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1.  Characterization of mouse orofacial pain and the effects of lesioning TRPV1-expressing neurons on operant behavior 
Molecular Pain  2008;4:43.
Background
Rodent models of orofacial pain typically use methods adapted from manipulations to hind paw; however, limitations of these models include animal restraint and subjective assessments of behavior by the experimenter. In contrast to these methods, assessment of operant responses to painful stimuli has been shown to overcome these limitations and expand the breadth of interpretation of the behavioral responses. In the current study, we used an operant model based on a reward-conflict paradigm to assess nociceptive responses in three strains of mice (SKH1-Hrhr, C57BL/6J, TRPV1 knockout). We previously validated this operant model in rats and hypothesized in this study that wild-type mice would demonstrate a similar thermal stimulus-dependent response and similar operant pain behaviors. Additionally, we evaluated the effects on operant behaviors of mice manipulated genetically (e.g., TRPV1 k.o.) or pharmacologically with resiniferatoxin (RTX), a lesioning agent for TRPV1-expressing neurons. During the reward-conflict task, mice accessed a sweetened milk reward solution by voluntarily position their face against a neutral or heated thermode (37–55°C).
Results
As the temperature of the thermal stimulus became noxiously hot, reward licking events in SKH1-Hrhr and C57BL/6J mice declined while licking events in TRPV1 k.o. mice were insensitive to noxious heat within the activation range of TRPV1 (37–52°C). All three strains displayed nocifensive behaviors at 55°C, as indicated by a significant decrease in reward licking events. Induction of neurogenic inflammation by topical application of capsaicin reduced licking events in SKH1-Hrhr mice, and morphine rescued this response. Again, these results parallel what we previously documented using rats in this operant system. Following intracisternal treatment with RTX, C57BL/6J mice demonstrated a block of noxious heat at both 48 and 55°C. RTX-treated TRPV1 k.o. mice and all vehicle-treated mice displayed similar reward licking events as compared to the pre-treatment baseline levels. Both TRPV1 k.o. and RTX-treated C57BL/6J had complete abolishment of eye-wipe responses following corneal application of capsaicin.
Conclusion
Taken together, these results indicate the benefits of using the operant test system to investigate pain sensitivity in mice. This ability provides an essential step in the development of new treatments for patients suffering from orofacial pain disorders.
doi:10.1186/1744-8069-4-43
PMCID: PMC2584042  PMID: 18828909
2.  Orofacial pain management: current perspectives 
Journal of Pain Research  2014;7:99-115.
Some of the most prevalent and debilitating pain conditions arise from the structures innervated by the trigeminal system (head, face, masticatory musculature, temporomandibular joint and associated structures). Orofacial pain (OFP) can arise from different regions and etiologies. Temporomandibular disorders (TMD) are the most prevalent orofacial pain conditions for which patients seek treatment. Temporomandibular disorders include a number of clinical problems that involve the masticatory musculature, the temporomandibular joint (TMJ) or both. Trigeminal neuropathic pain conditions can arise from injury secondary to dental procedures, infection, neoplasias, or disease or dysfunction of the peripheral and/or central nervous system. Neurovascular disorders, such as primary headaches, can present as chronic orofacial pain, such as in the case of facial migraine, where the pain is localized in the second and third division of the trigeminal nerve. Together, these disorders of the trigeminal system impact the quality of life of the sufferer dramatically. A multidisciplinary pain management approach should be considered for the optimal treatment of orofacial pain disorders including both non-pharmacological and pharmacological modalities.
doi:10.2147/JPR.S37593
PMCID: PMC3937250  PMID: 24591846
pain; orofacial; neuropathic; TMD; trigeminal; headache
3.  Assessment of chronic trigeminal neuropathic pain by the orofacial operant test in rats 
Behavioural brain research  2012;234(1):82-90.
Classical behavioral tests in animal models of trigeminal neuropathic pain measure reflexive responses that are not necessarily measures of pain. To overcome the problem, we created a chronic constrictive nerve injury rat model of pain (CCI) by ligation of the infraorbital nerve (ION), and applied the orofacial operant test to assess behavioral responses to mechanical and cold stimulation in these rats. Animals were trained to voluntarily contact their facial region to a mechanical or a cold stimulation module in order to access sweetened milk as a positive reward. ION-CCI rats displayed aversive behaviors to innocuous mechanical stimuli, as indicated by a significant decrease in both contact time and the numbers of long contact events in comparison with sham group. For cold stimulation, ION-CCI rats displayed aversive behaviors to both innocuous (17 °C) and noxious cold temperatures (12 °C and 5 °C), as indicated by a significant decrease in both contact time and the numbers of long contact events at the cooling temperatures. The decreases of the contact time and numbers in ION-CCI rats were partially abolished by morphine. Our orofacial operant test demonstrates mechanical allodynia, cold allodynia, and hyperalgesia in rats with chronic trigeminal nerve injury. The neuropathic pain in ION-CCI rats was partially alleviated by morphine. Thus, orofacial operant test provides a desirable behavioral assessment method for preclinical studies of chronic trigeminal neuropathic pain.
doi:10.1016/j.bbr.2012.06.020
PMCID: PMC3418659  PMID: 22743005
Trigeminal neuropathic pain; Mechanical allodynia; Cold allodynia; Behavioral assessment; Operant behavior
4.  Influences of adult-onset diabetes on orofacial pain and related health behaviors 
Journal of public health dentistry  2010;70(2):10.1111/j.1752-7325.2009.00147.x.
OBJECTIVES
This study tested the hypothesis that persons with orofacial pain and comorbid adult-onset diabetes will experience greater functional and emotional impact than persons experiencing orofacial pain without diabetes.
METHODS
A random-digit dialing sampling procedure was used for a disproportionate probability sample of 10,341 persons who were screened for orofacial pain in the past 6 months and diabetes. This paper reports on 1,767 individuals reporting toothache pain and 877 reporting painful oral sores. A structured telephone interview assessed diabetes history, orofacial pain characteristics, oral health care behaviors, and emotional and functional impacts of orofacial pain.
RESULTS
The 6-month point prevalence was 16.8% for toothache pain, 8.9% for painful oral sores, and 9.6% for adult-onset diabetes. Individuals with comorbid orofacial pain and adult-onset diabetes differed significantly on many of the pain characteristics and health behaviors compared to non-diabetic sufferers of orofacial pain. Diabetics were more likely than non-diabetics to have pain every day, to suffer negative emotions associated with pain, to experience disruption of daily activities and sleep, to make an emergency room visit for orofacial pain, and to report the current need for a pain-related health care visit.
