Ilkka K. Martikainen

Dopamine D2 receptor binding in the human brain is associated with the response to painful stimulation and pain modulatory capacity.

&NA; 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.

Striatal dopamine D2/D3 receptor availability correlates with individual response characteristics to pain

We studied in healthy humans the contribution of cerebral dopamine D2/D3 receptors to individual differences in response characteristics to painful stimulation. Positron emission tomography was used to measure the dopamine D2/D3 binding potential (D2/D3 BP) with [11C]raclopride in the striatum (n = 8) and with [11C]FLB 457 in the extrastriatal regions (n = 11). Sensitivity to cutaneous heat pain was assessed by a traditional threshold method and by an analysis based on the signal detection theory which allows the separation of an individual subjects discriminative capacity from the response criterion, i.e. the area under the receiver operating characteristic curve provides a measure of the sensory discriminability (sensory factor) and the response criterion gives an estimate of the subjects response bias or attitude (nonsensory factor). The pain threshold and response criterion were inversely correlated with the D2/D3 BP in the right putamen, whereas the discriminative capacity was not significantly correlated with the D2/D3 BP in any brain region. The correlation of the D2/D3 BP in the putamen with the pain threshold and the subjects response criterion may rather be explained by a dopaminergic effect on nonsensory factors determining the subjects attitude towards pain than by a dopaminergic effect on the subjects discriminative capacity. Alternatively, striatal dopamine D2/D3 receptors could control a modulatory pathway producing a parallel shift in the stimulus–response function for sensory signals, mimicking a change in the subjects response criterion.

Association of striatal dopamine D2/D3 receptor binding potential with pain but not tactile sensitivity or placebo analgesia.

Striatal dopamine D2/D3 receptors have been suggested to play a role in pain sensitivity and placebo effect. We studied whether the association of dopamine D2/D3 receptor binding potential (BP) with sensory thresholds is specific to the modality of pain, and whether striatal dopamine D2/D3 receptor BP predicts the magnitude of placebo analgesia. Pain and tactile thresholds, and placebo analgesia were assessed in eight healthy human male subjects who had previously participated in a dopamine D2/D3 receptor positron emission tomography study with [11C]raclopride. The results show that the cutaneous heat pain threshold was inversely correlated with dopamine D2/D3 receptor BP in the right putamen, but responses to tactile stimulation did not correlate with striatal dopamine D2/D3 receptor BP. Placebo-induced elevation of the heat pain threshold did not correlate with striatal dopamine D2/D3 receptor BP. These results suggest that the influence of striatal dopamine D2/D3 receptors on sensory thresholds is selective for the modality of pain. Moreover, striatal dopamine D2/D3 receptor BP appears not to predict individuals analgesic response to placebo.

Correlation of human cold pressor pain responses with 5-HT1A receptor binding in the brain

We determined whether serotonin 5-HT(1A) receptor availability in the brain is associated with cold pressor pain (CPP) or sympathetic reflex responses. Psychophysical testing was performed in eleven healthy males who had participated in a positron emission tomography study with [carbonyl-(11)C]WAY-100635 ligand for the assessment of 5-HT(1A) receptor binding potential (BP). Psychophysical testing consisted of determining CPP threshold, tolerance, intensity, unpleasantness and CPP threshold modulation by conditioning CPP. Autonomic control was assessed by determining the cutaneous vasoconstriction responses in the finger induced by CPP and Valsalva maneuver. CPP intensity was inversely correlated with 5-HT(1A) BP in multiple cortical and subcortical areas, including the prefrontal and cingulate cortices, insula, amygdala and the dorsal raphe. CPP unpleasantness was not significantly correlated with 5-HT(1A) BP in any of the regions of interest. Increase of CPP threshold by conditioning CPP was directly correlated with 5-HT(1A) BP in the amygdala and medial prefrontal cortex. Vasoconstriction induced by Valsalva but not CPP was directly correlated with 5-HT(1A) BP in the ventral part of the anterior cingulate cortex and the anterior insula. The results suggest that 5-HT(1A) receptors in the brain influence pain and Valsalva-induced sympathetic vasoconstriction reflex. In general, subjects with high availability of 5-HT(1A) receptors have low CPP intensity accompanied by a high capacity for central suppression of pain or a sympathetic vasoconstriction response by a Valsalva maneuver.

Spatial integration of cold pressor pain sensation in humans.

Spatial integration of cold pressor pain (CPP) in the hand was studied in healthy human subjects by measuring the latency to the ice water-induced first pain sensation with and without conditioning CPP. CPP alone showed a marked spatial summation effect. When conditioning and test CPP were applied at the same time, conditioning CPP suppressed test CPP both in an adjacent and a distant site. When test CPP was applied after the conditioning CPP (i.e. pain induced by conditioning CPP was considerably stronger than that evoked by test CPP) conditioning CPP suppressed the test CPP only in a distant site but enhanced it in an adjacent site. A decrease in the test stimulus area increased the suppressive effect by conditioning CPP. Thus, CPP shows spatial summation or inhibition depending on experimental parameters.

