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.
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.
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.
Trigeminal neuropathic pain (TNP) disorders, such as classical, atypical and postherpetic neuralgias, are persistent pain conditions that can be either spontaneous, or elicited by light touch to the face
. The fact that the current therapeutic modalities that focus only on peripheral mechanisms (e.g. microvascular decompression and percutaneous stereotactic rhizotomy) do not provide long lasting relief for these frequently treatment-refractory patients raises the possibility that the causes for the chronicity of those debilitating disorders may also be related to central nervous system alterations. In fact, cortical thickness changes were found in TNP patients, which co-localized with functional (de)activation following allodynic stimulation (brush induced pain)
. Furthermore, those neuroplastic changes in the TNP patients were confined to cortical systems associated with pain experience and modulation, especially associated with the μ-opioidergic system, arguably one of the mechanisms centrally involved in the regulation of multiple aspects of the pain experience
Studies with positron emission tomography (PET) using non-selective (e.g., 11C]diprenorphine) radiotracers or 11C]carfentanil, a selective μ-opioid receptor (μOR) radiotracer, have shown reduced opioid receptor availability in chronic pain syndromes such as rheumatoid arthritis
, neuropathic pain
 and complex regional pain syndrome
. Such findings might represent either greater occupancy of opioid receptors by their endogenous ligands, down-regulation of opioid receptors after persistent activation during pain, or both
. At the present time, it is unknown whether the μ-opioid system is involved in TNP, and the clinical consequences of that involvement. A down-regulation of μORs could explain hypersensitivity (e.g., allodynia, comorbidity with other pain disorders) and frequent treatment refractoriness, including that to opiate medications. Hence, in this preliminary study we investigated changes in the baseline μORs BPND in patients diagnosed with TNP when compared to age-matched pain-free healthy subjects. Based on the existing literature, we hypothesized that patients suffering from TNP would show reduced μOR BPND in regions related to pain regulation, possibly representing persistent activation of the endogenous opioid system and subsequent dysregulation due to the ongoing pain. To our knowledge, this is the first study investigating changes in the endogenous μ-opioid system of patients with TNP in vivo.
Materials and methods
We recruited four right-handed refractory TNP patients (three males and one female; mean age = 50.5 ± 16.5), and eight gender and age-matched healthy subjects (six males and two females, mean age = 44.1 ± 14.9). The selection of TNP patients met the criteria defined by the International Headache Society (IHS)
, American Academy of Orofacial Pain (AAOP)
 and International Association for the Study of Pain (IASP) Terminology
. We only included patients with: A) TNP for at least six months not adequately controlled by previous medicine therapies; B) Minimal average pain score of 4 (moderate to severe) in the visual analogue scale (VAS); C) Unilateral pain; D) Orofacial allodynic region to mechanical (light touch) or thermal stimulation (heat or cold) and E) ages from 18 to 65. The exclusion criteria included: A) Evidence of other local pathology (e.g., orofacial lesion); B) Recent unrelated orofacial surgery or trauma (< 6 months); C) History of systemic disorders (e.g., multiple sclerosis) or D) Chronic pain other than TNP (e.g., back pain or migraine); E) Use of narcotic analgesics (< 6 months); F) Major psychiatric illnesses (current schizophrenia, major depression with suicidal ideation, or substance abuse within two years); and G) Contra-indications to PET. All healthy controls were: right handed; with ages between 18 and 65 years old; with no history of chronic medical illnesses. Approximately 43 subjects applied to participate in the TNP group. However, only four were considered eligible and completed the study. The reasons that determined the exclusion of subjects for this group were: age (1), overweight (9), presence of other chronic pain disorders (18), multiple sclerosis (4) and use of opioid medication (7). Patients in opioid therapy were not recruited for this study. However, the use of other types of medications (e.g. analgesics, anticonvulsants and antidepressants) was not part of the exclusion criteria. This research investigation was carried out in accordance with the bioethical rules for studies involving human beings of the WMA (World Medical Association)––Declaration of Helsinki (1990), and all of the procedures applied were approved by the University of Michigan Investigational Review Board for Human Subject Use, and the Radioactive Drug Research Committee of the US Food and Drug Administration. All subjects gave written informed consent prior to the participation in the study.
