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1.  KCNQ channels in nociceptive cold-sensing trigeminal ganglion neurons as therapeutic targets for treating orofacial cold hyperalgesia 
Molecular Pain  2015;11:45.
Background
Hyperexcitability of nociceptive afferent fibers is an underlying mechanism of neuropathic pain and ion channels involved in neuronal excitability are potentially therapeutic targets. KCNQ channels, a subfamily of voltage-gated K+ channels mediating M-currents, play a key role in neuronal excitability. It is unknown whether KCNQ channels are involved in the excitability of nociceptive cold-sensing trigeminal afferent fibers and if so, whether they are therapeutic targets for orofacial cold hyperalgesia, an intractable trigeminal neuropathic pain.
Methods
Patch-clamp recording technique was used to study M-currents and neuronal excitability of cold-sensing trigeminal ganglion neurons. Orofacial operant behavioral assessment was performed in animals with trigeminal neuropathic pain induced by oxaliplatin or by infraorbital nerve chronic constrictive injury.
Results
We showed that KCNQ channels were expressed on and mediated M-currents in rat nociceptive cold-sensing trigeminal ganglion (TG) neurons. The channels were involved in setting both resting membrane potentials and rheobase for firing action potentials in these cold-sensing TG neurons. Inhibition of KCNQ channels by linopirdine significantly decreased resting membrane potentials and the rheobase of these TG neurons. Linopirdine directly induced orofacial cold hyperalgesia when the KCNQ inhibitor was subcutaneously injected into rat orofacial regions. On the other hand, retigabine, a KCNQ channel potentiator, suppressed the excitability of nociceptive cold-sensing TG neurons. We further determined whether KCNQ channel could be a therapeutic target for orofacial cold hyperalgesia. Orofacial cold hyperalgesia was induced in rats either by the administration of oxaliplatin or by infraorbital nerve chronic constrictive injury. Using the orofacial operant test, we showed that retigabine dose-dependently alleviated orofacial cold hyperalgesia in both animal models.
Conclusion
Taken together, these findings indicate that KCNQ channel plays a significant role in controlling cold sensitivity and is a therapeutic target for alleviating trigeminal neuropathic pain that manifests orofacial cold hyperalgesia.
doi:10.1186/s12990-015-0048-8
PMCID: PMC4521366  PMID: 26227020
2.  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
3.  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
4.  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
5.  Canadian Orofacial Pain Team workshop report on the Global Year Against Orofacial Pain 
This article summarizes the content of a workshop on the Global Year Against Orofacial Pain, held in Montreal, Quebec in November 2013. Topics discussed during the workshop included biopsychosocial markers and pain signatures for chronic orofacial pain; misuse of pain medications for chronic orofacial pain; and the use of complementary medicine, topical agents and the role of stress in chronic orofacial pain.
The year 2013–2014 has been designated the Global Year Against Orofacial Pain by the International Association for the Study of Pain. Accordingly, a multidisciplinary Canadian and international group of clinical, research and knowledge-transfer experts attended a workshop in Montreal, Quebec. The workshop had two aims: to identify new pathways for innovative diagnosis and management of chronic orofacial pain states; and to identify opportunities for further collaborative orofacial pain research and education in Canada.
Three topics related to chronic orofacial pain were explored: biomarkers and pain signatures for chronic orofacial pain; misuse of analgesic and opioid pain medications for managing chronic orofacial pain; and complementary alternative medicine, topical agents and the role of stress in chronic orofacial pain.
It was determined that further research is needed to: identify biomarkers of chronic orofacial post-traumatic neuropathic pain, with a focus on psychosocial, physiological and chemical-genetic factors; validate the short-and long-term safety (ie, no harm to health, and avoidance of misuse and addiction) of opioid use for two distinct conditions (acute and chronic orofacial pain, respectively); and promote the use of topical medications as an alternative treatment in dentistry, and further document the benefits and safety of complementary and alternative medicine, including stress management, in dentistry. It was proposed that burning mouth syndrome, a painful condition that is not uncommon and affects mainly postmenopausal women, should receive particular attention.
