Persistent Orofacial Pain Research Articles

RNA sequencing of the thalamus and rostral ventral medulla in rats with chronic orofacial pain.

Diagnosing and treating chronic orofacial pain is challenging due to its complex structure and limited understanding of its causes and mechanisms. In this study, we used RNA sequencing to identify differentially expressed genes (DEGs) in the rostral ventral medulla (RVM) and thalamus of rats with persistent orofacial pain, aiming to explore its development. DEGs were functionally analyzed using gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. Results showed a significant association between immune response and pain in this model. Key DEG mRNA expression trends were further validated using real-time quantitative polymerase chain reaction (RT-PCR), confirming their crucial roles in chronic orofacial pain. After injecting complete Freund's adjuvant (CFA) into the bilateral temporomandibular joint cavity for 14 days, we observed 293 upregulated genes and 14 downregulated genes in the RVM, and 1086 upregulated genes and 37 downregulated genes in the thalamus. Furthermore, we identified 27 common DEGs with altered expression (upregulation) in both the thalamus and RVM, including Cd74, C3, Cxcl13, C1qb, Itgal, Fcgr2b, C5ar1, and Tlr2, which are pain-associated genes. Protein-protein interaction (PPI) analysis using Cytoscape revealed the involvement of Toll-like receptors, complement system, differentiation clusters, and antigen presentation-related proteins in the interaction between the thalamus and RVM. The results of this study show that the immune system seems to have a more significant influence on chronic orofacial pain. There may be direct or indirect influence between the thalamus and RVM, which may participate in the regulation of chronic orofacial pain.

Orofacial pain for clinicians: A review of constant and attack-like facial pain syndromes.

Primary headache syndromes such as migraine are among the most common neurological syndromes. Chronic facial pain syndromes of non-odontogenic cause are less well known to neurologists despite being highly disabling. Given the pain localization, these patients often consult dentists first who may conduct unnecessary dental interventions even if a dental cause is not identified. Once it becomes clear that dental modalities have no effect on the pain, patients may be referred to another dentist or orofacial pain specialist, and later to a neurologist. Unfortunately, neurologists are also often not familiar with chronic orofacial pain syndromes although they share the neural system, i.e., trigeminal nerve and central processing areas for headache disorders. In essence, three broad groups of orofacial pain patients are important for clinicians: (i) Attack-like orofacial pain conditions, which encompass neuralgias of the cranial nerves and less well-known facial variants of primary headache syndromes; (ii) persistent orofacial pain disorders, including neuropathic pain and persistent idiopathic facial/dentoalveolar pain; and (iii) other differential diagnostically relevant orofacial pain conditions encountered by clinicians such as painful temporomandibular disorders, bruxism, sinus pain, dental pain, and others which may interfere (trigger) and overlap with headache. It is rewarding to know and recognize the clinical picture of these facial pain syndromes, given that, just like for headache, an internationally accepted classification system has been published and many of these syndromes can be treated with medications generally used by neurologists for other pain syndromes.

Pathophysiology, Clinical Implications and Management of Orofacial Neuropathic Pain- with special attention to Trigeminal neuralgia: A Narrative Review

Background: It is a widely held belief that if the trigeminal nerve is damaged, the victim would experience agonising and unrelenting external pain. A lesion to the trigeminal nerve may have a wide-reaching effect, such as on one side of the face in particular, or it might have a more localised effect, such as on some or all of your gums. The risk of damage increases the likelihood that it will be difficult to speak and swallow. This nerve provides sensation to a part of your face that may be constantly aching or tingling for some people. However, the trigeminal nerve injury-related persistent orofacial pain might be brought on by a wide variety of unknown triggers. Aim: In this study investigate the clinical manifestations of chronic orofacial pain brought on by a damage to the trigeminal nerve, as well as the diagnostic and therapeutic approaches available to treat this condition. Methodology Through the use of search phrases such as "Trigeminal nerve injury," "Trigeminal ganglion," "Trigeminal spinal subnucleus caudalis," "Craniofacial pain," "Oral prognosis," and "treatment," the computerised databases for the last twenty years have been investigated. There are now two hundred objects in total that have been accumulated. There have been around fifty of them that are pertinent to the discussion that is going on in this work. Majority of the patients fair enough with the pharmacology treatment/drugs like the carbamazepine & oxcarbazepine which forms the first line treatment options followed by lamotrigine & baclofen encompassing the second line of drugs along with adjuvant drug support of topiramate, levetiracetam, gabapentin, pregabalin. As the field of science has explored &advanced for the latest treatment options include microvascular decompression, gamma knife radiosurgery, percutaneous rhizotomies variable based on the evidences & guidelines 54 Conclusion: New diagnostic criteria and treatment alternatives have become available for people who suffer from trigeminal neuropathy and orofacial neuropathic pain as a result of recent developments in fundamental animal research that have led to their development. Despite the results, more research needs to investigate a greater variety of distinct non-neuronal cell feature approaches.

