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Striatal dopamine D1 and D2 receptors in burning mouth syndrome
Pain 101 (2003) 149–154 www.elsevier.com/locate/pain
Striatal dopamine D1 and D2 receptors in burning mouth syndrome Nora Hagelberg a, Heli Forssell b, Juha O. Rinne c, Harry Scheinin c,d, Tero Taiminen e, Sargo Aalto c, Sinikka Luutonen e, Kjell Na˚gren f, Satu Ja¨a¨skela¨inen g,* a
Department of Anesthesiology and Intensive Care, Turku University Central Hospital, P.O. Box 52, FIN-20521 Turku, Finland b Department of Oral Diseases, Turku University Central Hospital, Lemminka¨isenkatu 2, FIN-20520 Turku, Finland c Turku PET Centre, P.O. Box 52, FIN-20521 Turku, Finland d Department of Pharmacology and Clinical Pharmacology, University of Turku, Kiinamyllynkatu 10, FIN-20520 Turku, Finland e Department of Psychiatry, Turku University Central Hospital, PO Box 52, FIN-20521 Turku, Finland f Radiopharmaceutical Chemistry Laboratory, Turku PET Centre, P.O. Box 52, FIN-20521 Turku, Finland g Department of Clinical Neurophysiology, Turku University Central Hospital, P.O. Box 52, FIN-20521 Turku, Finland Received 18 June 2002; accepted 8 August 2002
Abstract Animal studies have indicated that the nigrostriatal dopaminergic system is involved in central pain modulation. In a recent positron emission tomography (PET) study, we demonstrated presynaptic dysfunction of the nigrostriatal dopaminergic pathway in burning mouth syndrome, which is a chronic pain state. The objective of the present study was to examine striatal dopamine D1 and D2 receptors in these patients. We used 11C-NNC 756 and 11C-raclopride to study D1 and D2 receptor binding in a PET study in ten burning mouth patients and 11 healthy controls. Patients underwent a structured psychiatric evaluation and an electrophysiological test for the excitability of the blink reflex. The striatal uptake of 11C-NNC 756 did not differ between patients and controls. In a voxel-level analysis, the uptake of 11C-raclopride was statistically significantly higher in the left putamen in burning mouth patients (corrected P-value 0.038 at cluster-level). In the region of interest analysis, the D1/D2 ratio was 7.7% lower in the right putamen (0.64 ^ 0.04 vs. 0.69 ^ 0.04, P ¼ 0:01) and 6.4 % lower in the left putamen (0.65 ^ 0.05 vs. 0.70 ^ 0.05, P ¼ 0:05) when compared to controls. Increased 11C-raclopride uptake and the subsequent decrease in the D1/D2 ratio may indicate a decline in endogenous dopamine levels in the putamen in burning mouth patients. q 2002 International Association for the Study of Pain. Published by Elsevier Science B.V. All rights reserved. Keywords: PET; Dopamine receptor; Burning mouth syndrome; Chronic pain
1. Introduction Central neural mechanisms involved in chronic pain are still poorly understood. In the context of clinical pain, receptor imaging studies have focused on the opioid system while other neurotransmitters have received relatively little attention. The implication of the dopaminergic system in pain transmission in man is still controversial, although animal studies indicate that dopamine plays a role in central pain modulation (Akil and Liebeskind, 1975; Dennis and Melzack, 1983; Paalzow and Paalzow, 1983; Lin et al., 1989). Evidence from experimental studies suggests that the inhibitory role of dopamine is mediated by dopamine D2 receptors, and that D1 receptors are not involved (Michael-Titus et al., 1990; Magnusson and Fisher, 2000). We have recently shown that dopamine D2 receptor binding * Corresponding author. Tel.: 1358-2-3131939; fax: 1358-2-3133922. E-mail address: [email protected] (S. Ja¨a¨skela¨inen).
