Back pain is common in the general population, but only a subgroup of back pain patients develops a disabling chronic pain state. The reasons for this are incompletely understood, but recent evidence implies that both preexisting and pain-related variations in the structure and function of the nervous system may contribute significantly to the development of chronic pain. Here, we addressed the role of striatal dopamine (DA) D2/D3 receptor (D2/D3R) function in chronic non-neuropathic back pain (CNBP) by comparing CNBP patients and healthy controls using PET and the D2/D3R-selective radioligand [ 11 C]raclopride. D2/D3R availability was measured at baseline and during a pain challenge, yielding in vivo measures of receptor availability (binding potential, BP ND ) and DA release (change in BP ND from baseline to activated state). At baseline, CNBP patients demonstrated reductions in D2/D3R BP ND in the ventral striatum compared with controls. These reductions were associated with greater positive affect scores and pain tolerance measures. The reductions in D2/D3R BP ND were also correlated with -opioid receptor BP ND and pain-induced endogenous opioid system activation in the amygdala, further associated with measures of positive affect, the affective component of back pain and pain tolerance. During the pain challenge, lower magnitudes of DA release, and therefore D2/D3R activation, were also found in the ventral striatum in the CNBP sample compared with controls. Our results show that CNBP is associated with adaptations in ventral striatal D2/D3R function, which, together with endogenous opioid system function, contribute to the sensory and affective-motivational features of CNBP.

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We developed a unique protocol where transcranial direct current stimulation (tDCS) of the motor cortex is performed during positron emission tomography (PET) scan using a μ-opioid receptor (μOR) selective radiotracer, [11C]carfentanil. This is one of the most important central neuromechanisms associated with pain perception and regulation. We measured μOR non-displaceable binding potential (μOR BPND) in a trigeminal neuropathic pain patient (TNP) without creating artifacts, or posing risks to the patient (e.g., monitoring of resistance). The active session directly improved in 36.2% the threshold for experimental cold pain in the trigeminal allodynic area, mandibular branch, but not the TNP patient’s clinical pain. Interestingly, the single active tDCS application considerably decreased μORBPND levels in (sub)cortical pain-matrix structures compared to sham tDCS, especially in the posterior thalamus. Suggesting that the μ-opioidergic effects of a single tDCS session are subclinical at immediate level, and repetitive sessions are necessary to revert ingrained neuroplastic changes related to the chronic pain. To our knowledge, we provide data for the first time in vivo that there is possibly an instant increase of endogenous μ-opioid release during acute motor cortex neuromodulation with tDCS.

The pain modulatory role of dopamine D2 receptors of the human forebrain was studied by determining the association between dopamine D2 receptor binding potential and the response to experimental pain. Nineteen healthy male volunteers participated in a dopamine D2 receptor positron emission tomography study. The extrastriatal regions of interest studied with [11C]FLB 457 as radioligand (n = 11) were the anterior cingulum, the medial and lateral thalamus, the medial and lateral frontal cortex, and the medial and lateral temporal cortex. The striatal regions of interest studied with [11C]raclopride (n = 8) were the caudate nucleus and the putamen. The latency to the ice water-induced cold pain threshold and tolerance were determined in a separate psychophysical test session. Moreover, the cutaneous heat pain threshold and its elevation by concurrent cold pain in the contralateral hand were determined in each subject. Cold pain threshold was inversely correlated with D2 binding potential in the right putamen and the cold pain tolerance was inversely correlated with D2 binding potential in the right medial temporal cortex. The magnitude of heat pain threshold elevation induced by concurrent cold pain was directly correlated with D2 binding potential in the left putamen. Other correlations of D2 binding potentials in varying brain regions with sensory responses were not significant. A psychophysical control study (n = 10) showed that cold pain responses were identical in the right and left hand. The results indicate that dopamine D2 receptor binding potential in the human forebrain, particularly in the striatum, may be an important parameter in determining the individual cold pain response and the potential for central pain modulation. Accordingly, an individual with only few available D2 receptors in the forebrain is likely to have a high tonic level of pain suppression, combined with a low capacity to recruit more (dopaminergic) central pain inhibition by noxious conditioning stimulation.

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.