Emerging role of microglia and astrocyte in the affective-motivational response induced by a rat model of persistent orofacial pain

Few studies are approaching the neural basis underlying the aggregation of emotional disorders in orofacial pain despite the stress, depression, and anxiety are some of the most commonly reported risk factors. Using a persistent orofacial pain rat model induced by complete Freund's adjuvant (CFA) injection into the temporomandibular joint, we have investigated the plasticity astrocytes and microglia key brain regions for the affective-emotional component of pain. We measured the expression and morphologic pattern of reactivation of glial fibrillary acidic protein (GFAP, astrocyte marker) and Iba-1 (microglial marker) by western blotting and immunohistochemistry analysis. The results showed no alterations on motor activity during inflammatory pain, indicating an exclusive effect of nociceptive behavior on the plasticity of limbic regions. CFA-induced temporomandibular inflammation changed GFAP and Iba-1 expression in distinct regions related to emotional behavior in a time-dependent manner. A significant increase in GFAP and Iba-1 expression was observed in the central nucleus of the amygdala, hippocampus and periaqueductal grey matter from day 3 to day 10 post-CFA injection. Moreover, a positive correlation between GFAP and Iba-1 upregulation and an increased mechanical hypersensitivity was observed. Conversely, no change on GFAP and Iba-1 expression was observed in the hypothalamus and colliculus during orofacial inflammatory pain. Our data suggest an important role for glial cells in the affective-motivational dimension of orofacial pain beyond their well-explored role in the traditional nociceptive transmission circuits.

Application of Botulinum Toxin in Temporomandibular Disorders: A Systematic Review of Randomized Controlled Trials (RCTs)

Temporomandibular disorders (TMDs) are multi-factorial and polysymptomatic pathologies and their management must be customized for every patient. Numerous therapy techniques are available to treat temporomandibular disorders-related muscular discomfort and persistent orofacial pain. Botulinum toxin (BoNT) has emerged as a popular option for patients with myofascial TMD who do not completely recover from their condition after receiving conservative care and medication. A systematic search of the literature, from January 2000 until 1 April 2022, was performed in the MEDLINE (PubMed), Web of Science, and Lilacs databases. The following search terms combination: (temporomandibular disorders) OR (botulinum) OR (toxin) was employed. A total of 357 articles were initially found in the electronic search. After screening, 11 full-text articles satisfied the inclusion criteria. The Cochrane risk of bias tool (RoB 2) tool, which uses seven domains of bias to assess random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment of self-reported outcomes, blinding of outcome assessment of objective measures, incomplete outcome data, selective reporting, and other biases, was employed to analyze randomized controlled trials. The aim of this systematic review of randomized controlled trials is to provide an overview of the use of BoNT for TMDs by comparing the application of BoNT with other therapeutic approaches. BoNT-A could help patients that do not respond to conservative treatments. Low doses are recommended when BoNT-A is considered for persistent orofacial pain related to TMD. Future research should, however, conduct clinical trials with a stricter design. The results of BoNT-A could be confirmed by more randomized controlled trials with larger sample sizes, less bias, and longer follow-up times.