in the putamen is associated with pain modulation induced by conditioning stimulation in healthy volunteers (Hagelberg et al., 2002). Also, clinical pathological conditions involving the nigrostriatal dopaminergic system such as Parkinson’s disease may be accompanied by pain of central origin (Koller, 1984; Schott, 1985; Ford et al., 1996). In addition, levodopa has been suggested to produce pain relief in some neuropathic pain conditions (Kernbaum and Hauchecorne, 1981; Ertas et al., 1998). Finally, diminished levels of dopamine metabolites have been documented in the cerebrospinal fluid of the trigeminal cistern in facial pain patients (Bouckoms et al., 1992). Burning mouth syndrome is an intensive chronic oral mucosal pain condition of unknown etiology. Typically, it affects middle-aged women and is described as a painful burning sensation comparable to severe toothache in intensity (see for review Zakrzewska, 1995). The prevalence of burning mouth syndrome has been suggested to be greater in patients with Parkinson’s disease than in the general popu-
0304-3959/02/$20.00 q 2002 International Association for the Study of Pain. Published by Elsevier Science B.V. All rights reserved. doi:10.1016/S0 304-3959(02)00 323-8
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lation (Clifford et al., 1998). Our previous neurophysiological and imaging studies suggest that dysfunction of the nigrostriatal dopaminergic pathway may play a role in the pathophysiology of this chronic pain state. Burning mouth patients exhibit abnormalities in the excitability of the blink reflex (Ja¨ a¨ skela¨ inen et al., 1997; Forssell et al., 2002), which is a brainstem reflex under inhibitory dopaminergic control (Evinger et al., 1993). In line with our electrophysiological findings, we have demonstrated presynaptic dopaminergic hypofunction in the putamen in a positron emission tomography (PET) study in these patients (Ja¨ a¨ skela¨ inen et al., 2001). The purpose of this study was to evaluate striatal dopamine D1 and D2 receptors in burning mouth patients using PET. 2. Materials and methods 2.1. Patients The study protocol was approved by the joint Ethical Committee of Turku University Central Hospital and University of Turku. All participants gave their written informed consent. Ten patients with burning mouth syndrome, whose diagnoses were confirmed by thorough clinical examinations, were included in the study. All were women. Seven of these patients had earlier been examined for 18F-FDOPA uptake at Turku PET Centre (Ja¨ a¨ skela¨ inen et al., 2001). The control subjects were 11 healthy women. The patients were 46–74 years old (mean age 63 ^ 9 years) and the controls were 44–62 years (mean age 56 ^ 6 years) (P ¼ 0:051 for the age difference between the groups). None of the patients were taking medication that could influence the dopaminergic system. All patients and controls were right handed. One patient was an occasional cigarette smoker (less than five cigarettes per week) and the rest were non-smokers. All patients and controls underwent a 1.5 T magnetic resonance imaging (MRI) scan of the brain (Magnetom, Siemens, Erlangen, Germany) which revealed no major pathology. Nine control subjects were studied with both radioligands, and two controls were scanned only once with either 11C-raclopride or 11C-NNC 756 due to technical problems. Because in psychotic patients, abnormalities have been found in dopamine D1 (Okubo et al., 1997) as well as D2 (Kestler et al., 2001) receptors, we wanted to rule out psychotic disorders in our patients. Eight of them underwent a structured psychiatric evaluation with the aid of SCID-I and SCID-II interviews (First et al., 1997a,b). Two patients refused the psychiatric evaluation giving distant place of residence as an excuse. All patients were tested for the excitability of the blink reflex as described earlier (Taiminen et al., 2000; Forssell et al., 2002). 2.2. PET imaging and data analysis The preparation of the dopamine D1 antagonist 11C-NNC
756 has been described earlier (Laihinen et al., 1994; Na˚ gren et al., 1995). The mean ^ SD injected dose and specific radioactivity of 11C-NNC 756 were 357 ^ 9 MBq and 61.8 ^ 15 MBq/nmol, yielding the mass of 2.0 ^ 0.6 mg. The dopamine D2 receptor antagonist 11Craclopride was prepared as previously described (Halldin et al., 1991; Rinne et al., 1993). The mean ^ SD injected dose, specific radioactivity and mass of 11C-raclopride were 189 ^ 9 MBq, 34.7 ^ 14 MBq/nmol, and 2.2 ^ 0.8 mg, respectively. The PET studies were performed with a GE Advance PET scanner (General Electric Medical Systems, Milwaukee, WI, USA) with 35 4.25 mm slices covering the whole brain in 3D mode. Each dynamic PET scan was preceded by a transmission scan for the attenuation of soft tissues. 11 C-NNC 756 uptake in the brain was measured for 80 min using 23 time frames, and 11C-raclopride uptake for 59 min using 28 time frames. No arterial metabolite or activity data were collected. Each subject underwent the two PET examinations on the same day with at least 2 h in between the radioligand injections (the half-life of the isotope 11C used to label both radioligands is 20.4 min). The 11C-raclopride study was performed first due to faster receptor kinetics of this ligand. After realigning the PET and MRI images (Pellizari et al., 1989), regions of interest (caudate nucleus, putamen, and cerebellum) were drawn on the matched MRI slices and transferred to corresponding PET images. The caudate nucleus and putamen were drawn on three planes at the level of the basal ganglia. The cerebellum was also drawn on three planes. In the data analysis, cerebellum was used as the reference region devoid of dopamine receptors (Hall et al., 1994). The uptake of 11C-raclopride in the striatum was analyzed using the linear graphical method (Logan et al., 1996) with reference tissue input function. This method yields the distribution volume ratio (DVR), which reflects the number of free receptors available. To be able to compare the uptake of the two radioligands, we used the linear graphical method (Logan plot analysis) also for the 11C-NNC 756 data. This approach has been used in our PET Center recently (Kemppainen et al., 2000). Finally, we calculated the ratio of the uptakes of 11C-NNC 756 and 11C-raclopride (D1/D2 ratio). To further evaluate the possible difference in the DVR of 11 C-raclopride and 11C-NNC 756 between patients and controls, we performed voxel-based statistical analyses to study the uptake of the radioligands without manual definition of regions of interest. Calculation of parametric images for the voxel-based statistical analysis was based on the same model as the region of interest based analysis, i.e. the linear graphical method (Logan et al., 1996) with reference tissue input function. Preprocessing and statistical analysis of parametric images were performed using the Statistical Parametric Mapping version 99 (SPM99; Friston et al., 1995) and Matlab 5.3 for Windows (Math Works, Natick, MA, USA). In spatial normalization, parametric
N. Hagelberg et al. / Pain 101 (2003) 149–154 Table 1 The mean ^ SD DVRs of 11C-NNC 756 (D1 DVR) and patients (n ¼ 10) and healthy controls (n ¼ 10) a
11
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C-raclopride (D2 DVR) and D1/D2 ratio in the caudate nucleus and putamen in burning mouth
Burning mouth patients
Controls
Right
Left
Right
Left
Caudate nucleus D1 DVR D2 DVR D1/D2 ratio b
2.23 ^ 0.22 3.18 ^ 0.28 0.70 ^ 0.06
2.22 ^ 0.22 3.22 ^ 0.29 0.69 ^ 0.06
2.27 ^ 0.15 3.06 ^ 0.28 0.74 ^ 0.04
2.22 ^ 0.13 3.09 ^ 0.29 0.71 ^ 0.05
Putamen D1 DVR D2 DVR D1/D2 ratio b
2.20 ^ 0.15 3.44 ^ 0.30 0.64 ^ 0.04
2.27 ^ 0.20 3.49 ^ 0.27 0.65 ^ 0.05
2.30 ^ 14 3.30 ^ 0.28 0.69 ^ 0.04
2.31 ^ 0.16 3.32 ^ 0.27 0.70 ^ 0.05
a b
D1/D2 ratio was 7.7% lower in the right (P ¼ 0:01) and 6.4% in the left (P ¼ 0:05) putamen in burning mouth patients when compared to controls. n ¼ 9, see text.