CONCLUSIONS
Although diabetes is well known to be associated with neuropathic pain, these results indicate that the experience of nociceptive pain is exacerbated by diabetes. Findings have significance for the subjective experience of oral pain, dental care outcomes and health-related quality of life associated with oral health outcomes among individuals with diabetes.
doi:10.1111/j.1752-7325.2009.00147.x
PMCID: PMC3813016  PMID: 19765201
orofacial pain; diabetes; toothache; self-care; self-medication
5.  Metabotropic glutamate receptor 5 contributes to inflammatory tongue pain via extracellular signal-regulated kinase signaling in the trigeminal spinal subnucleus caudalis and upper cervical spinal cord 
Background
In the orofacial region, limited information is available concerning pathological tongue pain, such as inflammatory pain or neuropathic pain occurring in the tongue. Here, we tried for the first time to establish a novel animal model of inflammatory tongue pain in rats and to investigate the roles of metabotropic glutamate receptor 5 (mGluR5)-extracellular signal-regulated kinase (ERK) signaling in this process.
Methods
Complete Freund’s adjuvant (CFA) was submucosally injected into the tongue to induce the inflammatory pain phenotype that was confirmed by behavioral testing. Expression of phosphorylated ERK (pERK) and mGluR5 in the trigeminal subnucleus caudalis (Vc) and upper cervical spinal cord (C1-C2) were detected with immunohistochemical staining and Western blotting. pERK inhibitor, a selective mGluR5 antagonist or agonist was continuously administered for 7 days via an intrathecal (i.t.) route. Local inflammatory responses were verified by tongue histology.
Results
Submucosal injection of CFA into the tongue produced a long-lasting mechanical allodynia and heat hyperalgesia at the inflamed site, concomitant with an increase in the pERK immunoreactivity in the Vc and C1-C2. The distribution of pERK-IR cells was laminar specific, ipsilaterally dominant, somatotopically relevant, and rostrocaudally restricted. Western blot analysis also showed an enhanced activation of ERK in the Vc and C1-C2 following CFA injection. Continuous i.t. administration of the pERK inhibitor and a selective mGluR5 antagonist significantly depressed the mechanical allodynia and heat hyperalgesia in the CFA-injected tongue. In addition, the number of pERK-IR cells in ipsilateral Vc and C1-C2 was also decreased by both drugs. Moreover, continuous i.t. administration of a selective mGluR5 agonist induced mechanical allodynia in naive rats.
Conclusions
The present study constructed a new animal model of inflammatory tongue pain in rodents, and demonstrated pivotal roles of the mGluR5-pERK signaling in the development of mechanical and heat hypersensitivity that evolved in the inflamed tongue. This tongue-inflamed model might be useful for future studies to further elucidate molecular and cellular mechanisms of pathological tongue pain such as burning mouth syndrome.
doi:10.1186/1742-2094-9-258
PMCID: PMC3543209  PMID: 23181395
Metabotropic glutamate receptor 5; Extracellular signal-regulated kinase; Tongue pain; Inflammation; Trigeminal subnucleus caudalis; Upper cervical spinal cord
6.  The Dolognawmeter: A Novel Instrument and Assay to Quantify Nociception in Rodent Models of Orofacial Pain 
Journal of neuroscience methods  2010;187(2):207-215.
Rodent pain models play an important role in understanding the mechanisms of nociception and have accelerated the search for new treatment approaches for pain. Creating an objective metric for orofacial nociception in these models presents significant technical obstacles. No animal assay accurately measures pain-induced orofacial dysfunction that is directly comparable to human orofacial dysfunction. We developed and validated a high throughput, objective, operant, nociceptive animal assay, and an instrument to perform the assay termed the dolognawmeter, for evaluation of conditions known to elicit orofacial pain in humans. Using the device our assay quantifies gnawing function in the mouse. We quantified a behavioral index of nociception and demonstrated blockade of nociception in three models of orofacial pain: (1) TMJ inflammation, (2) masticatory myositis, and (3) head and neck cancer. This assay will be useful in the study of nociceptive mediators involved in the development and progression of orofacial pain conditions and it will also provide a unique tool for development and assessment of new therapeutic approaches.
doi:10.1016/j.jneumeth.2010.01.012
PMCID: PMC2832714  PMID: 20096303
orofacial pain; oral cancer; cancer pain; myositis; TMJ pain; nociceptive assay
7.  Orofacial neuropathic pain mouse model induced by Trigeminal Inflammatory Compression (TIC) of the infraorbital nerve 
Molecular Brain  2012;5:44.
Background
Trigeminal neuropathic pain attacks can be excruciating for patients, even after being lightly touched. Although there are rodent trigeminal nerve research models to study orofacial pain, few models have been applied to studies in mice. A mouse trigeminal inflammatory compression (TIC) model is introduced here which successfully and reliably promotes vibrissal whisker pad hypersensitivity.
Results
The chronic orofacial neuropathic pain model is induced after surgical placement of chromic gut suture in the infraorbital nerve fissure in the maxillary bone. Slight compression and chemical effects of the chromic gut suture on the portion of the infraorbital nerve contacted cause mild nerve trauma. Nerve edema is observed in the contacting infraorbital nerve bundle as well as macrophage infiltration in the trigeminal ganglia. Centrally in the spinal trigeminal nucleus, increased immunoreactivity for an activated microglial marker is evident (OX42, postoperative day 70). Mechanical thresholds of the affected whisker pad are significantly decreased on day 3 after chromic gut suture placement, persisting at least 10 weeks. The mechanical allodynia is reversed by suppression of microglial activation. Cold allodynia was detected at 4 weeks.
Conclusions
A simple, effective, and reproducible chronic mouse model mimicking clinical orofacial neuropathic pain (Type 2) is induced by placing chromic gut suture between the infraorbital nerve and the maxillary bone. The method produces mild inflammatory compression with significant continuous mechanical allodynia persisting at least 10 weeks and cold allodynia measureable at 4 weeks.
doi:10.1186/1756-6606-5-44
PMCID: PMC3563613  PMID: 23270529
Orofacial neuropathic pain; Infraorbital nerve; Inflammation; Nerve compression; Chromic gut suture; Mechanical allodynia; Trigeminal ganglia; Trigeminal nucleus; Mice; Hypersensitivy; Tic douloureux
8.  Classifying orofacial pains: a new proposal of taxonomy based on ontology 
Journal of Oral Rehabilitation  2011;39(3):161-169.