Persistent Orofacial Pain Attendances at General Medical Practitioners

Patients with persistent orofacial pain (POFP) can go through complex care pathways to receive a diagnosis and management, which can negatively affect their pain. This study aimed to describe 44-y trends in attendances at Welsh medical practices for POFP and establish the number of attendances per patient and referrals associated with orofacial pain and factors that may predict whether a patient is referred. A retrospective observational study was completed using the nationwide Secure Anonymised Information Linkage Databank of visits to general medical practices in Wales (UK). Data were extracted using diagnostic codes (“Read codes”). Orofacial and migraine Read codes were extracted between 1974 and 2017. Data were analyzed using descriptive statistics and univariate and multivariable logistic regression. Over the 44-y period, there were 468,827 POFP and migraine diagnostic codes, accounting for 468,137 patient attendances, or 301,832 patients. The overall attendance rate was 4.22 attendances per 1,000 patient-years (95% confidence interval [CI], 4.21–4.23). The attendance rate increased over the study period. Almost one-third of patients (n = 92,192, 30.54%) attended more than once over the study period, and 15.83% attended more than once within a 12-mo period. There were 20,103 referral codes that were associated with 8,183 patients, with over half these patients being referred more than once. Odds of receiving a referral were highest in females (odds ratio [OR], 1.23; 95% CI, 1.17–1.29), in those living in rural locations (OR, 1.17; 95% CI, 1.12–1.22), and in the least deprived quintile (OR, 1.39; 95% CI, 1.29–1.48). Odds also increased with increasing age (OR, 1.03; 95% CI, 1.03–1.03). The increasing attendance may be explained by the increasing incidence of POFP within the population. These patients can attend on a repeated basis, and very few are referred, but when they are, this may occur multiple times; therefore, current care pathways could be improved.

DEEP Study: Modeling Outcomes and Costs of Persistent Orofacial Pain.

Despite a substantial number of consultations, individuals experiencing the care pathways in this study continued to have far from perfect health over their life course. The modeling suggests they would only experience 18 y in "perfect health." There is considerable scope to improve current care/outcomes and patient experience.

Persistent post-surgical orofacial pain

Delivery of pain-free dental treatment is the ultimate goal for clinicians, and the hoped-for result by patients. Thanks to the optimised use of local anaesthesia and high standards of clinical training, this goal is frequently achieved. Research also tells us that the incidence of persistent pain following dental procedures, while relatively low, is not zero. Given the number of procedures we perform as dentists, the number of patients affected with post-treatment pain is still substantial. Moreover, persistent pain is not exclusive to dentistry, but is a risk for all surgical interventions. When this pain lasts over six months it has been labelled persistent or chronic post-surgical pain (CPSP), and as expected it has a detrimental effect on the patient’s quality of life. While all persistent pain is vexing, it is especially true for persistent orofacial pain. It creates increased levels of stress, anxiety and confusion for the patient, which in turn may place a strain on the dentist-patient relationship. On occasions, patient dissatisfaction may even result in medicolegal litigation. This article describes some of the common clinical scenarios associated with chronic pain after dental procedures. Known risk factors are also discussed and recommendations are made so that clinicians might identify those at risk prior to an invasive procedure, and then possibly prevent post-surgical pain.

DEEP Study: Utility of the multidimensional pain inventory in persistent oro-facial pain.

Persistent oro-facial pain (POFP) is disabling, and patients' treatment outcomes are difficult to predict; psychosocial factors play a role. The West Haven-Yale Multidimensional Pain Inventory (MPI) is a self-report measure, which to our knowledge, has not been studied across primary and secondary care in heterogeneous POFP. Assess the MPI's ability to predict clinical outcome in POFP patients across primary and secondary care settings receiving usual care. About 146 patients receiving usual care for POFP were recruited from primary and secondary care medical and dental practices in north-east England. Participants completed the MPI (v3) and Graded Chronic Pain Scale (GCPS) at recruitment, and after 6, 12, 18 and 24months. The Patient Health Questionnaire-4 (PHQ-4) was completed at recruitment, 12, and 24months. 'Good' and 'poor' outcome status was assigned to participants based on their mode dichotomised GCPS score across timepoints. Logistic regression was used with overall GCPS outcome (good/poor) as the dependent variable and MPI subscale scores, demographic variables, and PHQ-4 scores as predictors. 110 participants had a 'good', and 36 had a 'poor' outcome. In the 'poor' outcome group, age, mean income, and life control scores were lower; deprivation, months in pain, PHQ-4, pain severity, interference, and affective distress scores were higher. In the 'good' group, MPI scores improved over time. Interference was the only consistent predictor of 'poor' outcome in the logistic regression model (OR: 1.14-1.98, p<0.05). The MPI interference subscale may help to identify patients with POFP who are likely to have consistent pain-related disability over time; it may therefore be useful clinically to identify patients likely to need early intervention.