PMCID: PMC4325893  PMID: 25522352
Biomarkers; Complementary and alternative medicine; Opioid misuse; Orofacial pain; Pain; Topical analgesics
6.  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
7.  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
8.  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
9.  Temporal dynamics of anxiety phenotypes in a dental pulp injury model 
Molecular Pain  2015;11:40.
Background
Accumulating clinical and preclinical evidence indicates that chronic pain is often comorbid with persistent low mood and anxiety. However, the mechanisms underlying pain-induced anxiety, such as its causality, temporal progression, and relevant neural networks are poorly understood, impeding the development of efficacious therapeutic approaches.
Results
Here, we have identified the sequential emergence of anxiety phenotypes in mice subjected to dental pulp injury (DPI), a prototypical model of orofacial pain that correlates with human toothache. Compared with sham controls, mice subjected to DPI by mechanically exposing the pulp to the oral environment exhibited significant signs of anxiogenic effects, specifically, altered behaviors on the elevated plus maze (EPM), novelty-suppressed feeding (NSF) tests at 1 but not 3 days after the surgery. Notably, at 7 and 14 days, the DPI mice again avoided the open arm, center area, and novelty environment in the EPM, open field, and NSF tests, respectively. In particular, DPI-induced social phobia and increased repetitive grooming did not occur until 14 days after surgery, suggesting that DPI-induced social anxiety requires a long time. Moreover, oral administration of an anti-inflammatory drug, ibuprofen, or an analgesic agent, ProTx-II, which is a selective inhibitor of NaV1.7 sodium channels, both significantly alleviated DPI-induced avoidance in mice. Finally, to investigate the underlying central mechanisms, we pharmacologically blocked a popular form of synaptic plasticity with a GluA2-derived peptide, long-term depression, as that treatment significantly prevented the development of anxiety phenotype upon DPI.
Conclusions
Together, these results suggest a temporally progressive causal relationship between orofacial pain and anxiety, calling for more in-depth mechanistic studies on concomitant pain and anxiety disorders.
doi:10.1186/s12990-015-0040-3
PMCID: PMC4487070  PMID: 26122003
Dental pulp injury; Pain; Anxiety; Social phobia; Synaptic plasticity
10.  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
11.  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
12.  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
13.  Trigeminal nerve injury induced thrombospondin-4 upregulation contributes to orofacial neuropathic pain states in a rat model 
Background
Injury to the trigeminal nerve often results in the development of chronic pain states including tactile allodynia, or hypersensitivity to light touch, in orofacial area, but its underlying mechanisms are poorly understood. Peripheral nerve injury has been shown to cause upregulation of thrombospondin-4 (TSP4) in dorsal spinal cord that correlates with neuropathic pain development. In this study, we examined whether injury-induced TSP4 is critical in mediating orofacial pain development in a rat model of chronic constriction injury to the infraorbital nerve (CCI-ION).
Methods
Orofacial sensitivity to mechanical stimulation was examined in a unilateral infraorbital nerve ligation rat model. The levels of TSP4 in trigeminal ganglia and associated spinal subnucleus caudalis and C1/C2 spinal cord (Vc/C2) from injured rats were examined at time points correlating with the initiation and peak orofacial hypersensitivity. TSP4 antisense and mismatch oligodeoxynucleotides were intrathecally injected into injured rats to see if antisense oligodeoxynucleotide treatment could reverse injury-induced TSP4 upregulation and orofacial behavioral hypersensitivity.
Results
Our data indicated that trigeminal nerve injury induced TSP4 upregulation in Vc/C2 at a time point correlated with orofacial tactile allodynia. In addition, intrathecal treatment with TSP4 antisense, but not mismatch, oligodeoxynucleotides blocked both injury-induced TSP4 upregulation in Vc/C2 and behavioral hypersensitivity.
Conclusions
Our data support that infraorbital nerve injury leads to TSP4 upregulation in trigeminal spinal complex that contributes to orofacial neuropathic pain states. Blocking this pathway may provide an alternative approach in management of orofacial neuropathic pain states.
doi:10.1002/j.1532-2149.2013.00396.x
PMCID: PMC3947726  PMID: 24019258
14.  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)
15.  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
16.  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
17.  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
18.  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  PMID: 25653753
Pilocarpine; Atropine; Naloxone; Orofacial pain; Rat
19.  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
20.  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
21.  Chronic at-level thermal hyperalgesia following rat cervical contusion spinal cord injury is accompanied by neuronal and astrocyte activation and loss of the astrocyte glutamate transporter, GLT1, in superficial dorsal horn 
Brain research  2014;0:64-79.