SUMMARY
Propose a new taxonomy model based on ontological principles for disorders that manifest themselves through the symptom of persistent orofacial pain and are commonly seen in clinical practice and difficult to manage. Consensus meeting of eight experts from various geographic areas representing different perspectives (orofacial pain, headache, oral medicine and ontology) as an initial step towards improving the taxonomy. Ontological principles were introduced, reviewed and applied during the consensus building process. Diagnostic criteria for persistent dento-alveolar pain disorder (PDAP) were formulated as an example to be used to model the taxonomical structure of all orofacial pain conditions. These criteria have the advantage of being (i) anatomically defined, (ii) in accordance with other classification systems for the provision of clinical care, (iii) descriptive and succinct, (iv) easy to adapt for applications in varying settings, (v) scalable and (vi) transferable for the description of pain disorders in other orofacial regions of interest. Limitations are that the criteria introduce new terminology, do not have widespread acceptance and have yet to be tested. These results were presented to the greater conference membership and were unanimously accepted. Consensus for the diagnostic criteria of PDAP was established within this working group. This is an initial first step towards developing a coherent taxonomy for orofacial pain disorders, which is needed to improve clinical research and care.
doi:10.1111/j.1365-2842.2011.02247.x
PMCID: PMC3383028  PMID: 21848527
Non-odontogenic tooth pain; chronic tooth pain; atypical odontalgia; phantom tooth pain; consensus; taxonomy; ontology; diagnosis; diagnostic criteria
9.  Operant behavioral responses to orofacial cold stimuli in rats with chronic constrictive trigeminal nerve injury: effects of menthol and capsazepine 
Molecular Pain  2013;9:28.
Both spinal and trigeminal somatosensory systems use the TRPM8 channel as a principal transducer for detecting cold stimuli. It is currently unclear whether this cold transducer may play a role in trigeminal neuropathic pain manifesting cold allodynia and hyperalgesia. In the present study, trigeminal neuropathy was induced by chronic constrictive nerve injury of the infraorbital nerve (ION-CCI). Behavioral responses to cold stimuli in orofacial regions were assessed by the newly developed orofacial operant test in the ION-CCI rats. We tested menthol and capsazepine, two compounds that can activate and inhibit TRPM8 respectively, on orofacial operant responses to cold stimuli in ION-CCI rats. Testing animals performed operant tasks by voluntarily contacting their orofacial regions to a cold stimulation module in order to access sweetened milk as a reward, and contact time and number of the operant behaviors were automatically recorded. Total contact time was significantly reduced at the cooling temperatures of 17°C and 12°C in ION-CCI group in comparison with sham group, indicating the presence of cold allodynia and hyperalgesia in ION-CCI rats. When menthol was administered to ION-CCI rats, total contact time was further reduced and total contact number increased at the cooling temperatures. In contrast, after administration of capsazepine to ION-CCI rats, total contact time was significantly increased at the cooling temperatures. The behavioral outcomes support the idea that TRPM8 plays a role in cold allodynia and hyperalgesia following chronic trigeminal nerve injury.
doi:10.1186/1744-8069-9-28
PMCID: PMC3750444  PMID: 23767981
Trigeminal neuropathic pain; TRPM8 channel; Cold allodynia and hyperalgesia; Orofacial operant behavior test; Menthol; Capsazepine
10.  Lesion of the dopaminergic nigrostriatal pathway induces trigeminal dynamic mechanical allodynia 
Brain and Behavior  2014;4(3):368-380.
Background
Pain constitutes the major non motor syndrome in Parkinson's disease (PD) and includes neuropathic pain; however current drug therapies used to alleviate it have only limited efficacy. This is probably due to poor understanding of the mechanisms underlying it.
Aims
We investigated a major class of trigeminal neuropathic pain, dynamic mechanical allodynia (DMA), in a rat model of PD and in which a bilateral 6-hydroxy dopamine (6-OHDA) injection was administered to produce a lesion of the nigrostriatal dopaminergic pathway.
Results and discussion
Lesioned animals presented significant DMA in the orofacial area that occurred from 4 days to 5 weeks post-injury. To investigate a segmental implication in the neuropathic pain induced by dopamine depletion, the expression of the isoform gamma of the protein kinase C (PKCg) and phosphorylated extracellular signal-regulated kinases 1/2 (pERK1/2) was explored in the medullary dorsal horn (MDH). There was a high increase in PKCg expression in the III and IIi laminae of the MDH of lesioned-animals compared to shams. pERK1/2 expression was also significantly high in the ipsilateral MDH of lesioned rats in response to non-noxious tactile stimulus of the orofacial region. Since pERK1/2 is expressed only in response to nociceptive stimuli in the dorsal spinal horn, the current study demonstrates that non-noxious stimuli evoke allodynic response. Intraperitoneal and intracisternal administrations of bromocriptine, a dopamine 2 receptor (D2R) agonist, significantly decreased DMA compared to control rats injected with saline. These data demonstrate for the first time that nigrostriatal dopaminergic depletion produces trigeminal neuropathic pain that at least involves a segmental mechanism. In addition, bromocriptine was shown to have a remarkable analgesic effect on this neuropathic pain symptom.
doi:10.1002/brb3.214
PMCID: PMC4055187  PMID: 24944866
Atypical facial algia; basal ganglia; burning mouth syndrome; orofacial pain; Parkinson disease; trigeminal subnucleus caudalis (Sp5C)
11.  Protective Effect of Leaves of Murraya koenigii on Reserpine-Induced Orofacial Dyskinesia 
Murraya koenigii L. (Rutaceae), commonly known as curry leaf tree, closely associated with south India where the word “curry” originates from the Tamil “kari” for spiced sauces. Curry leaves are a rich source of carbazole alkaloids which possess various biological activities such as antitumor, antioxidant and anti-inflammatory. Curry leaf has a potential role in the treatment of diabetes. Reserpine-induced orofacial dyskinesia in rats is an animal model of tardive dyskinesia that has been linked with free radical generation and oxidative stress. In this study, neuroprotective potential and in-vivo antioxidant status of methanol extract of the leaves of Murraya koenigii (MEMK) in reserpine-induced orofacial dyskinesia are investigated. Reserpine was used to induce orofacial dyskinesia. The effect of MEMK on locomotion and catalepsy was studied using Open-field apparatus and Bar-test, respectively. The effect of MEMK on the levels of protective anti-oxidant enzymes i.e. superoxide dismutase (SOD), catalase (CAT), glutathione reductase (GSH) and inhibited lipid peroxidation (LPO) in forebrain region were investigated in reserpine-treated animals. Results demonstrated that the MEMK significantly inhibited the reserpine-induced vacuous chewing movements (VCM), tongue protrusion (TP), orofacial burst (OB) and catalepsy. MEMK significantly increased the number of squares traversed and rearing in open field apparatus. Treatment with MEMK significantly restored the levels of protective anti-oxidant enzymes i.e. SOD, CAT, GSH and inhibited LPO in forebrain region when compared with reserpine. It also inhibited haloperidol-induced catalepsy. The present study concludes that the oxidative stress might play an important role in reserpine-induced abnormal oral movements, and Murraya koenigii may have great potential in the treatment of neuroleptic-induced orofacial dyskinesia
PMCID: PMC3832166  PMID: 24250488
Vacuous chewing movements; Tongue protrusions; Free radicals; Murraya koenigii
12.  Chemokine CCL2 and its receptor CCR2 in the medullary dorsal horn are involved in trigeminal neuropathic pain 
Background
Neuropathic pain in the trigeminal system is frequently observed in clinic, but the mechanisms involved are largely unknown. In addition, the function of immune cells and related chemicals in the mechanism of pain has been recognized, whereas few studies have addressed the potential role of chemokines in the trigeminal system in chronic pain. The present study was undertaken to test the hypothesis that chemokine C-C motif ligand 2 (CCL2)-chemokine C-C motif receptor 2 (CCR2) signaling in the trigeminal nucleus is involved in the maintenance of trigeminal neuropathic pain.