Orofacial Neuropathic Pain-Basic Research and Their Clinical Relevancies.

Trigeminal nerve injury is known to cause severe persistent pain in the orofacial region. This pain is difficult to diagnose and treat. Recently, many animal studies have reported that rewiring of the peripheral and central nervous systems, non-neuronal cell activation, and up- and down-regulation of various molecules in non-neuronal cells are involved in the development of this pain following trigeminal nerve injury. However, there are many unknown mechanisms underlying the persistent orofacial pain associated with trigeminal nerve injury. In this review, we address recent animal data regarding the involvement of various molecules in the communication of neuronal and non-neuronal cells and examine the possible involvement of ascending pathways in processing pathological orofacial pain. We also address the clinical observations of persistent orofacial pain associated with trigeminal nerve injury and clinical approaches to their diagnosis and treatment.

Acute and Chronic Pain from Facial Skin and Oral Mucosa: Unique Neurobiology and Challenging Treatment.

The oral cavity is a portal into the digestive system, which exhibits unique sensory properties. Like facial skin, the oral mucosa needs to be exquisitely sensitive and selective, in order to detect harmful toxins versus edible food. Chemosensation and somatosensation by multiple receptors, including transient receptor potential channels, are well-developed to meet these needs. In contrast to facial skin, however, the oral mucosa rarely exhibits itch responses. Like the gut, the oral cavity performs mechanical and chemical digestion. Therefore, the oral mucosa needs to be insensitive, to some degree, in order to endure noxious irritation. Persistent pain from the oral mucosa is often due to ulcers, involving both tissue injury and infection. Trigeminal nerve injury and trigeminal neuralgia produce intractable pain in the orofacial skin and the oral mucosa, through mechanisms distinct from those seen in the spinal area, which is particularly difficult to predict or treat. The diagnosis and treatment of idiopathic chronic pain, such as atypical odontalgia (idiopathic painful trigeminal neuropathy or post-traumatic trigeminal neuropathy) and burning mouth syndrome, remain especially challenging. The central integration of gustatory inputs might modulate chronic oral and facial pain. A lack of pain in chronic inflammation inside the oral cavity, such as chronic periodontitis, involves the specialized functioning of oral bacteria. A more detailed understanding of the unique neurobiology of pain from the orofacial skin and the oral mucosa should help us develop novel methods for better treating persistent orofacial pain.

Temporomandibular inflammation regulates the matrix metalloproteinases MMP-2 and MMP-9 in limbic structures.

Temporomandibular disorder (TMD) is characterized by acute or chronic orofacial pain, which can be associated with inflammatory processes in the temporomandibular joint (TMJ) and emotional disorders. Peripheral and central sensitization in painful orofacial processes is common, and it can be triggered by peripheral inflammatory challenge with consequent neuroinflammation phenomena. Such neuroinflammation comes from inflammatory products from supportive cells, blood-brain barrier, and extracellular matrix. Here, we evaluated the possible recruitment of limbic structures for modified matrix metalloproteinases (MMPs) expression and activity during temporomandibular inflammation-induced orofacial persistent pain. The inflammatory process in TMJs of rats was induced by Freund's Complete Adjuvant (CFA) administration. The activity and expression of MMPs-2 and 9 were assessed by in situ zymography and conventional zymography, respectively. A glial colocalization with the MMPs was performed using immunofluorescence. The results evidenced both short- and long-term alterations on MMP-2 and -9 expression in the limbic structures following CFA-induced temporomandibular inflammation. The gelatinolytic activity was increased in the central amygdala, hippocampus, hypothalamus, ventrolateral periaqueductal gray (vlPAG), superior colliculus, and inferior colliculus. Finally, an increase of colocalization of MMP-2/GFAP and MMP-9/GFAP in CFA-induced inflammation groups was observed when compared with saline groups in the central amygdala and vlPAG. It is possible to suggest that glial activation is partly responsible for the production of gelatinases in the persistent orofacial pain, and it is involved in the initiation and maintenance of this process, indicating that inhibition of MMPs might be pursued as a potential new therapeutic target for TMD.