All subjects were initially screened by obtaining the medical history, and performing a clinical orofacial pain exam by a pain specialist. During this visit each subject was asked to complete the McGill Pain Questionnaire (MPQ)
, which provided quantitative measures of clinical pain. This questionnaire has three major classes of pain descriptors (sensory, affective and evaluative), used to measure the subjective pain experience. It also provides the total Pain Rating Index (PRI), based on the rank values of the words selected as descriptors and the Present Pain Intensity (PPI), a 0–5 intensity scale. In addition to the MPQ, patients with TNP were requested to complete an craniofacial pain map
. Implemented in an in-house mobile application (PainTrek®, University of Michigan), this method provides a 3D head and facial map based on a squared grid system with vertical and horizontal coordinates using anatomical landmarks. Each quadrangle, measuring approximately 1.6 cm × 1.6 cm, frames well-detailed craniofacial and cervical areas and can be filled by the patient to express his/her exact pain location. The method allowed the investigators to precisely localize and measure the total pain area, as well as the dermatomes involved in each TNP patient (Figure
A T1-weighted anatomical MRI scan was acquired on a 3 Tesla scanner (General Electric, Milwaukee, WI). The MRI acquisition utilized the following sequence parameters: axial spoiled-gradient recalled (SPGR) 3D acquisition, 15.63 bandwidth, repetition time [TR] = 9.2 ms, echo time [TE] = 1.9 ms, inversion recovery preparation 500 ms, flip angle = 15°, 25/26 FOV, number of excitations [NEX] = 1, 144 contiguous slices, 1.0 mm slice thickness, 256 x 256 matrix. VBM8 toolbox (
http://dbm.neuro.uni-jena.de/vbm.html) in SPM8 (Wellcome Department of Imaging Neuroscience Group, London, UK) was used for the normalization of the MRI data to MNI (Montreal Neurological Institute) space. PET scans (HR+ scanner; Siemens, Knoxville, TN) were acquired in 3D mode (reconstructed full-width/half-maximum resolution 5.5 mm in-plane and 5.0 mm axially), with septa retracted and scatter correction. Tracer quantity 11C]carfentanil was administered (10–15 mCi, ≤ 0.03 μg/kg) through an intravenous line (50% in initial bolus and remainder continuously infused to more rapidly achieve constant plasma concentrations). 11C]carfentanil was synthesized at high specific activity (> 2000 Ci/mmol) by the reaction of 11C]methyliodide and a non-methyl precursor as previously described
[13, 14]. Images were decay-corrected and reconstructed, and the dynamic frames were coregistered to each other and transformed into tracer transport (K1 ratio) and receptor-related (BPND, binding potential) measures. To avoid the need for arterial blood sampling, these measures were calculated using a modified Logan graphical analysis
, with occipital cortex (a region devoid of μ- opioid receptors) as the reference region. After 5–7 minutes of radiotracer administration, the Logan plot becomes linear with slope = BPND + 1, which is proportional to μOR concentrations (Bmax)/receptor radiotracer affinity (Kd) (Bmax/Kd ≈ BPND). PET images were co-registered to the individual T1-weighted MRI and then normalized by applying the deformation matrix obtained from the normalization of the T1-weighted MRI data to μOR binding maps.
The control subjects and patients with TNP were compared voxel-by-voxel using unpaired t-test on μOR BPND data. In view of the small sample size of this pilot study, we set significance at p ≤ 0.001, uncorrected with a priori hypothesis (regions involved in pain modulation). Cluster size is reported for voxels with p < 0.01 in the area of statistical significance.
No age differences were found between groups (TNP and healthy controls, unpaired t-test, t = 0.676, p = 0.86). TNP patients had average pain duration of 5.4 ± 1.6 years; two patients presented with either spontaneous or evoked pain, while the other two presented both pain modalities. On a scale from 0 to 10 (zero representing no pain and ten representing worst pain possible) the average of spontaneous pain intensity (n = 3) was 5.5 ± 1.3, while the average of evoked pain (n = 3) was 5.4 ± 3.9. All TNP patients had previously tried medications for pain control, including: carbamazepine (subject TNP 3), oxcarbazepine, gabapentin (subjects TNP1 and TNP4), pregabalin (subjects TNP 2 and TNP 4) and amitriptyline (subject TNP 2). Subjects TNP1, TNP2 and TNP3 were under pain control medication during the study. As described before, patients taking opioids were not recruited for this study. The Figure
1 summarizes the main clinical characteristics from each TNP patient included in this study.