Methods
The inferior alveolar nerve and mental nerve transection (IAMNT) was used to induce trigeminal neuropathic pain. The expression of ATF3, CCL2, glial fibrillary acidic protein (GFAP), and CCR2 were detected by immunofluorescence histochemical staining and western blot. The cellular localization of CCL2 and CCR2 were examined by immunofluorescence double staining. The effect of a selective CCR2 antagonist, RS504393 on pain hypersensitivity was checked by behavioral testing.
Results
IAMNT induced persistent (>21 days) heat hyperalgesia of the orofacial region and ATF3 expression in the mandibular division of the trigeminal ganglion. Meanwhile, CCL2 expression was increased in the medullary dorsal horn (MDH) from 3 days to 21 days after IAMNT. The induced CCL2 was colocalized with astroglial marker GFAP, but not with neuronal marker NeuN or microglial marker OX-42. Astrocytes activation was also found in the MDH and it started at 3 days, peaked at 10 days and maintained at 21 days after IAMNT. In addition, CCR2 was upregulated by IAMNT in the ipsilateral medulla and lasted for more than 21 days. CCR2 was mainly colocalized with NeuN and few cells were colocalized with GFAP. Finally, intracisternal injection of CCR2 antagonist, RS504393 (1, 10 μg) significantly attenuated IAMNT-induced heat hyperalgesia.
Conclusion
The data suggest that CCL2-CCR2 signaling may be involved in the maintenance of orofacial neuropathic pain via astroglial–neuronal interaction. Targeting CCL2-CCR2 signaling may be a potentially important new treatment strategy for trigeminal neuralgia.
doi:10.1186/1742-2094-9-136
PMCID: PMC3391989  PMID: 22721162
13.  Satellite glial cell P2Y12 receptor in the trigeminal ganglion is involved in lingual neuropathic pain mechanisms in rats 
Molecular Pain  2012;8:23.
Background
It has been reported that the P2Y12 receptor (P2Y12R) is involved in satellite glial cells (SGCs) activation, indicating that P2Y12R expressed in SGCs may play functional roles in orofacial neuropathic pain mechanisms. However, the involvement of P2Y12R in orofacial neuropathic pain mechanisms is still unknown. We therefore studied the reflex to noxious mechanical or heat stimulation of the tongue, P2Y12R and glial fibrillary acidic protein (GFAP) immunohistochemistries in the trigeminal ganglion (TG) in a rat model of unilateral lingual nerve crush (LNC) to evaluate role of P2Y12R in SGC in lingual neuropathic pain.
Results
The head-withdrawal reflex thresholds to mechanical and heat stimulation of the lateral tongue were significantly decreased in LNC-rats compared to sham-rats. These nocifensive effects were apparent on day 1 after LNC and lasted for 17 days. On days 3, 9, 15 and 21 after LNC, the mean relative number of TG neurons encircled with GFAP-immunoreactive (IR) cells significantly increased in the ophthalmic, maxillary and mandibular branch regions of TG. On day 3 after LNC, P2Y12R expression occurred in GFAP-IR cells but not neuronal nuclei (NeuN)-IR cells (i.e. neurons) in TG. After 3 days of successive administration of the P2Y12R antagonist MRS2395 into TG in LNC-rats, the mean relative number of TG neurons encircled with GFAP-IR cells was significantly decreased coincident with a significant reversal of the lowered head-withdrawal reflex thresholds to mechanical and heat stimulation of the tongue compared to vehicle-injected rats. Furthermore, after 3 days of successive administration of the P2YR agonist 2-MeSADP into the TG in naïve rats, the mean relative number of TG neurons encircled with GFAP-IR cells was significantly increased and head-withdrawal reflex thresholds to mechanical and heat stimulation of the tongue were significantly decreased in a dose-dependent manner compared to vehicle-injected rats.
Conclusions
The present findings provide the first evidence that the activation of P2Y12R in SGCs of TG following lingual nerve injury is involved in the enhancement of TG neuron activity and nocifensive reflex behavior, resulting in neuropathic pain in the tongue.
doi:10.1186/1744-8069-8-23
PMCID: PMC3386019  PMID: 22458630
Neuron-Glia interactions; Lingual nerve injury; Mechanical allodynia; Heat hyperalgesia; Purinergic receptor
14.  Effect of pilocarpine on the formalin-induced orofacial pain in rats 
Veterinary Research Forum  2012;3(2):91-95.
In this study, the effects of subcutaneous (SC) injection of pilocarpine (a cholinomimetic agent) and atropine (a muscarinic receptors antagonist) were investigated on a tonic model of orofacial pain in rats. The contribution of the endogenous analgesic opioid system was assessed using naloxone (an opioid receptors antagonist). Tonic orofacial pain was induced by SC injection of a diluted formalin solution (1%, 50 μL) in the right upper lip, and the time spent face rubbing was measured in five min blocks for 1 h. Formalin induced a biphasic (first phase: 0-5 min and second phase: 15-35 min) pain response. Pilocarpine significantly (P < 0.05) suppressed both phases of orofacial pain. Atropine did not have any effect and naloxone non-significantly increased the intensity of pain when used alone. In the pre-injection examinations, atropine prevented, but naloxone did not reverse the antinociceptive effect of pilocarpine. The results indicated that SC injection of formalin in the orofacial region induced a marked biphasic pain. Pilocarpine via muscarinic cholinergic receptors produced antinociceptive effect in the orofacial formalin-induced pain. The endogenous opioid analgesic system may not have a role in pilocarpine-induced antinociception.