Effect of Telithromycin on the Pharmacokinetics and Pharmacodynamics of Oral Oxycodone

The aim of this study is to determine whether the inhibition of CYP2D6 and CYP3A4 enzyme activity with telithromycin affects the pharmacokinetics and pharmacodynamics of orally administered oxycodone in a randomized 2‐phase crossover study. Eleven healthy subjects were pretreated with 800 mg of oral telithromycin or placebo for 4 days. On day 3, they ingested 10 mg of immediate‐release oxycodone. Plasma concentrations of oxycodone and its oxidative metabolites were measured for 48 hours, and pharmacodynamic effects were evaluated. Telithromycin increased the area under the plasma concentration‐time curve (AUC0‐∞) of oxycodone by 80% (P < .001) and reduced the AUC0‐∞ of noroxycodone by 46% (P < .001). Most of the pharmacokinetic changes were seen in the elimination phase, with little effect by telithromycin on the peak concentration of oxycodone. Pharmacodynamic effects of oxycodone were modestly enhanced by telithromycin. In conclusion, telithromycin clearly reduces the N‐demethylation of oxycodone to noroxycodone by inhibiting the CYP450 3A4 enzyme. The use of telithromycin in patients receiving multiple doses of oxycodone for pain relief may increase the risk of opioid adverse effects. Reduction of oxycodone dose by 25% to 50% followed by readjustment according to the clinical response might be appropriate.

Striatal μ-opioid receptor availability predicts cold pressor pain threshold in healthy human subjects

Previous PET studies in healthy humans have shown that brain μ-opioid receptor activation during experimental pain is associated with reductions in the sensory and affective ratings of the individual pain experience. The aim of this study was to find out whether brain μ-opioid receptor binding at the resting state, in absence of painful stimulation, can be a long-term predictor of experimental pain sensitivity. We measured μ-opioid receptor binding potential (BP(ND)) with μ-opioid receptor selective radiotracer [(11)C]carfentanil and positron emission tomography (PET) in 12 healthy male subjects. Later, we recruited these subjects to participate in a separate psychophysical testing session to measure cold pressor pain threshold, cold pressor pain tolerance and tactile sensitivity with von Frey monofilaments. We used both voxel-by-voxel and region-of-interest image analyses to examine the potential associations between μ-opioid receptor BP(ND) and psychophysical measures. The results show that striatal μ-opioid receptor BP(ND) predicts cold pressor pain threshold, but not cold pressor pain tolerance or tactile sensitivity. This finding suggests that striatal μ-opioid receptor density is involved in setting individual pain threshold.

Kainate down-regulates a subset of GABAA receptor subunits expressed in cultured mouse cerebellar granule cells.

The effect of kainate, an agonist selective for ionotropic AMPA/kainate type of glutamate receptors, on GABAA receptor subunit expression in cultured mouse cerebellar granule cells was studied using quantitative RT-PCR, ligand binding and electrophysiology. Chronic kainate treatment, without producing excitotoxicity, resulted in preferential, dose- and time-dependent down-regulation of αl, α6 and β2 subunit mRNA expression, the expression of β3, γ2 and δ subunit mRNAs being less affected. The down-regulation was reversed by DNQX, an AMPA/kainate-selective glutamate receptor antagonist. A 14-day kainate treatment resulted in 46% decrease of total [3H]Ro 15-4513 binding to the benzodiazepine sites. Diazepam-insensitive [3H]Ro 15-4513 binding was decreased by 89% in accordance with very low amount of α6 subunit mRNA present. Diazepam-sensitive [3H]Ro 15-4513 binding was decreased only by 40%, contrasting > 90% decrease in α1 subunit mRNA expression. However, this was consistent with lower potentiation of GABA-evoked currents in kainate-treated than control cells by the α1-selective benzodiazepine site ligand zolpidem, suggesting compensatory expression of α5 (and/or α2 or α3) subunits producing diazepam-sensitive but zolpidem-insensitive receptor subtypes. In conclusion, chronic kainate treatment of cerebellar granule cells selectively down-regulates α1, α6 and β2 subunits resulting in altered GABAA receptor pharmacology.

Differential associations between brain 5-HT1A receptor binding and response to pain versus touch

We studied whether brain serotonin 5-HT1A receptor availability is associated with response to noxious heat versus tactile stimuli, and short-term memory for heat pain. Psychophysical performance was assessed in 16 healthy subjects who had participated in a positron emission tomography study using [carbonyl-11C]WAY-100635 ligand for the assessment of 5-HT1A receptor binding potential (BPND). Signal detection theory was applied to allow separate analysis of the subject’s sensory-discriminative capacity (sensory factor) and the attitude toward reporting a sensation (response criterion; non-sensory factor). Subject’s response criterion for heat pain was inversely correlated with 5-HT1ABPND in the dorsal raphe, middle temporal gyrus, orbitofrontal cortex and posterior cingulum, whereas the subject’s discriminative capacity for touch was inversely correlated with 5-HT1ABPND in the cingulum, inferior temporal gyrus, and medial prefrontal cortex. Certainty ratings of the responses, but not hit rates, in the pain memory task were correlated with 5-HT1ABPND in the dorsal raphe.

Spatial discrimination of one versus two test stimuli in the human skin: dissociation of mechanisms depending on the task and the modality of stimulation.

We determined whether the ability to localize a single noxious cold versus innocuous tactile stimulus is associated with the ability to discriminate between two stimuli in the forearm skin of healthy human subjects. When single stimuli were applied, the localization of a noxious cold stimulus was at least as good as that of a tactile stimulus. With both of these modalities, the localization of a single stimulus was more accurate in the radial-ulnar than proximo-distal direction. In contrast to localization of a single stimulus, the discrimination of two cutaneous test stimuli from each other was an order of magnitude worse for noxious cold than touch. This dissociation indicates that localization of single cutaneous stimuli and discrimination of two cutaneous stimuli from each other are based on different mechanisms.