TNP patients displayed a significant reduction of the μOR BPND in the ventral striatal area (z = 2.98, cluster size 989 mm3, p = 0.001) of the basal ganglia, with the greatest difference being found in the left nucleus accumbens (NAc) (peak MNI coordinates x/y/z: -4/4/-5). (Figure
The correlation analysis between clinical pain levels and μOR BPND availability in TNP patients showed that McGill Total PRI scores coincided with reduced μOR in the left NAc. Reduced μOR BPND in the left NAc was also associated to higher McGill sensory subscale scores (Figure
The present study compared the μOR BPND of TNP patients to age-matched healthy controls. We found a significant decrease of μOR BPND in the basal ganglia, located mainly in the left NAc of patients with TNP, when compared to controls. Other groups have found reductions in opioid receptor BPND measured with the non-selective radiotracer 11C]diprenorphine in other chronic pain disorders, such as rheumatoid arthritis
, complex regional pain syndrome
, cluster headache
 and neuropathic pain
[5, 17, 18]. Those changes involved brain regions known to play important roles in pain processing, such as the insula, anterior cingulate cortex, amygdala, hypothalamus, caudate nucleus and NAc. A significant increase in the volume of distribution of 11C]diprenorphine (availability of opioid receptors) was also shown after treatment with radiofrequency thermocoagulation (RFTC) in patients with trigeminal pain
. Our findings reinforce the concept that the ongoing pain experience in TNP is linked to the persistent activation of endogenous opioid neurotransmission and the subsequent downregulation of μ-opioid receptors. Considering the limited number of patients recruited for this study, it is possible that increasing the sample size might expand our results to a broader set of brain structures.
In our study, the most significant peak in binding potential reduction of μ-opioid receptors was in the left nucleus accumbens (NAc) of TNP patients when compared to age-matched healthy subjects (Figure
2D). The NAc is located in the ventral striatum, at the interface of sensorimotor and limbic systems, and is part of the circuit involved in the integration of cognitive, affective and motor responses, which is modulated by the endogenous opioid system
[20–22]. It receives inputs from limbic areas, such as amygdala and prefrontal cortex and projects to different structures, including brainstem and ventral pallidum
. It is largely recognized to be involved in reward and aversive behaviors, and in placebo response
. However, there is substantial evidence from both animal
[25–27] and clinical studies
[3, 24, 28] that the NAc is involved in pain processing, including TNP
. More recently, functional changes in the NAc signal were observed in a model of peripheral nerve injury
, and a decrease in the NAc gray matter volume was demonstrated in TNP patients
. Along similar line, NAc was the only brain region differentiating healthy volunteers and chronic low back pain patients in an fMRI study examining regional brain activations related to acute painful thermal stimulation
[30, 31]. Regarding its relationship to the endogenous μ-opioid system, the NAc was one of the areas where reductions in μOR BPND were identified in fibromyalgia patients when compared to healthy controls. Conversely, short- and long-term increases in the μOR BPND were observed in the same area after traditional chinese acupuncture, which were associated with improvements in clinical pain ratings in fibromyalgia patients
. The results of our study support the evidence of the NAc participation in the pain processing, previously proposed in the Motivation-Decision Model of pain
Differences in function of NAc μ-opioid receptors could ultimately contribute to the clinical pain in trigeminal neuropathic pain disorders. A negative relationship was detected between the μOR BPND in the left NAc and the McGill scores (MPQPRI and MPQ sensory) in sample of four TNP patients (Figure
2E). Subjects with higher McGill scores exhibited lower μOR BPND, and subjects with lower McGill scores displayed higher μOR BPND. Although the reduced sample size limits the conclusions about this relationship, the results suggest a relationship between the clinical presentation of TNP disorders, and μ-opioid neurotransmission in the NAc, an area related to both pain processing and motivational mechanism. Based on our results, it is possible to hypothesize that the chronicity of trigeminal neuropathic pain is also related to central nervous system molecular neuroplasticity at the level of the μORs in the limbic area of the basal ganglia. This initial proof of concept study supports the initiation of further studies to examine the central molecular mechanisms, such as endogenous opioid neurotransmission, that may influence the clinical course and treatment responses of patients afflicted with persistent TNP.
This work was supported by the following grants: Dr. DaSilva was supported by MICHR Clinical Trial Planning Program/CTSA high-tech funding UL1RR024986, University of Michigan. Dr. Santos was also supported by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Brazil, and by the University of Michigan, Ann Arbor, USA. Dr. Martikainen was supported by the Swedish Cultural Foundation in Finland, Helsinki, Finland. The authors acknowledge the PET Center Nuclear Medicine Technologists (Jill M. Rothley, Edward J. McKenna Andrew R. Weeden and Paul Kison).