PMCID: PMC4312802
Pilocarpine; Atropine; Naloxone; Orofacial pain; Rat
15.  Spontaneous behavioral responses in the orofacial region: A model of trigeminal pain in mouse 
Headache  2012;53(1):137-151.
OBJECTIVES
To develop a translational mouse model for the study and measurement of non-evoked pain in the orofacial region by establishing markers of nociceptive-specific grooming behaviors in the mouse.
BACKGROUND
Some of the most prevalent and debilitating conditions involve pain in the trigeminal distribution. Although there are current therapies for these pain conditions, for many patients they are far from optimal. Understanding the pathophysiology of pain disorders arising from structures innervated by the trigeminal nerve is still limited and most animal behavioral models focus on the measurement of evoked pain. In patients, spontaneous (non-evoked) pain responses provide a more accurate representation of the pain experience than do responses that are evoked by an artificial stimulus. Therefore, the development of animal models that measure spontaneous nociceptive behaviors may provide a significant translational tool for a better understanding of pain neurobiology.
METHODS
C57BL/6 mice received either an injection of 0.9% Saline solution or complete Freund’s adjuvant (CFA) into the right masseter muscle. Animals were video recorded and then analyzed by an observer blind to the experiment group. The duration of different facial grooming patterns performed in the area of injection were measured. After 2 hrs, mice were euthanized, perfused and the brainstem was removed. Fos protein expression in the trigeminal nucleus caudalis was quantified using immunohistochemistry to investigate nociceptive-specific neuronal activation. A separate group of animals was treated with morphine sulfate, to determine the nociceptive-specific nature of their behaviors.
RESULTS
We characterized and quantified 3 distinct patterns of acute grooming behaviors: fore-paw rubbing, lower lip skin/cheek rubbing against enclosure floor and hind paw scratching. These behaviors occurred with a reproducible frequency and time course, and were inhibited by the analgesic morphine. CFA-injected animals also showed Fos labeling consistent with neuronal activation in nociceptive-specific pathways of the trigeminal nucleus after two hours.
CONCLUSIONS
These behaviors and their correlated cellular responses represent a model of trigeminal pain that can be used to better understand basic mechanisms of orofacial pain and identify new therapeutic approaches to this common and challenging condition.
doi:10.1111/j.1526-4610.2012.02226.x
PMCID: PMC3664930  PMID: 22830495
Trigeminal; mouse; orofacial; spontaneous nociception; pain
16.  Involvement of Endoplasmic Reticulum Stress Response in Orofacial Inflammatory Pain 
Experimental Neurobiology  2014;23(4):372-380.
Endoplasmic reticulum (ER) stress is involved in many neurological diseases and inflammatory responses. Inflammatory mediators induce neuronal damage and trigger the neuropathic or inflammatory pain. But there is very little data on the role of the ER stress response in pain mechanisms. In this study, we explored whether the ER stress response is involved in orofacial inflammatory pain by using a complete Freund's adjuvant (CFA)-injected rat model. The thermal pain hypersensitivity increased significantly after CFA injection. We found that the protein and mRNA levels of ER stress response genes, GRP78/Bip and p-eIF2α, increased significantly in trigeminal ganglion (TG) of CFA-injected rats compared to control animals. In immunofluorescence analysis, a significant increase of GRP78 and p-eIF2α immunopositive neurons was observed in CFA-injected TG compared to control TG. When we administered an ER stress modulator, salubrinal, CFA-induced thermal pain hypersensitivity was temporally reduced. Thus, our study suggests that ER stress responses in TG neurons contribute to CFA-induced inflammatory pain, and may comprise an important molecular mechanism underlying the orofacial inflammatory pain pathway.
doi:10.5607/en.2014.23.4.372
PMCID: PMC4276808  PMID: 25548537
ER stress; trigeminal ganglion; inflammatory pain; orofacial pain
17.  Antinociceptive Effects of H3 (R-Methylhistamine) and GABAB (Baclofen)-Receptor Ligands in an Orofacial Model of Pain in Rats 
Neurotoxicity Research  2013;24(2):258-264.
The present study explored the antinociceptive effects of H3 (R-alpha-methylhistamine) and GABAB (baclofen) receptor ligands in an orofacial model of pain in rats. Orofacial pain was induced by subcutaneous injection of formalin (50 μl, 5 %) in the upper lip region, and the number of jumps and time spent face rubbing was recorded for 40 min. Formalin produced a marked biphasic pain response; first phase, 0–10 min (jumps), and second phase, 15–40 min, (rubbing). Baclofen (50 μg) injected into the rat wiskerpad 5 min before formalin administration suppressed both phases of pain whereas R-alpha-methylhistamine (12.5 μg) abolished the first phase only. Brains were taken immediately after behavioral testing was completed. HPLC/ED analysis showed that 5-hydroxytryptamine (5-HT) turnover was increased in hippocampus, thalamus, and brain stem of all formalin groups, excepting the baclofen group in which the balance of 5-HT metabolism was restored to control values. These findings demonstrate that GABAB receptors represent peripheral targets for analgesia. Consequently, locally administered baclofen may be a useful approach in treating inflammatory trigeminal pain.
doi:10.1007/s12640-013-9385-4
PMCID: PMC3691488  PMID: 23463522
H3 receptor; GABAB receptor; Orofacial pain; Formalin test; Rats
18.  Spinal trigeminal neurons demonstrate an increase in responses to dural electrical stimulation in the orofacial formalin test 
Primary headaches are often associated with pain in the maxillofacial region commonly classified under the term “orofacial pain” (OFP). In turn, long-lasting OFP can trigger and perpetuate headache as an independent entity, which is able to persist after the resolution of the main disorder. A close association between OFP and headache complicates their cause and effect definition and leads to misdiagnosis. The precise mechanisms underlying this phenomenon are poorly understood, partly because of the deficiency of research-related findings. We combined the animal models of OFP and headache—the orofacial formalin test and the model of trigeminovascular nociception—to investigate the neurophysiological mechanisms underlying their comorbidity. In anesthetized rats, the ongoing activity of single convergent neurons in the spinal trigeminal nucleus was recorded in parallel to their responses to the electrical stimulation of the dura mater before and after the injection of formalin into their cutaneous receptive fields. Subcutaneous formalin resulted not only in the biphasic increase in the ongoing activity, but also in an enhancement of neuronal responses to dural electrical stimulation, which had similar time profile. These results demonstrated that under tonic pain in the orofacial region a nociceptive signaling from the dura mater to convergent trigeminal neurons is significantly enhanced apparently because of the development of central sensitization; this may contribute to the comorbidity of OFP and headache.