Microglia-Astrocyte Communication via C1q Contributes to Orofacial Neuropathic Pain Associated with Infraorbital Nerve Injury.

Trigeminal nerve injury causes a distinct time window of glial activation in the trigeminal spinal subnucleus caudalis (Vc), which are involved in the initiation and maintenance phases of orofacial neuropathic pain. Microglia-derived factors enable the activation of astrocytes. The complement component C1q, which promotes the activation of astrocytes, is known to be synthesized in microglia. However, it is unclear whether microglia–astrocyte communication via C1q is involved in orofacial neuropathic pain. Here, we analyzed microglia-astrocyte communication in a rat model with infraorbital nerve injury (IONI). The orofacial mechanical hypersensitivity induced by IONI was significantly attenuated by preemptive treatment with minocycline. Immunohistochemical analyses revealed that minocycline inhibited the increase in c-Fos immune-reactive (IR) cells and the fluorescence intensity of both Iba1 and glial fibrillary acidic protein (GFAP) in the Vc following IONI. Intracisternal administration of C1q caused orofacial mechanical hypersensitivity and an increase in the number of c-Fos-IR cells and fluorescence intensity of GFAP. C1q-induced orofacial mechanical hypersensitivity was completely abrogated by intracisternal administration of fluorocitrate. The present findings suggest that the enhancement in the excitability of Vc nociceptive neurons is produced by astrocytic activation via the signaling of C1q released from activated microglia in the Vc following IONI, resulting in persistent orofacial neuropathic pain.

Biopsychosocial assessment and management of persistent orofacial pain

AbstractPersistent orofacial pain (OFP) presents as a range of conditions of complex aetiology which include interacting biological, psychological and social aspects. Biopsychosocial factors have an impact on the development, maintenance and severity of pain disorders as well as on their treatment. Since OFP is unlikely to be cured, given current knowledge, patients need to play an active role in using strategies to reduce their pain or the impact it has on their life. This is known as self‐management and provides a firm foundation for tailored medical management strategies. Biopsychosocial considerations have an important role in supporting successful self‐management. This review describes biopsychosocial factors that may be important to consider in routine care settings. Psychological factors that are known to affect outcome include anxiety and depression and, more specifically catastrophising and self‐efficacy. Research into pain management in other conditions also stresses the importance of psychological flexibility, the ability to respond in a helpful way even when this involves maintaining awareness of difficult feelings and thoughts. Patients' understanding of their pain, including beliefs about its meaning and how it should be managed is also important. Social factors include communication and relationship‐building in clinic, both of which are key. Outside the clinic, other social factors might compromise a patients’ ability to engage in treatment, and clinicians need to be alert to their possible presence. Suggestions are made for incorporating biopsychosocial principles into routine assessment and treatment and for deciding when specialist referral to psychology services might be required.

Peripheral and Central Mechanisms of Persistent Orofacial Pain.

Neuroplastic changes in the neuronal networks involving the trigeminal ganglion (TG), trigeminal spinal subnucleus caudalis (Vc), and upper cervical spinal cord (C1/C2) are considered the mechanisms underlying the ectopic orofacial hypersensitivity associated with trigeminal nerve injury or orofacial inflammation. It has been reported that peripheral nerve injury causes injury discharges in the TG neurons, and a barrage of action potentials is generated in TG neurons and conveyed to the Vc and C1/C2 after trigeminal nerve injury. Long after trigeminal nerve injury, various molecules are produced in the TG neurons, and these molecules are released from the soma of TG neurons and are transported to the central and peripheral terminals of TG neurons. These changes within the TG cause neuroplastic changes in TG neurons and they become sensitized. The neuronal activity of TG neurons is further accelerated, and Vc and C1/C2 neurons are also sensitized. In addition to this cascade, non-neuronal glial cells are also involved in the enhancement of the neuronal activity of TG, Vc, and C1/C2 neurons. Satellite glial cells and macrophages are activated in the TG after trigeminal nerve injury and orofacial inflammation. Microglial cells and astrocytes are also activated in the Vc and C1/C2 regions. It is considered that functional interaction between non-neuronal cells and neurons in the TG, Vc, and C1/C2 regions is a key mechanism involved in the enhancement of neuronal excitability after nerve injury or inflammation. In this article, the detailed mechanisms underlying ectopic orofacial hyperalgesia associated with trigeminal nerve injury and orofacial inflammation are addressed.