Headache & Orofacial Pain Effort (H.O.P.E.), Department of Biologic and Materials Sciences and MCOHR, School of Dentistry, University of Michigan
Translational Neuroimaging Laboratory, Molecular and Behavioral Neuroscience Institute (MBNI), University of Michigan
Faculdade de Medicina, Universidade Federal do Rio de Janeiro
Faculdade de Odontologia, Universidade Federal do Rio de Janeiro
UM3D Lab, Digital Media Commons/MLibrary, University of Michigan
DaSilva AF, DosSantos MF: The role of sensory fiber demography in trigeminal and postherpetic neuralgias.J Dent Res 2012, 91: 17–24. 10.1177/0022034511411300PubMed CentralView ArticlePubMed
DaSilva AF, Becerra L, Pendse G, Chizh B, Tully S, Borsook D: Colocalized structural and functional changes in the cortex of patients with trigeminal neuropathic pain.PLoS One 2008, 3: e3396. 10.1371/journal.pone.0003396PubMed CentralView ArticlePubMed
Zubieta J, Smith Y, Bueller J, Xu Y, Kilbourn M, Jewett D, Meyer C, Koeppe R, Stohler C: Regional mu opioid receptor regulation of sensory and affective dimensions of pain.Science 2001, 293: 311–315. 10.1126/science.1060952View ArticlePubMed
Jones AK, Cunningham VJ, Ha-Kawa S, Fujiwara T, Luthra SK, Silva S, Derbyshire S, Jones T: Changes in central opioid receptor binding in relation to inflammation and pain in patients with rheumatoid arthritis.Br J Rheumatol 1994, 33: 909–916. 10.1093/rheumatology/33.10.909View ArticlePubMed
Maarrawi J, Peyron R, Mertens P, Costes N, Magnin M, Sindou M, Laurent B, Garcia-Larrea L: Differential brain opioid receptor availability in central and peripheral neuropathic pain.Pain 2007, 127: 183–194. 10.1016/j.pain.2006.10.013View ArticlePubMed
Harris RE, Clauw DJ, Scott DJ, McLean SA, Gracely RH, Zubieta JK: Decreased central mu-opioid receptor availability in fibromyalgia.J Neurosci 2007, 27: 10000–10006. 10.1523/JNEUROSCI.2849-07.2007View ArticlePubMed
Klega A, Eberle T, Buchholz HG, Maus S, Maihöfner C, Schreckenberger M, Birklein F: Central opioidergic neurotransmission in complex regional pain syndrome.Neurology 2010, 75: 129–136. 10.1212/WNL.0b013e3181e7ca2eView ArticlePubMed
Society IH: The International Classification of Headache Disorders.Cephalagia 2004, 24: 1–160.
Okeson J: Orofacial Pain: guidelines for assessment, classification, and management/the American Academy of Orofacial Pain. Carol Stream: Quitessencen Publishing Co; 1996.
Taxonomy ITFo: Classification of Chronic Pain. IASP Press: Second Edition ed. Seattle; 1994.
Melzack R: The McGill Pain Questionnaire: major properties and scoring methods.Pain 1975, 1: 277–299. 10.1016/0304-3959(75)90044-5View ArticlePubMed
DaSilva: Somatotopic activation in the human trigeminal pain pathway. Harvard University, School of Dental Medicine: PhD thesis; 2002.