doi:10.1007/s10194-011-0404-7
PMCID: PMC3253149  PMID: 22116533
Formalin test; Trigeminal; Sensitization; Orofacial; Headache
19.  Spinal trigeminal neurons demonstrate an increase in responses to dural electrical stimulation in the orofacial formalin test 
Primary headaches are often associated with pain in the maxillofacial region commonly classified under the term “orofacial pain” (OFP). In turn, long-lasting OFP can trigger and perpetuate headache as an independent entity, which is able to persist after the resolution of the main disorder. A close association between OFP and headache complicates their cause and effect definition and leads to misdiagnosis. The precise mechanisms underlying this phenomenon are poorly understood, partly because of the deficiency of research-related findings. We combined the animal models of OFP and headache—the orofacial formalin test and the model of trigeminovascular nociception—to investigate the neurophysiological mechanisms underlying their comorbidity. In anesthetized rats, the ongoing activity of single convergent neurons in the spinal trigeminal nucleus was recorded in parallel to their responses to the electrical stimulation of the dura mater before and after the injection of formalin into their cutaneous receptive fields. Subcutaneous formalin resulted not only in the biphasic increase in the ongoing activity, but also in an enhancement of neuronal responses to dural electrical stimulation, which had similar time profile. These results demonstrated that under tonic pain in the orofacial region a nociceptive signaling from the dura mater to convergent trigeminal neurons is significantly enhanced apparently because of the development of central sensitization; this may contribute to the comorbidity of OFP and headache.
doi:10.1007/s10194-011-0404-7
PMCID: PMC3253149  PMID: 22116533
Formalin test; Trigeminal; Sensitization; Orofacial; Headache
20.  Anti-nociceptive effect of a conjugate of substance P and light chain of botulinum neurotoxin type A 
Pain  2013;154(11):10.1016/j.pain.2013.07.041.
Neuropathic pain is a debilitating condition resulting from damage to sensory transmission pathways in the peripheral and central nervous system. A potential new way of treating chronic neuropathic pain is to target specific pain processing neurons based on their expression of particular receptor molecules. We hypothesized that a toxin-neuropeptide conjugate would alter pain by first being taken up by specific receptors for the neuropeptide expressed on the neuronal cells. Then, once inside the cell the toxin would inhibit the neurons’ activity without killing the neurons, thereby providing pain relief without lesioning the nervous system. In an effort to inactivate the nociceptive neurons in the trigeminal nucleus caudalis in mice we targeted the NK1 receptor (NK1R) using substance P (SP). The catalytically active light chain of botulinum neurotoxin type A (LC/A) was conjugated with SP. Our results indicate that the conjugate BoNT/A-LC:SP is internalized in cultured NK1R expressing neurons and also cleaves the target of botulinum toxin, a component docking motif necessary for release of neurotransmitters called SNAP-25. The conjugate was next tested in a mouse model of Taxol induced neuropathic pain. An intracisternal injection of BoNT/A-LC:SP decreased thermal hyperalgesia as measured by the operant orofacial nociception assay. These findings indicate that conjugates of the light chain of botulinum toxin are extremely promising agents for use in suppressing neuronal activity for extended time periods and that BoNT/A-LC:SP may be a useful agent for treating chronic pain.
doi:10.1016/j.pain.2013.07.041
PMCID: PMC3808523  PMID: 23933181
Neuropathic pain; Neurokinin receptor; Botulinum neurotoxin
21.  Age and Skeletal Sites Affect BMP-2 Responsiveness of Human Bone Marrow Stromal Cells 
Connective tissue research  2009;50(4):270-277.
Bone marrow stromal cells (BMSCs) contain osteoprogenitors responsive to stimulation by osteogenic growth factors like bone morphogenetic proteins (BMPs). When used as grafts, BMSCs can be harvested from different skeletal sites such as axial, appendicular and orofacial bones, but the lower therapeutic efficacy of BMPs on BMSCs-responsiveness in humans compared to animal models may be partly due to effects of skeletal site and age of donor. We previously reported superior differentiation capacity and osteogenic properties of orofacial BMSCs relative to iliac crest BMSCs in same individuals. This study tested the hypothesis that recombinant human BMP-2 (rhBMP-2) stimulates human BMSCs differently based on age and skeletal site of harvest. Adult maxilla, mandible and iliac crest BMSCs from same individuals and pediatric iliac crest BMSCs were comparatively assessed for BMP-2 responsiveness under serum-containing and serum-free insulin-supplemented culture conditions. Adult orofacial BMSCs were more BMP-2-responsive than iliac crest BMSCs based on higher gene transcripts of alkaline phosphatase, osteopontin and osteogenic transcription factors MSX-2 and Osterix in serum-free insulin-containing medium. Pediatric iliac crest BMSCs were more responsive to rhBMP-2 than adult iliac crest BMSCs based on higher expression of alkaline phosphatase and osteopontin in serum-containing medium. Unlike orofacial BMSCs, MSX-2 and Osterix transcripts were similarly expressed by adult and pediatric iliac crest BMSCs in response to rhBMP-2. These data demonstrate that age and skeletal site-specific differences exist in BMSC osteogenic responsiveness to BMP-2 stimulation and suggest that MSX-2 and Osterix may be potential regulatory transcription factors in BMP-mediated osteogenesis of adult orofacial cells.
doi:10.1080/03008200902846262
PMCID: PMC2905683  PMID: 19637063
Bone morphogenic proteins; age; skeletal site; stem cells
22.  A Novel Tool for the Assessment of Pain: Validation in Low Back Pain 
PLoS Medicine  2009;6(4):e1000047.
Joachim Scholz and colleagues develop and validate an assessment tool that distinguishes between radicular and axial low back pain.
Background
Adequate pain assessment is critical for evaluating the efficacy of analgesic treatment in clinical practice and during the development of new therapies. Yet the currently used scores of global pain intensity fail to reflect the diversity of pain manifestations and the complexity of underlying biological mechanisms. We have developed a tool for a standardized assessment of pain-related symptoms and signs that differentiates pain phenotypes independent of etiology.