Predicting Persistent Orofacial Pain: The Role of Illness Perceptions, Anxiety, and Depression.

Persistent orofacial pain (POFP) can be caused by a range of conditions affecting the mouth and face and is often associated with significant disability. Biopsychosocial factors are known to be important predictors and have not yet been fully explored in this population. This study aimed to explore whether illness perceptions and psychological distress (anxiety and depression) could predict long-term outcome in a community-based sample of patients receiving routine care for POFP. A longitudinal cohort design study assessed 198 patients recruited from primary or secondary health care settings on 5 separate occasions over a 2-y period. Outcome was measured by the Graded Chronic Pain Scale and dichotomized into good or poor outcome categories. Independent variables included subscale scores of the psychometrically shortened Illness Perception Questionnaire and the Patient Health Questionnaire-4 (PHQ-4, assessing anxiety and depressive symptomatology). Logistic regressions were performed to test whether scores on each subscale would be associated with different outcomes for patients at 12 and 24 mo and overall. Beliefs about consequences predicted outcome category (good vs. poor) above and beyond other illness perception subscales, anxiety, and depressive symptomatology (z = 3.78; P < 0.000; odds ratio [OR], 3.05; 95% confidence interval [CI], 1.71-5.43). Both depressive symptomatology, measured by the PHQ-2 (P = 0.001; OR, 4.06; 95% CI, 1.74-9.52), and psychological distress (mixed anxiety and depression; P = 0.029; OR, 2.88; 95% CI, 1.12-7.41), measured by the PHQ-4, were also predictive of poor outcome, but these effects were no longer significant once measures of illness perceptions were added. Beliefs about the consequences of POFP are important predictors of outcome independent of other variables and can easily and briefly be included in assessments to inform management decisions. The results of this study are relevant because they will allow clinicians to consider the use of brief and easy-to-administer self-report measures to identify POFP patients at higher risk of poor outcome so that management can be planned accordingly.

Experimental Methods to Inform Diagnostic Approaches for Painful TMJ Osteoarthritis

Temporomandibular joint (TMJ) osteoarthritis (OA) is a degenerative disease of the joint that can produce persistent orofacial pain as well as functional and structural changes to its bone, cartilage, and ligaments. Despite advances in the clinical utility and reliability of the Diagnostic Criteria for Temporomandibular Disorders, clinical tools inadequately predict which patients will develop chronic TMJ pain and degeneration, limiting clinical management. The challenges of managing and treating TMJ OA are due, in part, to a limited understanding of the mechanisms contributing to the development and maintenance of TMJ pain. OA is initiated by multiple factors, including injury, aging, abnormal joint mechanics, and atypical joint shape, which can produce microtrauma, remodeling of joint tissues, and synovial inflammation. TMJ microtrauma and remodeling can increase expression of cytokines, chemokines, and catabolic factors that damage synovial tissues and can activate free nerve endings in the joint. Although studies have separately investigated inflammation-driven orofacial pain, acute activity of the trigeminal nerve, or TMJ tissue degeneration and/or damage, the temporal mechanistic factors leading to chronic TMJ pain are undefined. Limited understanding of the interaction between degeneration, intra-articular chemical factors, and pain has further restricted the development of targeted, disease-modifying drugs to help patients avoid long-term pain and invasive procedures, like TMJ replacement. A range of animal models captures features of intra-articular inflammation, joint overloading, and tissue damage. Although those models traditionally measure peripheral sensitivity as a surrogate for pain, recent studies recognize the brain’s role in integrating, modulating, and interpreting nociceptive inputs in the TMJ, particularly in light of psychosocial influences on TMJ pain. The articular and neural contributors to TMJ pain, imaging modalities with clinical potential to identify TMJ OA early, and future directions for clinical management of TMJ OA are reviewed in the context of evidence in the field.