Neuropathic pain is a form of pathological nociception that occurs in a significant portion of traumatic spinal cord injury (SCI) patients, resulting in debilitating and often long-term physical and psychological burdens. While many peripheral and central mechanisms have been implicated in neuropathic pain, central sensitization of dorsal horn spinothalamic tract (STT) neurons is a major underlying substrate. Furthermore, dysregulation of extracellular glutamate homeostasis and chronic astrocyte activation play important underlying roles in persistent hyperexcitability of these superficial dorsal horn neurons. To date, central sensitization and astrocyte changes have not been characterized in cervical SCI-induced neuropathic pain models, despite the fact that a major portion of SCI patients suffer contusion trauma to cervical spinal cord. In this study, we have characterized two rat models of unilateral cervical contusion SCI that behaviorally result in chronic persistence of thermal hyperalgesia in the ipsilateral forepaw. In addition, we find that STT neurons are chronically activated in both models when compared to laminectomy-only uninjured rats. Finally, persistent astrocyte activation and significantly reduced expression of the major CNS glutamate transporter, GLT1, in superficial dorsal horn astrocytes are associated with both excitability changes in STT neurons and the neuropathic pain behavioral phenotype. In conclusion, we have characterized clinically-relevant rodent models of cervical contusion-induced neuropathic pain that result in chronic activation of both STT neurons and astrocytes, as well as compromise in astrocyte glutamate transporter expression. These models can be used as important tools to further study mechanisms underlying neuropathic pain post-SCI and to test potential therapeutic interventions.
doi:10.1016/j.brainres.2014.05.003
PMCID: PMC4157084  PMID: 24833066
spinal cord injury; contusion; cervical; neuropathic pain; hyperalgesia; astrocyte; GLT1; glutamate transporter; hyperexcitability
22.  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
23.  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
24.  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
25.  Case studies illustrating the management of trigeminal neuropathic pain using topical 5% lidocaine plasters 
British Journal of Pain  2013;7(2):107-113.
Chronic trigeminal pain, with its severe related functional problems, is difficult to treat. Treatment is often empirically based on medications used for other chronic pain conditions. Systemic sodium channel and calcium channel blocking agents may cause a multitude of complications that are often poorly tolerated by the patient.
Aim:
The aim of this case report was to assess the efficacy of topical 5% lidocaine plasters in reducing pain and reducing adjuvant medication in patients with orofacial neuropathic pain.
Method:
Fourteen patients with chronic orofacial pain conditions referred to the oral surgery department were instructed to wear 5% lidocaine plasters for 12 hours each day over the painful area. The conditions included post-surgical neuropathy (n = 10), multiple sclerosis-related pain (n = 1), persistent idiopathic facial pain (n = 1), Ramsay Hunt syndrome (post-herpetic neuralgia, n = 1) and trigeminal neuralgia (n = 1). Data were collected on patient demographics, pain levels and medication.
Results:
Pain levels improved in 12 out of 14 patients. Nine patients had a reduction in adjuvant medication, two of whom completely stopped adjuvant treatment.
Conclusion:
This case series demonstrates that of the use of 5% lidocaine plasters may play a useful role in the management of chronic trigeminal pain. A suggested novel approach for the management of orofacial pain, for clinicians, is presented.
Summary points
Management of chronic orofacial pain continues to be a major challenge to the clinician.
Patients are often placed on a multitude of medications in an attempt to alleviate pain without success.
Topical 5% lidocaine plasters, currently used for the management of post-herpetic neuralgia, offer the option of locally targeting trigeminal pain without the multiple side-effects of systemic medication.
This case series demonstrates that lidocaine plasters decrease verbal pain scores in extraoral, trigeminal and neuropathic pain, and reduce the use of other neuromodulatory agents in some, but not all, patients.
The plasters should be considered as a useful adjuvant in the management of pain in these patients.
doi:10.1177/2049463713483459
PMCID: PMC4590123  PMID: 26516508
Chronic; lidocaine; neuropathic; pain; topical; trigeminal

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