images were transformed onto standard stereotactic space using a transformation matrix that was estimated with sum images and standard PET template distributed with SPM 99. After spatial normalization, parametric images were smoothed using 12 mm Gaussian filter. The voxel-based analysis was applied separately for 11C-raclopride and 11 C-NNC 756 data. To determine the voxels where the DVR of 11C-raclopride or 11C-NNC 756 in burning mouth patients differed significantly from the controls, subtraction analysis with two T-contrast was performed.
2.3. Statistical analysis The statistical significance of the difference in 11C-raclopride and 11C-NNC 756 DVRs as well as the D1/D2 ratio between burning mouth patients and controls was assessed with unpaired Student’s t-test. In the voxel-based analysis, corrected P-value of 0.05 at cluster-level was considered as a criterion of significance. The associations of age or blink reflex habituation indices with dopamine receptor binding characteristics were analyzed applying Spearman’s correlation coefficients. P-values less than 0.05 were considered statistically significant. The data are presented as means ^ SD.
3. Results The striatal uptake of 11C-NNC 756 in burning mouth patients did not differ from controls. In the quantitative region of interest based analysis, the DVR of 11C-raclopride tended to be higher in burning mouth patients but there were no statistically significant differences between the groups (Table 1). The voxel-based statistical analysis revealed that the uptake of 11C-raclopride was higher in the left putamen in burning mouth patients when compared to controls (corrected P-value 0.038 at cluster-level) (Fig. 1). The D1/ D2 ratio was 7.7% lower in the right putamen (0.64 ^ 0.04 vs. 0.69 ^ 0.04, P ¼ 0:01) and 6.4% lower in the left putamen (0.65 ^ 0.05 vs. 0.70 ^ 0.05, P ¼ 0:05) in burning mouth patients (Fig. 2). There was a positive correlation between the D1/D2 ratio and age in the right putamen in healthy controls (P ¼ 0:028, n ¼ 9) but there were no other age-related associations in the D1/D2 ratio in any of the brain areas studied. Fig. 3 demonstrates typical 11C-NNC 756 and 11C-raclopride PET scans of a burning mouth patient. Seven of the patients had bilateral symptoms and three patients had symptoms only on the left (two) or right (one) side. The mean ^ SD blink reflex habituation indices were normal (4.6 ^ 0.5) in five burning mouth patients and
Fig. 1. A voxel-level statistical analysis showing increased 11C-raclopride uptake in the left putamen in burning mouth patients when compared to controls (P ¼ 0:038). The color intensity represents T-statistic values at voxel-level according to the color bar. The results are visualized on an MRI template image and presented in accordance with neurological convention (right is right).
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Fig. 2. Individual values of D1/D2 ratios in burning mouth patients (BM) (n ¼ 10) and healthy controls (CONT) (n ¼ 9) for the left (P ¼ 0:05) and right (P ¼ 0:01) putamen.
abnormal (9.3 ^ 1.9) in five patients. Deficient habituation of the blink reflex was not associated with DVRs of 11CNNC 756 or 11C-raclopride, or D1/D2 ratio in the striatum. Neither were there any statistically significant correlations between the DVRs of 11C-NNC 756 or 11C-raclopride, or D1/D2 ratio and 18F-FDOPA Ki in the seven patients who had participated in the previous 18F-FDOPA (Ja¨ a¨ skela¨ inen et al., 2001) study (data not shown). None of the eight patients who underwent psychiatric evaluation had a current or previous psychotic disorder. 4. Discussion The results of this study show increased 11C-raclopride uptake and a subsequent decrease in the D1/D2 ratio in the
Fig. 3. An example of 11C-raclopride (upper row) and 11C-NNC 756 (lower row) PET scan of a typical burning mouth patient. The dopamine D2 receptor antagonist 11C-raclopride binds to striatal D2 receptors, whereas the dopamine D1 receptor antagonist 11C-NNC 756 uptake demonstrates D1 receptor distribution.