Methods and Findings
Using a structured interview (16 questions) and a standardized bedside examination (23 tests), we prospectively assessed symptoms and signs in 130 patients with peripheral neuropathic pain caused by diabetic polyneuropathy, postherpetic neuralgia, or radicular low back pain (LBP), and in 57 patients with non-neuropathic (axial) LBP. A hierarchical cluster analysis revealed distinct association patterns of symptoms and signs (pain subtypes) that characterized six subgroups of patients with neuropathic pain and two subgroups of patients with non-neuropathic pain. Using a classification tree analysis, we identified the most discriminatory assessment items for the identification of pain subtypes. We combined these six interview questions and ten physical tests in a pain assessment tool that we named Standardized Evaluation of Pain (StEP). We validated StEP for the distinction between radicular and axial LBP in an independent group of 137 patients. StEP identified patients with radicular pain with high sensitivity (92%; 95% confidence interval [CI] 83%–97%) and specificity (97%; 95% CI 89%–100%). The diagnostic accuracy of StEP exceeded that of a dedicated screening tool for neuropathic pain and spinal magnetic resonance imaging. In addition, we were able to reproduce subtypes of radicular and axial LBP, underscoring the utility of StEP for discerning distinct constellations of symptoms and signs.
Conclusions
We present a novel method of identifying pain subtypes that we believe reflect underlying pain mechanisms. We demonstrate that this new approach to pain assessment helps separate radicular from axial back pain. Beyond diagnostic utility, a standardized differentiation of pain subtypes that is independent of disease etiology may offer a unique opportunity to improve targeted analgesic treatment.
Editors' Summary
Background
Pain, although unpleasant, is essential for survival. Whenever the body is damaged, nerve cells detecting the injury send an electrical message via the spinal cord to the brain and, as a result, action is taken to prevent further damage. Usually pain is short-lived, but sometimes it continues for weeks, months, or years. Long-lasting (chronic) pain can be caused by an ongoing, often inflammatory condition (for example, arthritis) or by damage to the nervous system itself—experts call this “neuropathic” pain. Damage to the brain or spinal cord causes central neuropathic pain; damage to the nerves that convey information from distant parts of the body to the spinal cord causes peripheral neuropathic pain. One example of peripheral neuropathic pain is “radicular” low back pain (also called sciatica). This is pain that radiates from the back into the legs. By contrast, axial back pain (the most common type of low back pain) is confined to the lower back and is non-neuropathic.
Why Was This Study Done?
Chronic pain is very common—nearly 10% of American adults have frequent back pain, for example—and there are many treatments for it, including rest, regulated exercise (physical therapy), pain-killing drugs (analgesics), and surgery. However, the best treatment for any individual depends on the exact nature of their pain, so it is important to assess their pain carefully before starting treatment. This is usually done by scoring overall pain intensity, but this assessment does not reflect the characteristics of the pain (for example, whether it occurs spontaneously or in response to external stimuli) or the complex biological processes involved in pain generation. An assessment designed to take such factors into account might improve treatment outcomes and could be useful in the development of new therapies. In this study, the researchers develop and test a new, standardized tool for the assessment of chronic pain that, by examining many symptoms and signs, aims to distinguish between pain subtypes.
What Did the Researchers Do and Find?
One hundred thirty patients with several types of peripheral neuropathic pain and 57 patients with non-neuropathic (axial) low back pain completed a structured interview of 16 questions and a standardized bedside examination of 23 tests. Patients were asked, for example, to choose words that described their pain from a list provided by the researchers and to grade the intensity of particular aspects of their pain from zero (no pain) to ten (the maximum imaginable pain). Bedside tests included measurements of responses to light touch, pinprick, and vibration—chronic pain often alters responses to harmless stimuli. Using “hierarchical cluster analysis,” the researchers identified six subgroups of patients with neuropathic pain and two subgroups of patients with non-neuropathic pain based on the patterns of symptoms and signs revealed by the interviews and physical tests. They then used “classification tree analysis” to identify the six questions and ten physical tests that discriminated best between pain subtypes and combined these items into a tool for a Standardized Evaluation of Pain (StEP). Finally, the researchers asked whether StEP, which took 10–15 minutes, could identify patients with radicular back pain and discriminate them from those with axial back pain in an independent group of 137 patients with chronic low back pain. StEP, they report, accurately diagnosed these two conditions and was well accepted by the patients.
What Do These Findings Mean?
These findings indicate that a standardized assessment of pain-related signs and symptoms can provide a simple, quick diagnostic procedure that distinguishes between radicular (neuropathic) and axial (non-neuropathic) low back pain. This distinction is crucial because these types of back pain are best treated in different ways. In addition, the findings suggest that it might be possible to identify additional pain subtypes using StEP. Because these subtypes may represent conditions in which different pain mechanisms are acting, classifying patients in this way might eventually enable physicians to tailor treatments for chronic pain to the specific needs of individual patients rather than, as at present, largely guessing which of the available treatments is likely to work best.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000047.
This study is further discussed in a PLoS Medicine Perspective by Giorgio Cruccu and and Andrea Truini
The US National Institute of Neurological Disorders and Stroke provides a primer on pain in English and Spanish
In its 2006 report on the health status of the US, the National Center for Health Statistics provides a special feature on the epidemiology of pain, including back pain
The Pain Treatment Topics Web site is a resource, sponsored partly by associations and manufacturers, that provides information on all aspects of pain and its treatment for health care professionals and their patients
Medline Plus provides a brief description of pain and of back pain and links to further information on both topics (in English and Spanish)
The MedlinePlus Medical Encyclopedia also has a page on low back pain (in English and Spanish)
doi:10.1371/journal.pmed.1000047
PMCID: PMC2661253  PMID: 19360087
23.  Decreased MicroRNA-125a-3p Contributes to Upregulation of p38 MAPK in Rat Trigeminal Ganglions with Orofacial Inflammatory Pain 
PLoS ONE  2014;9(11):e111594.
Orofacial inflammatory pain is a difficult clinical problem, and the specific molecular mechanisms for this pain remain largely unexplained. The present study aimed to determine the differential expression of microRNAs (miRNAs) and disclose the underlying role of miR-125a-3p in orofacial inflammatory pain induced by complete Freund's adjuvant (CFA). Thirty-two differentially expressed miRNAs were first screened using a microarray chip in ipsilateral trigeminal ganglions (TGs) following CFA injection into the orofacial skin innervated by trigeminal nerve, and a portion of them, including miR-23a*, -24-2*, -26a, -92a, -125a-3p, -183 and -299 were subsequently selected and validated by qPCR. The target genes were predicted based on the miRWalk website and were further analyzed by gene ontology (GO). Further studies revealed miR-125a-3p expression was down-regulated, whereas both the expression of p38 MAPK (mitogen-activated protein kinase) alpha and CGRP (calcitonin gene-related peptide) were up-regulated in ipsilateral TGs at different time points after CFA injection compared with control. Furthermore, mechanistic study revealed that miR-125a-3p negatively regulates p38 alpha gene expression and is positively correlated with the head withdrawal threshold reflecting pain. Luciferase assay showed that binding of miR-125a-3p to the 3′UTR of p38 alpha gene suppressed the transcriptional activity, and overexpression of miR-125a-3p significantly inhibited the p38 alpha mRNA level in ND8/34 cells. Taken together, our results show that miR-125a-3p is negatively correlated with the development and maintenance of orofacial inflammatory pain via regulating p38 MAPK.
doi:10.1371/journal.pone.0111594
PMCID: PMC4224409  PMID: 25380251
24.  Systemic pregabalin attenuates facial hypersensitivity and noxious stimulus-evoked release of glutamate in medullary dorsal horn in a rodent model of trigeminal neuropathic pain 
Neurochemistry international  2013;62(6):831-835.