Voluntary biting behavior as a functional measure of orofacial pain in mice

IntroductionPain-related behavior secondary to masticatory function can be assessed with the rodent bite force model. A reduction of the bite force has been shown to be related to pain associated with the masseter muscle and jaw activity, while an increase in bite force suggests improvement of muscle function and less pain. To evaluate the usefulness of the bite force measure in studying long-lasting orofacial pain we analyzed biting parameters during prolonged myofascial pain induced by ligation injury of the masseter muscle tendon (TL) in mice. MethodsC57Bl/6 mice were habituated to bite at a pair of aluminum plates attached to a force displacement transducer. The transduced voltage signals were amplified and converted to force through calibration with a standard weight set. Voluntary biting behavior was recorded for 100 s/session and those with bite forces ≥980 mN were analyzed. Nociception was also verified with von Frey, conditioned place avoidance (CPA) tests and mouse grimace scale. Persistent orofacial pain was induced with unilateral ligation of one tendon of the masseter muscle (TL). ResultsTo reduce interference of random bites of smaller forces, the top 5 or 15 bite forces (BF5/15) were chosen as a measure of masticatory function and related to pain behavior. Both male and female mice exhibited similar BF5/15. For the first nascent test of all mice, mean bite force was significantly and positively correlated with the body weight. However, this correlation was less clear in the latter tests (2–8 w). TL induced a reduction of BF5/15 that peaked at 1 w and returned to the baseline within 3 w. The von Frey and CPA tests indicated that mechanical allodynia/hyperalgesia persisted at the time when the BF had returned to the pre-injury level. Infusion of pain-relieving bone marrow stromal cells improved biting behavior in both male and female mice as shown by significantly increased BF5/15, compared to vehicle-treated mice. ConclusionsMouse voluntary biting behavior can be reliably measured and quantified with a simplified setup. The bite force showed an inverse relationship with the level of pain after TL and was improved by pain-relieving manipulations. However, the injury-induced reduction of bite force peaked early and did not parallel with other measures of nociception in the later phase of hyperalgesia. The results suggest that multiple factors such as the level of habituation, cognitive motive, physical status, and feeding drive may affect random voluntary biting and confound the biting parameters related to maintained hyperalgesia.

Role of neuron and non-neuronal cell communication in persistent orofacial pain.

It is well known that trigeminal nerve injury causes hyperexcitability in trigeminal ganglion neurons, which become sensitized. Long after trigeminal nerve damage, trigeminal spinal subnucleus caudalis and upper cervical spinal cord (C1/C2) nociceptive neurons become hyperactive and are sensitized, resulting in persistent orofacial pain. Communication between neurons and non-neuronal cells is believed to be involved in these mechanisms. In this article, the authors highlight several lines of evidence that neuron-glial cell and neuron macrophage communication have essential roles in persistent orofacial pain mechanisms associated with trigeminal nerve injury and/or orofacial inflammation.

Blast-induced brain injury in rats leads to transient vestibulomotor deficits and persistent orofacial pain

ABSTRACTBlast-induced traumatic brain injury (blast-TBI) is associated with vestibulomotor dysfunction, persistent post-traumatic headaches and post-traumatic stress disorder, requiring extensive treatments and reducing quality-of-life. Treatment and prevention of these devastating outcomes require an understanding of their underlying pathophysiology through studies that take advantage of animal models. Here, we report that cranium-directed blast-TBI in rats results in signs of pain that last at least 8 weeks after injury. These occur without significantly elevated behavioural markers of anxiety-like conditions and are not associated with glial up-regulation in sensory thalamic nuclei. These injuries also produce transient vestibulomotor abnormalities that resolve within 3 weeks of injury. Thus, blast-TBI in rats recapitulates aspects of the human condition.