putamen in burning mouth patients when compared to healthy controls. The striatal uptake of 11C-NNC 756 in patients did not differ from controls. The increased D2 receptor binding may reflect depletion of endogenous dopamine in the putamen, and the findings thus support the presumption of nigrostriatal dopaminergic hypofunction in the pathophysiology of burning mouth syndrome. Dopamine D2 receptor binding has been shown to decline with age (Wong et al., 1984; Rinne et al., 1993) and an agerelated loss of D1 receptors has been demonstrated in the human brain as well (Rinne et al., 1990; Wang et al., 1998). However, the impact of aging on D1/D2 ratio is unclear. In this study, we found no association between striatal D1/D2 ratio and age either in burning mouth patients or healthy controls, except for the right putamen where there was a positive correlation in the control group. As our patients were slightly older than controls, the influence of age on the uptake of 11C-raclopride would have led to a decrease rather than the observed increase. Several analytical approaches can be applied to receptor PET data. To be able to compare the uptakes of 11C-NNC 756 and 11C-raclopride, we used the linear graphical method which is applicable to both radioligands (Logan et al., 1996). In the region of interest based analysis, striatal 11C-raclopride uptake in burning mouth patients tended to be higher. To further evaluate the possible difference between patients and controls, we applied a novel voxelbased analysis to the 11C-NNC 756 and 11C-raclopride PET data. In this analysis, a statistically significant increase in the DVR of 11C-raclopride in the left putamen was seen in the patient group. The voxel-based method discards many sources of error such as problems with coregistration of MRI and PET images, or manual delineation of regions of interest, and it may reveal subtle changes in radioligand uptake not detected by conventional region-of-interest based methods. Animal studies suggest that not only the mesolimbic but also the nigrostriatal dopaminergic pathway is involved in pain modulation. Increased dopamine levels in the nucleus accumbens inhibit pain (see for review, Altier and Stewart, 1999). In line with this, a lesion of striatal neurons by kainic acid (Lin et al., 1984) and striatal dopaminergic terminals by 6-hydroxydopamine (Lin et al., 1981; Saade´ et al., 1997) have been shown to facilitate pain responses in rats. Although animal models are poor equivalents of clinical chronic pain in man, tonic (prolonged) pain induced by the formalin test (Dennis and Melzack, 1983; Morgan and Franklin, 1991; Altier and Stewart, 1998; Magnusson and Fisher, 2000) or autotomy following peripheral neurectomy (Saade´ et al., 1997) in laboratory rats appear to involve the dopaminergic system. Similarily, brain imaging studies in healthy human volunteers show activation of striatal areas by painful stimuli (Jones et al., 1991; Coghill et al., 1999). Despite findings from animal studies and some preliminary work from human imaging studies the involvement of dopamine in pain is unclear. Receptor PET technology needs to
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be applied in order to evaluate the role of various neurotransmitter systems in clinical pain conditions. Burning mouth patients typically exhibit pain symptoms bilaterally in the mouth and the most commonly affected sites are the tongue and the lips. The intensity of the symptoms may vary during the day and for most patients, the pain remains fairly constant over the years (Zakrzewska, 1995). Similarily, most of our patients had bilateral symptoms. In the voxel-based analysis, however, the observed increase in the uptake of 11C-raclopride was lateralized to the left putamen although there was a tendency on the right side as well in the region of interest based analysis. The lack of association between the lateralization of our PET results and the location of symptoms or electrophysiological findings may be due to the small number of patients, or it may reflect a heterogeneous etiology of this pain state. In addition, we cannot rule out the possibility that some patients may exhibit a dysfunction in the mesolimbic dopaminergic pathway instead of the nigrostriatal. A high-affinity D2 receptor ligand such as 11C-FLB 457 would be needed to study extrastriatal D2 receptor binding in cortical areas where the receptor density is low. 11 C-Raclopride uptake is sensitive to changes in endogenous dopamine concentrations (Young et al., 1991; Dewey et al., 1993), whereas 11C-NNC 756 uptake is not affected by an endogenous dopamine surge (Abi-Dargham et al., 1999). We have previously demonstrated that burning mouth patients exhibit diminished 18F-FDOPA uptake in the putamen when compared to healthy age-matched controls (Ja¨ a¨ skela¨ inen et al., 2001). Although 18F-FDOPA uptake does not directly measure dopamine concentration, experimental studies in monkeys have suggested that 18F-FDOPA is a good index of striatal dopamine levels (Yee et al., 2001). Thus, the increased 11C-raclopride uptake in burning mouth patients could result in lowered D1/D2 ratio reflecting diminished endogenous dopamine levels in the putamen. Another possible explanation for the observed difference in the D1/D2 ratio between patients and controls might be an imbalance between D1 and D2 receptor mediated pathways, as it has been proposed that the interaction of D1 and D2 receptors is disrupted early in pathological conditions involving the basal ganglia area (Shi et al., 2000). In conclusion, the results of this study are in line with our earlier findings of diminished 18F-FDOPA uptake in the putamen in burning mouth patients. Increased 11C-raclopride uptake and the subsequent decrease in the D1/D2 ratio may indicate a decline in endogenous dopamine levels in the putamen in burning mouth patients. Our results support the findings of previous animal studies, which suggest that striatal dopamine plays an inhibitory role in central pain modulation.
Acknowledgements We want to thank the staff of Turku PET Center for
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excellent technical assistance. This study was supported by grants from the Finnish Association for the Study of Pain, Turku University Central Hospital and Finnish Dental Association.
