Reduced basal ganglia μ-opioid receptor availability in trigeminal neuropathic pain: A pilot study

Abstract Background Although neuroimaging techniques have provided insights into the function of brain regions involved in Trigeminal Neuropathic Pain (TNP) in humans, there is little understanding of the molecular mechanisms affected during the course of this disorder. Understanding these processes is crucial to determine the systems involved in the development and persistence of TNP. Findings In this study, we examined the regional μ-opioid receptor (μOR) availability in vivo (non-displaceable binding potential BPND) of TNP patients with positron emission tomography (PET) using the μOR selective radioligand [11C]carfentanil. Four TNP patients and eight gender and age-matched healthy controls were examined with PET. Patients with TNP showed reduced μOR BPND in the left nucleus accumbens (NAc), an area known to be involved in pain modulation and reward/aversive behaviors. In addition, the μOR BPND in the NAc was negatively correlated with the McGill sensory and total pain ratings in the TNP patients. Conclusions Our findings give preliminary evidence that the clinical pain in TNP patients can be related to alterations in the endogenous μ-opioid system, rather than only to the peripheral pathology. The decreased availability of μORs found in TNP patients, and its inverse relationship to clinical pain levels, provide insights into the central mechanisms related to this condition. The results also expand our understanding about the impact of chronic pain on the limbic system.http://deepblue.lib.umich.edu/bitstream/2027.42/112555/1/12990_2012_Article_533.pd

Brief Report: Excitatory and Inhibitory Brain Metabolites as Targets of Motor Cortex Transcranial Direct Current Stimulation Therapy and Predictors of Its Efficacy in Fibromyalgia

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/110535/1/art38945.pd

Building up analgesia in humans via the endogenous μ-opioid system by combining placebo and active tDCS: a preliminary report.

Transcranial Direct Current Stimulation (tDCS) is a method of non-invasive brain stimulation that has been frequently used in experimental and clinical pain studies. However, the molecular mechanisms underlying tDCS-mediated pain control, and most important its placebo component, are not completely established. In this pilot study, we investigated in vivo the involvement of the endogenous μ-opioid system in the global tDCS-analgesia experience. Nine healthy volunteers went through positron emission tomography (PET) scans with [11C]carfentanil, a selective μ-opioid receptor (MOR) radiotracer, to measure the central MOR activity during tDCS in vivo (non-displaceable binding potential, BPND)--one of the main analgesic mechanisms in the brain. Placebo and real anodal primary motor cortex (M1/2mA) tDCS were delivered sequentially for 20 minutes each during the PET scan. The initial placebo tDCS phase induced a decrease in MOR BPND in the periaqueductal gray matter (PAG), precuneus, and thalamus, indicating activation of endogenous μ-opioid neurotransmission, even before the active tDCS. The subsequent real tDCS also induced MOR activation in the PAG and precuneus, which were positively correlated to the changes observed with placebo tDCS. Nonetheless, real tDCS had an additional MOR activation in the left prefrontal cortex. Although significant changes in the MOR BPND occurred with both placebo and real tDCS, significant analgesic effects, measured by improvements in the heat and cold pain thresholds, were only observed after real tDCS, not the placebo tDCS. This study gives preliminary evidence that the analgesic effects reported with M1-tDCS, can be in part related to the recruitment of the same endogenous MOR mechanisms induced by placebo, and that such effects can be purposely optimized by real tDCS

μ ‐Opioid activation in the midbrain during migraine allodynia – brief report II

We investigated in vivo the allodynic response of the central μ ‐opioid system during spontaneous migraine headaches, following a sustained pain threshold challenge on the trigeminal ophthalmic region. Six migraineurs were scanned during the ictal and interictal phases using positron emission tomography ( PET ) with the selective μ ‐opioid receptor ( μ OR ) radiotracer [11C]carfentanil. Females were scanned during the mid‐late follicular phase of two separate cycles. Patients showed ictal trigeminal allodynia during the thermal challenge that was concurrent and positively correlated with μ OR activation in the midbrain, extending from red nucleus to ventrolateral periaqueductal gray matter. These findings demonstrate for the first time in vivo the high μ OR activation in the migraineurs' brains in response to their allodynic experience.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/107586/1/acn366.pd

μ ‐Opioid activation in the prefrontal cortex in migraine attacks – brief report I

We evaluated in vivo the μ ‐opioid system during spontaneous episodic migraine headaches. Seven patients were scanned at different phases of their migraine using positron emission tomography with the selective μ ‐opioid receptor ( μ OR ) radiotracer [11C]carfentanil. In the ictal phase, there was μ OR activation in the medial prefrontal cortex, which was strongly associated with the μ OR availability level during the interictal phase. Furthermore, μ ‐opioid binding changes showed moderate negative correlation with the combined extension and severity of the attacks. These results indicate for the first time that there is high μ OR activation in the migraineurs' brains during headache attacks in response to their pain.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/107492/1/acn365.pd

μ

We evaluated in vivo the μ ‐opioid system during spontaneous episodic migraine headaches. Seven patients were scanned at different phases of their migraine using positron emission tomography with the selective μ ‐opioid receptor ( μ OR ) radiotracer [11C]carfentanil. In the ictal phase, there was μ OR activation in the medial prefrontal cortex, which was strongly associated with the μ OR availability level during the interictal phase. Furthermore, μ ‐opioid binding changes showed moderate negative correlation with the combined extension and severity of the attacks. These results indicate for the first time that there is high μ OR activation in the migraineurs' brains during headache attacks in response to their pain.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/107492/1/acn365.pd

Box plot representing tDCS (placebo and real) effects in the heat pain thresholds of both sides of the face.

<p>Statistically significant changes occurred in the heat pain thresholds of the left face (<i>p</i> = 0.032).</p

Box plot illustrating cold pain thresholds variations related to placebo and real tDCS.

<p>Statistically significant changes occurred in the cold pain thresholds of the left face (<i>p</i> = 0.012) throughout the experiment.</p

Correlation between placebo and real tDCS-induced MOR activation.

<p>MOR BP_ND during placebo (x axis) and real (y axis) tDCS for each subject in the clusters of μ-opioid activation induced by placebo (A–C) and real (D–F) tDCS. The same clusters are illustrated in the <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0102350#pone-0102350-g002" target="_blank">figure 2</a>. Positive correlations can be observed in precuneus and PAG (red lines) but not in thalamus and PFC (blue lines). Statistically significant values at p<0.05 were found in the PAG cluster activated during placebo tDCS (r_p = 0.760, p = 0.013, 3B) and in the precuneus cluster activated during active tDCS (r_p = 0.788, p = 0.008, 3D).</p

Experimental design used in the second PET scan.

<p>Placebo tDCS was applied during the early PET phase (15 to 35 min post-tracer administration) and real tDCS during the late PET phase (60 to 80 min). QST was performed before the PET, in the period between placebo and real tDCS and immediately after the PET.</p