioid that has potency for multiple opioid receptor types (m-, d-, and k-opioid-like receptor 1/ nociceptin) (Sadee et al, 1982;Rothman et al, 1995;Hawkinson et al, 2000;Huang et al, 2001), the partial agonist action of buprenorphine at supraspinal m-opioid receptor site is thought to be the major driver of its analgesic effect (Lutfy et al, 2003;Ide et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Parallel Buprenorphine phMRI Responses in Conscious Rodents and Healthy Human Subjects

Becerra

Upadhyay

Chang

et al. 2013

J Pharmacol Exp Ther

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Pharmacological magnetic resonance imaging (phMRI) is one method by which a drug's pharmacodynamic effects in the brain can be assessed. Although phMRI has been frequently used in preclinical and clinical settings, the extent to which a phMRI signature for a compound translates between rodents and humans has not been systematically examined. In the current investigation, we aimed to build on recent clinical work in which the functional response to 0.1 and 0.2 mg/70 kg i.v. buprenorphine (partial m-opioid receptor agonist) was measured in healthy humans. Here, we measured the phMRI response to 0.04 and 0.1 mg/kg i.v. buprenorphine in conscious, naive rats to establish the parallelism of the phMRI signature of buprenorphine across species. PhMRI of 0.04 and 0.1 mg/kg i.v. buprenorphine yielded dose-dependent activation in a brain network composed of the somatosensory cortex, cingulate, insula, striatum, thalamus, periaqueductal gray, and cerebellum. Similar dose-dependent phMRI activation was observed in the human phMRI studies. These observations indicate an overall preservation of pharmacodynamic responses to buprenorphine between conscious, naive rodents and healthy human subjects, particularly in brain regions implicated in pain and analgesia. This investigation further demonstrates the usefulness of phMRI as a translational tool in neuroscience research that can provide mechanistic insight and guide dose selection in drug development.

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FMRI Measurement of CNS Responses to Naloxone Infusion and Subsequent Mild Noxious Thermal Stimuli in Healthy Volunteers

Cited by 105 publications

References 68 publications

Smoking Modulation of μ-Opioid and Dopamine D2 Receptor-Mediated Neurotransmission in Humans

Smoking Modulation of μ-Opioid and Dopamine D2 Receptor-Mediated Neurotransmission in Humans

Negative affect, pain and sex: The role of endogenous opioids

Parallel Buprenorphine phMRI Responses in Conscious Rodents and Healthy Human Subjects

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