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Striatal dopamine D1 and D2 receptors in burning mouth syndrome Nora Hagelberg a, Heli Forssell b, Juha O. Rinne c, Harry Scheinin c,d, Tero Taiminen e, Sargo Aalto c, Sinikka Luutonen e, Kjell Na˚gren f, Satu Ja¨a¨skela¨inen g,* a
Department of Anesthesiology and Intensive Care, Turku University Central Hospital, P.O. Box 52, FIN-20521 Turku, Finland b Department of Oral Diseases, Turku University Central Hospital, Lemminka¨isenkatu 2, FIN-20520 Turku, Finland c Turku PET Centre, P.O. Box 52, FIN-20521 Turku, Finland d Department of Pharmacology and Clinical Pharmacology, University of Turku, Kiinamyllynkatu 10, FIN-20520 Turku, Finland e Department of Psychiatry, Turku University Central Hospital, PO Box 52, FIN-20521 Turku, Finland f Radiopharmaceutical Chemistry Laboratory, Turku PET Centre, P.O. Box 52, FIN-20521 Turku, Finland g Department of Clinical Neurophysiology, Turku University Central Hospital, P.O. Box 52, FIN-20521 Turku, Finland Received 18 June 2002; accepted 8 August 2002
Abstract Animal studies have indicated that the nigrostriatal dopaminergic system is involved in central pain modulation. In a recent positron emission tomography (PET) study, we demonstrated presynaptic dysfunction of the nigrostriatal dopaminergic pathway in burning mouth syndrome, which is a chronic pain state. The objective of the present study was to examine striatal dopamine D1 and D2 receptors in these patients. We used 11C-NNC 756 and 11C-raclopride to study D1 and D2 receptor binding in a PET study in ten burning mouth patients and 11 healthy controls. Patients underwent a structured psychiatric evaluation and an electrophysiological test for the excitability of the blink reflex. The striatal uptake of 11C-NNC 756 did not differ between patients and controls. In a voxel-level analysis, the uptake of 11C-raclopride was statistically significantly higher in the left putamen in burning mouth patients (corrected P-value 0.038 at cluster-level). In the region of interest analysis, the D1/D2 ratio was 7.7% lower in the right putamen (0.64 ^ 0.04 vs. 0.69 ^ 0.04, P ¼ 0:01) and 6.4 % lower in the left putamen (0.65 ^ 0.05 vs. 0.70 ^ 0.05, P ¼ 0:05) when compared to controls. Increased 11C-raclopride uptake and the subsequent decrease in the D1/D2 ratio may indicate a decline in endogenous dopamine levels in the putamen in burning mouth patients. q 2002 International Association for the Study of Pain. Published by Elsevier Science B.V. All rights reserved. Keywords: PET; Dopamine receptor; Burning mouth syndrome; Chronic pain
1. Introduction Central neural mechanisms involved in chronic pain are still poorly understood. In the context of clinical pain, receptor imaging studies have focused on the opioid system while other neurotransmitters have received relatively little attention. The implication of the dopaminergic system in pain transmission in man is still controversial, although animal studies indicate that dopamine plays a role in central pain modulation (Akil and Liebeskind, 1975; Dennis and Melzack, 1983; Paalzow and Paalzow, 1983; Lin et al., 1989). Evidence from experimental studies suggests that the inhibitory role of dopamine is mediated by dopamine D2 receptors, and that D1 receptors are not involved (Michael-Titus et al., 1990; Magnusson and Fisher, 2000). We have recently shown that dopamine D2 receptor binding * Corresponding author. Tel.: 1358-2-3131939; fax: 1358-2-3133922. E-mail address: [email protected] (S. Ja¨a¨skela¨inen).