Dannals RF, Ravert HT, Frost JJ, Wilson AA, Burns HD, Wagner HN: Radiosynthesis of an opiate receptor binding radiotracer: [11C]carfentanil.Int J Appl Radiat Isot 1985, 36: 303–306. 10.1016/0020-708X(85)90089-4View ArticlePubMed
Jewett DM: A simple synthesis of [11C]carfentanil using an extraction disk instead of HPLC.Nucl Med Biol 2001, 28: 733–734. 10.1016/S0969-8051(01)00226-8View ArticlePubMed
Logan J, Fowler JS, Volkow ND, Wang GJ, Ding YS, Alexoff DL: Distribution volume ratios without blood sampling from graphical analysis of PET data.J Cereb Blood Flow Metab 1996, 16: 834–840.View ArticlePubMed
Sprenger T, Willoch F, Miederer M, Schindler F, Valet M, Berthele A, Spilker ME, Förderreuther S, Straube A, Stangier I, et al.: Opioidergic changes in the pineal gland and hypothalamus in cluster headache: a ligand PET study.Neurology 2006, 66: 1108–1110. 10.1212/01.wnl.0000204225.15947.f8View ArticlePubMed
Willoch F, Schindler F, Wester HJ, Empl M, Straube A, Schwaiger M, Conrad B, Tölle TR: Central poststroke pain and reduced opioid receptor binding within pain processing circuitries: a [11C]diprenorphine PET study.Pain 2004, 108: 213–220. 10.1016/j.pain.2003.08.014View ArticlePubMed
Jones AK, Watabe H, Cunningham VJ, Jones T: Cerebral decreases in opioid receptor binding in patients with central neuropathic pain measured by [11C]diprenorphine binding and PET.Eur J Pain 2004, 8: 479–485. 10.1016/j.ejpain.2003.11.017View ArticlePubMed
Jones AK, Kitchen ND, Watabe H, Cunningham VJ, Jones T, Luthra SK, Thomas DG: Measurement of changes in opioid receptor binding in vivo during trigeminal neuralgic pain using [11C] diprenorphine and positron emission tomography.J Cereb Blood Flow Metab 1999, 19: 803–808.View ArticlePubMed
Love TM, Stohler CS, Zubieta JK: Positron emission tomography measures of endogenous opioid neurotransmission and impulsiveness traits in humans.Arch Gen Psychiatry 2009, 66: 1124–1134. 10.1001/archgenpsychiatry.2009.134PubMed CentralView ArticlePubMed
Mogenson GJ, Yang CR: The contribution of basal forebrain to limbic-motor integration and the mediation of motivation to action.Adv Exp Med Biol 1991, 295: 267–290. 10.1007/978-1-4757-0145-6_14View ArticlePubMed
Cooper JC, Knutson B: Valence and salience contribute to nucleus accumbens activation.Neuroimage 2008, 39: 538–547. 10.1016/j.neuroimage.2007.08.009PubMed CentralView ArticlePubMed
Becerra L, Borsook D: Signal valence in the nucleus accumbens to pain onset and offset.Eur J Pain 2008, 12: 866–869. 10.1016/j.ejpain.2007.12.007PubMed CentralView ArticlePubMed
Scott DJ, Stohler CS, Egnatuk CM, Wang H, Koeppe RA, Zubieta JK: Individual differences in reward responding explain placebo-induced expectations and effects.Neuron 2007, 55: 325–336. 10.1016/j.neuron.2007.06.028View ArticlePubMed
Gear RW, Levine JD: Antinociception produced by an ascending spino-supraspinal pathway.J Neurosci 1995, 15: 3154–3161.PubMed
Imai S, Saeki M, Yanase M, Horiuchi H, Abe M, Narita M, Kuzumaki N, Suzuki T: Change in microRNAs associated with neuronal adaptive responses in the nucleus accumbens under neuropathic pain.J Neurosci 2011, 31: 15294–15299. 10.1523/JNEUROSCI.0921-11.2011View ArticlePubMed
Scott DJ, Heitzeg MM, Koeppe RA, Stohler CS, Zubieta JK: Variations in the human pain stress experience mediated by ventral and dorsal basal ganglia dopamine activity.J Neurosci 2006, 26: 10789–10795. 10.1523/JNEUROSCI.2577-06.2006View ArticlePubMed
Gustin SM, Peck CC, Wilcox SL, Nash PG, Murray GM, Henderson LA: Different pain, different brain: thalamic anatomy in neuropathic and non-neuropathic chronic pain syndromes.J Neurosci 2011, 31: 5956–5964. 10.1523/JNEUROSCI.5980-10.2011View ArticlePubMed
Baliki MN, Geha PY, Fields HL, Apkarian AV: Predicting value of pain and analgesia: nucleus accumbens response to noxious stimuli changes in the presence of chronic pain.Neuron 2010, 66: 149–160. 10.1016/j.neuron.2010.03.002PubMed CentralView ArticlePubMed
Zubieta JK: Pain signal as threat and reward.Neuron 2010, 66: 6–7. 10.1016/j.neuron.2010.04.002View ArticlePubMed
Harris RE, Zubieta JK, Scott DJ, Napadow V, Gracely RH, Clauw DJ: Traditional Chinese acupuncture and placebo (sham) acupuncture are differentiated by their effects on mu-opioid receptors (MORs).Neuroimage 2009, 47: 1077–1085. 10.1016/j.neuroimage.2009.05.083PubMed CentralView ArticlePubMed
Fields HL: Understanding how opioids contribute to reward and analgesia.Reg Anesth Pain Med 2007, 32: 242–246.View ArticlePubMed
Leknes S, Tracey I: A common neurobiology for pain and pleasure.Nat Rev Neurosci 2008, 9: 314–320.View ArticlePubMed
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (
http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.