Pregabalin is effective in treating many neuropathic pain conditions. However, the mechanisms of its analgesic effects remain poorly understood. The aim of the present study was to determine whether pregabalin suppresses facial mechanical hypersensitivity and evoked glutamate release in the medullary dorsal horn (MDH) in a rodent model of trigeminal neuropathic pain. Nociceptive mechanical sensitivity was assessed pre-operatively, and then post-operatively 1 h following pregabalin or vehicle (saline) treatment on post-operative days 2 and 5 following infraorbital nerve transection (IONX). In addition, an in vivo microdialysis probe was inserted into the exposed medulla post-operatively and dialysate samples were collected. Glutamate release was then evoked by mustard oil (MO) application to the tooth pulp, and the effects of pregabalin or vehicle were examined on the MDH glutamate release. Glutamate concentrations in the dialysated samples were determined by HPLC, and data analysed by ANOVA. IONX animals (but not control animals) showed facial mechanical hypersensitivity for several days post-operatively. In addition, tooth pulp stimulation with MO evoked a transient release of glutamate in the MDH in IONX animals. Compared to vehicle, administration of pregabalin significantly attenuated the facial mechanical hypersensitivity as well as the MO-evoked glutamate release in MDH. This study provides evidence in support of recent findings pointing to the usefulness of pregabalin in the treatment of orofacial neuropathic pain.1
doi:10.1016/j.neuint.2013.02.022
PMCID: PMC3622144  PMID: 23454190
nociception; glutamate; medullary dorsal horn; pregabalin; tooth pulp; neuropathic pain
25.  Evaluation of a magnetic resonance-compatible dentoalveolar tactile stimulus device 
BMC Neuroscience  2010;11:142.
Abstract
Background
Few methods exist to study central nervous system processes following dentoalveolar tactile stimulation using functional magnetic resonance imaging (fMRI), likely due to inherent technical difficulties. Our primary goal was to develop and perform feasibility testing of a novel device capable of delivering valid and reliable dentoalveolar stimuli at dental chair-side and during MRI. Details of a device designed to deliver dentoalveolar dynamic pressure stimuli are described. Device testing took place in three settings: a) laboratory testing to assess range of stimulus force intensities, b) dental chair-side to assess reliability, validity and discriminant ability in force-pain relationship; and c) MRI to evaluate magnetic compatibility and ability to evoke brain activation in painfree subjects similar to those described in the literature.
Results
A novel device capable of delivering valid and reliable dentoalveolar somatosensory stimulation was developed (ICC = 0.89, 0.78-1 [95% CI]). Psychophysical data analysis showed high discriminant ability in differentiating painfree controls from cases with chronic dentoalveolar pain related to deafferenting dental procedures (sensitivity = 100%, specificity = 86.7%, area under ROC curve = 0.99). FMRI results of dentoalveolar dynamic pressure pain in painfree subjects revealed activation of brain areas typically associated with acute pain processing including thalamus, primary/secondary somatosensory, insular and prefrontal cortex.
Conclusions
A novel psychophysical method to deliver dynamic dentoalveolar pressure stimulation was developed and validated, allowing non-invasive MRI-based exploration of central nervous system function in response to intraoral somatosensation.
Background
The organization of the trigeminal system is unique as it provides somatosensory innervation to the face, masticatory and oral structures, the majority of the intracranial contents [1] and to specialized structures (tongue, nasal mucosa, auricle, tympanic membrane, cornea and part of the conjunctiva) [2]. Somatic sensory information transmitted by the trigeminal nerve is crucial for normal orofacial function; however, the mechanisms of many chronic pain conditions affecting areas innervated by this sensory system are not well understood [3-5]. The clinical presentation of chronic intraoral pain in the area of a tooth or in a site formally occupied by a tooth with no clinical or radiological signs of pathology, referred to as atypical odontalgia (AO) [6,7], is one such chronic pain condition of particular interest to dentists that is difficult to diagnose and manage. Recent research suggests both peripheral and central nervous system mechanisms being involved in AO pathophysiology [8-10], but the majority of mechanism-based research of patients with AO has focused on the "peripheral aspect" [7].
Functional magnetic resonance imaging (fMRI) is an established research technique to study the central aspects of pain [11]. Of existing neuroimaging techniques, fMRI provides good spatial resolution of cortical and subcortical structures critical in the processing of nociception, acceptable temporal resolution, does not involve ionizing radiation, and can be performed using most MRI systems that already exist in research centers and the community. For these reasons, we sought to develop a protocol that allows us to use this tool to investigate the central mechanisms involved in the processes of intraoral pain arising from the dentoalveolar region. Using this device, our long-term objective is to improve our understanding of the underlying mechanisms of persistent dentoalveolar pain.
In the past few years several studies used fMRI to investigate the human trigeminal system [12,13], with a limited subset focusing on intraoral stimulation - specifically on the dentoalveolar processes, such as lip, tongue and teeth stimulation [14] or only teeth [15-17]. Some reasons for scarce literature on this topic may be the technical challenges involved in delivering facial/intraoral stimulation inside a MR scanner [17,18]: possibility of magnetic interference, detriment of image quality, subject discomfort and reduced working space between the subject's head and the radiofrequency coil. As a consequence a MR-compatible device would need to not only overcome these challenges but also be capable of delivering a controlled and reproducible stimuli [19], as reliability/reproducibility is a necessary feature of sensory testing [20].
Existing MR-compatible methods of dentoalveolar stimulation are limited and do not adequately deliver stimuli across a range of non-painful to painful intensities and/or cannot be adjusted to reach posterior aspects of the dentoalveolar region. Therefore our goal was to develop and test the feasibility of a device able to: 1) provide reliable and valid dentoalveolar stimuli, 2) deliver such stimulation within the restricted space of an MR head coil, 3) be compatible for use within an MR environment, and 4) produce brain activation in painfree controls consistent to those observed by others using fMRI.
doi:10.1186/1471-2202-11-142
PMCID: PMC2988799  PMID: 21029454

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