in the putamen is associated with pain modulation induced by conditioning stimulation in healthy volunteers (Hagelberg et al., 2002). Also, clinical pathological conditions involving the nigrostriatal dopaminergic system such as Parkinson’s disease may be accompanied by pain of central origin (Koller, 1984; Schott, 1985; Ford et al., 1996). In addition, levodopa has been suggested to produce pain relief in some neuropathic pain conditions (Kernbaum and Hauchecorne, 1981; Ertas et al., 1998). Finally, diminished levels of dopamine metabolites have been documented in the cerebrospinal fluid of the trigeminal cistern in facial pain patients (Bouckoms et al., 1992). Burning mouth syndrome is an intensive chronic oral mucosal pain condition of unknown etiology. Typically, it affects middle-aged women and is described as a painful burning sensation comparable to severe toothache in intensity (see for review Zakrzewska, 1995). The prevalence of burning mouth syndrome has been suggested to be greater in patients with Parkinson’s disease than in the general popu-
0304-3959/02/$20.00 q 2002 International Association for the Study of Pain. Published by Elsevier Science B.V. All rights reserved. doi:10.1016/S0 304-3959(02)00 323-8
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lation (Clifford et al., 1998). Our previous neurophysiological and imaging studies suggest that dysfunction of the nigrostriatal dopaminergic pathway may play a role in the pathophysiology of this chronic pain state. Burning mouth patients exhibit abnormalities in the excitability of the blink reflex (Ja¨ a¨ skela¨ inen et al., 1997; Forssell et al., 2002), which is a brainstem reflex under inhibitory dopaminergic control (Evinger et al., 1993). In line with our electrophysiological findings, we have demonstrated presynaptic dopaminergic hypofunction in the putamen in a positron emission tomography (PET) study in these patients (Ja¨ a¨ skela¨ inen et al., 2001). The purpose of this study was to evaluate striatal dopamine D1 and D2 receptors in burning mouth patients using PET. 2. Materials and methods 2.1. Patients The study protocol was approved by the joint Ethical Committee of Turku University Central Hospital and University of Turku. All participants gave their written informed consent. Ten patients with burning mouth syndrome, whose diagnoses were confirmed by thorough clinical examinations, were included in the study. All were women. Seven of these patients had earlier been examined for 18F-FDOPA uptake at Turku PET Centre (Ja¨ a¨ skela¨ inen et al., 2001). The control subjects were 11 healthy women. The patients were 46–74 years old (mean age 63 ^ 9 years) and the controls were 44–62 years (mean age 56 ^ 6 years) (P ¼ 0:051 for the age difference between the groups). None of the patients were taking medication that could influence the dopaminergic system. All patients and controls were right handed. One patient was an occasional cigarette smoker (less than five cigarettes per week) and the rest were non-smokers. All patients and controls underwent a 1.5 T magnetic resonance imaging (MRI) scan of the brain (Magnetom, Siemens, Erlangen, Germany) which revealed no major pathology. Nine control subjects were studied with both radioligands, and two controls were scanned only once with either 11C-raclopride or 11C-NNC 756 due to technical problems. Because in psychotic patients, abnormalities have been found in dopamine D1 (Okubo et al., 1997) as well as D2 (Kestler et al., 2001) receptors, we wanted to rule out psychotic disorders in our patients. Eight of them underwent a structured psychiatric evaluation with the aid of SCID-I and SCID-II interviews (First et al., 1997a,b). Two patients refused the psychiatric evaluation giving distant place of residence as an excuse. All patients were tested for the excitability of the blink reflex as described earlier (Taiminen et al., 2000; Forssell et al., 2002). 2.2. PET imaging and data analysis The preparation of the dopamine D1 antagonist 11C-NNC
756 has been described earlier (Laihinen et al., 1994; Na˚ gren et al., 1995). The mean ^ SD injected dose and specific radioactivity of 11C-NNC 756 were 357 ^ 9 MBq and 61.8 ^ 15 MBq/nmol, yielding the mass of 2.0 ^ 0.6 mg. The dopamine D2 receptor antagonist 11Craclopride was prepared as previously described (Halldin et al., 1991; Rinne et al., 1993). The mean ^ SD injected dose, specific radioactivity and mass of 11C-raclopride were 189 ^ 9 MBq, 34.7 ^ 14 MBq/nmol, and 2.2 ^ 0.8 mg, respectively. The PET studies were performed with a GE Advance PET scanner (General Electric Medical Systems, Milwaukee, WI, USA) with 35 4.25 mm slices covering the whole brain in 3D mode. Each dynamic PET scan was preceded by a transmission scan for the attenuation of soft tissues. 11 C-NNC 756 uptake in the brain was measured for 80 min using 23 time frames, and 11C-raclopride uptake for 59 min using 28 time frames. No arterial metabolite or activity data were collected. Each subject underwent the two PET examinations on the same day with at least 2 h in between the radioligand injections (the half-life of the isotope 11C used to label both radioligands is 20.4 min). The 11C-raclopride study was performed first due to faster receptor kinetics of this ligand. After realigning the PET and MRI images (Pellizari et al., 1989), regions of interest (caudate nucleus, putamen, and cerebellum) were drawn on the matched MRI slices and transferred to corresponding PET images. The caudate nucleus and putamen were drawn on three planes at the level of the basal ganglia. The cerebellum was also drawn on three planes. In the data analysis, cerebellum was used as the reference region devoid of dopamine receptors (Hall et al., 1994). The uptake of 11C-raclopride in the striatum was analyzed using the linear graphical method (Logan et al., 1996) with reference tissue input function. This method yields the distribution volume ratio (DVR), which reflects the number of free receptors available. To be able to compare the uptake of the two radioligands, we used the linear graphical method (Logan plot analysis) also for the 11C-NNC 756 data. This approach has been used in our PET Center recently (Kemppainen et al., 2000). Finally, we calculated the ratio of the uptakes of 11C-NNC 756 and 11C-raclopride (D1/D2 ratio). To further evaluate the possible difference in the DVR of 11 C-raclopride and 11C-NNC 756 between patients and controls, we performed voxel-based statistical analyses to study the uptake of the radioligands without manual definition of regions of interest. Calculation of parametric images for the voxel-based statistical analysis was based on the same model as the region of interest based analysis, i.e. the linear graphical method (Logan et al., 1996) with reference tissue input function. Preprocessing and statistical analysis of parametric images were performed using the Statistical Parametric Mapping version 99 (SPM99; Friston et al., 1995) and Matlab 5.3 for Windows (Math Works, Natick, MA, USA). In spatial normalization, parametric
N. Hagelberg et al. / Pain 101 (2003) 149–154 Table 1 The mean ^ SD DVRs of 11C-NNC 756 (D1 DVR) and patients (n ¼ 10) and healthy controls (n ¼ 10) a
11
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C-raclopride (D2 DVR) and D1/D2 ratio in the caudate nucleus and putamen in burning mouth
Burning mouth patients
Controls
Right
Left
Right
Left
Caudate nucleus D1 DVR D2 DVR D1/D2 ratio b
2.23 ^ 0.22 3.18 ^ 0.28 0.70 ^ 0.06
2.22 ^ 0.22 3.22 ^ 0.29 0.69 ^ 0.06
2.27 ^ 0.15 3.06 ^ 0.28 0.74 ^ 0.04
2.22 ^ 0.13 3.09 ^ 0.29 0.71 ^ 0.05
Putamen D1 DVR D2 DVR D1/D2 ratio b
2.20 ^ 0.15 3.44 ^ 0.30 0.64 ^ 0.04
2.27 ^ 0.20 3.49 ^ 0.27 0.65 ^ 0.05
2.30 ^ 14 3.30 ^ 0.28 0.69 ^ 0.04
2.31 ^ 0.16 3.32 ^ 0.27 0.70 ^ 0.05
a b
D1/D2 ratio was 7.7% lower in the right (P ¼ 0:01) and 6.4% in the left (P ¼ 0:05) putamen in burning mouth patients when compared to controls. n ¼ 9, see text.
images were transformed onto standard stereotactic space using a transformation matrix that was estimated with sum images and standard PET template distributed with SPM 99. After spatial normalization, parametric images were smoothed using 12 mm Gaussian filter. The voxel-based analysis was applied separately for 11C-raclopride and 11 C-NNC 756 data. To determine the voxels where the DVR of 11C-raclopride or 11C-NNC 756 in burning mouth patients differed significantly from the controls, subtraction analysis with two T-contrast was performed.
2.3. Statistical analysis The statistical significance of the difference in 11C-raclopride and 11C-NNC 756 DVRs as well as the D1/D2 ratio between burning mouth patients and controls was assessed with unpaired Student’s t-test. In the voxel-based analysis, corrected P-value of 0.05 at cluster-level was considered as a criterion of significance. The associations of age or blink reflex habituation indices with dopamine receptor binding characteristics were analyzed applying Spearman’s correlation coefficients. P-values less than 0.05 were considered statistically significant. The data are presented as means ^ SD.
3. Results The striatal uptake of 11C-NNC 756 in burning mouth patients did not differ from controls. In the quantitative region of interest based analysis, the DVR of 11C-raclopride tended to be higher in burning mouth patients but there were no statistically significant differences between the groups (Table 1). The voxel-based statistical analysis revealed that the uptake of 11C-raclopride was higher in the left putamen in burning mouth patients when compared to controls (corrected P-value 0.038 at cluster-level) (Fig. 1). The D1/ D2 ratio was 7.7% lower in the right putamen (0.64 ^ 0.04 vs. 0.69 ^ 0.04, P ¼ 0:01) and 6.4% lower in the left putamen (0.65 ^ 0.05 vs. 0.70 ^ 0.05, P ¼ 0:05) in burning mouth patients (Fig. 2). There was a positive correlation between the D1/D2 ratio and age in the right putamen in healthy controls (P ¼ 0:028, n ¼ 9) but there were no other age-related associations in the D1/D2 ratio in any of the brain areas studied. Fig. 3 demonstrates typical 11C-NNC 756 and 11C-raclopride PET scans of a burning mouth patient. Seven of the patients had bilateral symptoms and three patients had symptoms only on the left (two) or right (one) side. The mean ^ SD blink reflex habituation indices were normal (4.6 ^ 0.5) in five burning mouth patients and
Fig. 1. A voxel-level statistical analysis showing increased 11C-raclopride uptake in the left putamen in burning mouth patients when compared to controls (P ¼ 0:038). The color intensity represents T-statistic values at voxel-level according to the color bar. The results are visualized on an MRI template image and presented in accordance with neurological convention (right is right).
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Fig. 2. Individual values of D1/D2 ratios in burning mouth patients (BM) (n ¼ 10) and healthy controls (CONT) (n ¼ 9) for the left (P ¼ 0:05) and right (P ¼ 0:01) putamen.
abnormal (9.3 ^ 1.9) in five patients. Deficient habituation of the blink reflex was not associated with DVRs of 11CNNC 756 or 11C-raclopride, or D1/D2 ratio in the striatum. Neither were there any statistically significant correlations between the DVRs of 11C-NNC 756 or 11C-raclopride, or D1/D2 ratio and 18F-FDOPA Ki in the seven patients who had participated in the previous 18F-FDOPA (Ja¨ a¨ skela¨ inen et al., 2001) study (data not shown). None of the eight patients who underwent psychiatric evaluation had a current or previous psychotic disorder. 4. Discussion The results of this study show increased 11C-raclopride uptake and a subsequent decrease in the D1/D2 ratio in the
Fig. 3. An example of 11C-raclopride (upper row) and 11C-NNC 756 (lower row) PET scan of a typical burning mouth patient. The dopamine D2 receptor antagonist 11C-raclopride binds to striatal D2 receptors, whereas the dopamine D1 receptor antagonist 11C-NNC 756 uptake demonstrates D1 receptor distribution.
putamen in burning mouth patients when compared to healthy controls. The striatal uptake of 11C-NNC 756 in patients did not differ from controls. The increased D2 receptor binding may reflect depletion of endogenous dopamine in the putamen, and the findings thus support the presumption of nigrostriatal dopaminergic hypofunction in the pathophysiology of burning mouth syndrome. Dopamine D2 receptor binding has been shown to decline with age (Wong et al., 1984; Rinne et al., 1993) and an agerelated loss of D1 receptors has been demonstrated in the human brain as well (Rinne et al., 1990; Wang et al., 1998). However, the impact of aging on D1/D2 ratio is unclear. In this study, we found no association between striatal D1/D2 ratio and age either in burning mouth patients or healthy controls, except for the right putamen where there was a positive correlation in the control group. As our patients were slightly older than controls, the influence of age on the uptake of 11C-raclopride would have led to a decrease rather than the observed increase. Several analytical approaches can be applied to receptor PET data. To be able to compare the uptakes of 11C-NNC 756 and 11C-raclopride, we used the linear graphical method which is applicable to both radioligands (Logan et al., 1996). In the region of interest based analysis, striatal 11C-raclopride uptake in burning mouth patients tended to be higher. To further evaluate the possible difference between patients and controls, we applied a novel voxelbased analysis to the 11C-NNC 756 and 11C-raclopride PET data. In this analysis, a statistically significant increase in the DVR of 11C-raclopride in the left putamen was seen in the patient group. The voxel-based method discards many sources of error such as problems with coregistration of MRI and PET images, or manual delineation of regions of interest, and it may reveal subtle changes in radioligand uptake not detected by conventional region-of-interest based methods. Animal studies suggest that not only the mesolimbic but also the nigrostriatal dopaminergic pathway is involved in pain modulation. Increased dopamine levels in the nucleus accumbens inhibit pain (see for review, Altier and Stewart, 1999). In line with this, a lesion of striatal neurons by kainic acid (Lin et al., 1984) and striatal dopaminergic terminals by 6-hydroxydopamine (Lin et al., 1981; Saade´ et al., 1997) have been shown to facilitate pain responses in rats. Although animal models are poor equivalents of clinical chronic pain in man, tonic (prolonged) pain induced by the formalin test (Dennis and Melzack, 1983; Morgan and Franklin, 1991; Altier and Stewart, 1998; Magnusson and Fisher, 2000) or autotomy following peripheral neurectomy (Saade´ et al., 1997) in laboratory rats appear to involve the dopaminergic system. Similarily, brain imaging studies in healthy human volunteers show activation of striatal areas by painful stimuli (Jones et al., 1991; Coghill et al., 1999). Despite findings from animal studies and some preliminary work from human imaging studies the involvement of dopamine in pain is unclear. Receptor PET technology needs to
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be applied in order to evaluate the role of various neurotransmitter systems in clinical pain conditions. Burning mouth patients typically exhibit pain symptoms bilaterally in the mouth and the most commonly affected sites are the tongue and the lips. The intensity of the symptoms may vary during the day and for most patients, the pain remains fairly constant over the years (Zakrzewska, 1995). Similarily, most of our patients had bilateral symptoms. In the voxel-based analysis, however, the observed increase in the uptake of 11C-raclopride was lateralized to the left putamen although there was a tendency on the right side as well in the region of interest based analysis. The lack of association between the lateralization of our PET results and the location of symptoms or electrophysiological findings may be due to the small number of patients, or it may reflect a heterogeneous etiology of this pain state. In addition, we cannot rule out the possibility that some patients may exhibit a dysfunction in the mesolimbic dopaminergic pathway instead of the nigrostriatal. A high-affinity D2 receptor ligand such as 11C-FLB 457 would be needed to study extrastriatal D2 receptor binding in cortical areas where the receptor density is low. 11 C-Raclopride uptake is sensitive to changes in endogenous dopamine concentrations (Young et al., 1991; Dewey et al., 1993), whereas 11C-NNC 756 uptake is not affected by an endogenous dopamine surge (Abi-Dargham et al., 1999). We have previously demonstrated that burning mouth patients exhibit diminished 18F-FDOPA uptake in the putamen when compared to healthy age-matched controls (Ja¨ a¨ skela¨ inen et al., 2001). Although 18F-FDOPA uptake does not directly measure dopamine concentration, experimental studies in monkeys have suggested that 18F-FDOPA is a good index of striatal dopamine levels (Yee et al., 2001). Thus, the increased 11C-raclopride uptake in burning mouth patients could result in lowered D1/D2 ratio reflecting diminished endogenous dopamine levels in the putamen. Another possible explanation for the observed difference in the D1/D2 ratio between patients and controls might be an imbalance between D1 and D2 receptor mediated pathways, as it has been proposed that the interaction of D1 and D2 receptors is disrupted early in pathological conditions involving the basal ganglia area (Shi et al., 2000). In conclusion, the results of this study are in line with our earlier findings of diminished 18F-FDOPA uptake in the putamen in burning mouth patients. Increased 11C-raclopride uptake and the subsequent decrease in the D1/D2 ratio may indicate a decline in endogenous dopamine levels in the putamen in burning mouth patients. Our results support the findings of previous animal studies, which suggest that striatal dopamine plays an inhibitory role in central pain modulation.
Acknowledgements We want to thank the staff of Turku PET Center for
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excellent technical assistance. This study was supported by grants from the Finnish Association for the Study of Pain, Turku University Central Hospital and Finnish Dental Association.
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