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Aims: To compare the modulatory effects of tonic mechanical or thermal craniofacial painful conditioning stimuli on pain sensitivity in craniofacial and spinal test sites in healthy men and women. Methods: Mechanical and cold headbands were developed and tested on 12 healthy men and 12 age-matched women (mean +/- SEM: 27 +/- 1.5 years). The pressure applied by the mechanical headband around the skull above the eyebrows could be adjusted over time via feedback from a 0 to 10 electronic visual analog scale (VAS) to maintain the pain intensity at a given level for 10 minutes (3 to 7 on VAS). The cold headband consisted of a series of plastic bags filled with antifreeze water having a temperature of approx 3 degrees C. During the 10 minutes of application, the subjects were asked to rate the pain intensity on a 10-cm VAS. Pressure pain thresholds (PPT) were recorded over the right and left masseter muscles (MAR, MAL), right splenius muscle (neck), right elbow (elbow), and right middle finger (finger) by a pressure algometer (1-cm2 area probe). The PPTs at each of the five sites were determined at baseline and during the mechanical or cold-induced pain. The two sessions with mechanical or cold headbands were performed at an interval of 30 minutes. Results: Women had significantly lower absolute PPT values than men at most test sites (Unpaired t-test: P < .027). The mechanical headband caused pain in both men (peak pain mean +/- SEM: 4.7 +/- 0.4 cm) and women (4.9 +/- 0.4 cm) (P = .455). A significant PPT elevation was found at MAR, MAL, neck, and finger in men (11% to 17%; P < .031) and at MAR, MAL, and neck in women (15% to 22%; P < .020) during the mechanical-induced pain. The cold headband caused pain in both men (4.0 +/- 0.4 cm) and women (4.5 +/- 0.4 cm) (P = .285). During the cold-induced pain, a significant PPT elevation was found at all test sites in men (P < .023) and at all sites (P < .021) except for the finger in women. The relative changes in PPT values were not significantly different between men and women at any test site (unpaired t-test: P > .446). Conclusion: This study has documented that mechanical and thermal painful tonic stimuli applied to the craniofacial region can evoke diffuse noxious inhibitory control (DNIC)-like effects in the craniofacial region as well as spinally innervated areas, but without sex differences. J Orofac Pain 2010;24:255-261. [ABSTRACT FROM AUTHOR]

Aim: To determine if glutamate injected into the healthy temporomandibular joint (TMJ) evokes pain through peripheral N-methyl-D-aspartate (NMDA) receptors and if such pain is influenced by sex or sex steroid hormones. Methods: Sixteen healthy men and 36 healthy women were included and subjected to two randomized and double-blind intra-articular injections of the TMJ. Experimental TMJ pain was induced by injection of glutamate (1.0 mol/L) and NMDA block was achieved by co-injection of the NMDA antagonist ketamine (10 mmol/L). The TMJ pain intensity in the joint before and during a 25-minute postinjection period was continuously recorded on an electronic visual analog scale (0 to 10). Estradiol, progesterone, and testosterone levels in serum were analyzed. Results: Glutamate-induced pain showed a median (25/75 percentile) duration of 8.3 (5.2/12.2) minutes. The peak pain intensity was 6.1 (4.2/8.2), the time to peak was 50 (30/95) seconds, and the area under the curve was 59 (29/115) arbitrary units. The women reported higher maximum pain intensity than the men and shorter time to peak. The sex hormone levels were not significantly related to the glutamate-induced TMJ pain. NMDA block significantly reduced the glutamate-induced TMJ pain, mainly in the women. There were no significant correlations between sex hormone levels and the effects of NMDA block for any pain variable. Conclusion: Glutamate evokes immediate pain in the healthy human TMJ that is partly mediated by peripheral NMDA receptors in the TMJ. J Orofac Pain 2010;24:172-180. [ABSTRACT FROM AUTHOR]

Aims: To characterize and contrast human sensory and vascular changes produced by topical application of the algesic chemical capsaicin to the glabrous lips and tongue. Methods: Applications of 1% capsaicin or vehicle cream to the glabrous lips and tongue were randomized between two two-trial sessions. The capsaicin trial followed the vehicle trial for each session. Before and 5, 15, and 30 minutes after capsaicin or vehicle cream application, six parameters were recorded from the glabrous lips or the tongue dorsum: (1) burning pain intensity, as measured on a visual analog scale; (2) burning pain area, as indicated by subjects on an orofacial drawing; (3) mechanical sensitivity, as measured by a von Frey filament; (4) visual flare; (5) blood flow and temperature, as measured by laser-Doppler imaging and thermography, respectively; and (6) areas of increased temperature (hot spots), as calculated by a digital tracer from the thermographs. Data were analyzed by ANOVAs and Pearson's correlations. Results: Compared to vehicle application, capsaicin elicited burning pain, increases in blood flow and temperature, but no change in mechanical sensitivity in the glabrous lips or tongue. Greater increases in blood flow and temperature paralleled more intense burning pain and larger areas of perceived pain for the lips compared to the tongue. The location of distinct areas of increased temperature within the orofacial area differed between the capsaicin-lip and capsaicin-tongue trials. Conclusion: The several differences between these responses to noxious stimulation of the glabrous lips and tongue may have implications for examinations of orofacial somatosensory functions. [ABSTRACT FROM AUTHOR]

AIMS: To investigate the effects of local intramuscular injection of the N-methyl-D-aspartate (NMDA) receptor antagonist ketamine on chronic myofascial pain and mandibular function in temporomandibular disorder patients. METHODS: Fourteen myofascial temporomandibular disorder pain patients (10 women and 4 men) were recruited. The subjects completed 2 sessions in a double-blinded randomized and placebo-controlled trial. They received a single injection of 0.2 mL ketamine or placebo (buffered isotonic saline [NaCl], 155 mmol/L) into the most painful part of the masseter muscle. The primary outcome parameters were spontaneous pain assessed on an electronic visual analog scale and numeric rating scale. In addition, numeric rating scale of unpleasantness, numeric rating scale of pain relief, pressure pain threshold, pressure pain tolerance, completion of a McGill Pain Questionnaire and pain drawing areas, maximum voluntary bite force and maximum voluntary jaw opening were obtained. Paired t tests and analysis of variance were performed to compare the data. RESULTS: There were no main effects of the treatment on the outcome parameters except for a significant effect of time for maximum voluntary bite force (analysis of variance; P = .030) and effects of treatment, time, and interactions between treatment and time for maximum voluntary jaw opening (analysis of variance; P < .047). CONCLUSION: These results suggest that peripheral NMDA receptors do not play a major role in the pathophysiology of chronic myofascial temporomandibular disorder pain. Although there was a minor effect of ketamine on maximum voluntary jaw opening, local administration may not be promising treatment for these patients. [ABSTRACT FROM AUTHOR]

AIMS: To test the hypothesis that local injection of the N-methyl-D-aspartate (NMDA) receptor antagonist ketamine would significantly attenuate glutamate-evoked masseter mechanical sensitization and muscle pain in healthy young women either taking oral contraceptives (W+OC) or not taking oral contraceptives (W-OC). METHODS: Experimental pain was evoked in 47 healthy female subjects (W+OC, n=25; W-OC, n=22) by 2 injections of glutamate (0.2 mL, 1 mol/L) into the masseter muscle. A first injection of glutamate alone was followed by a second injection, 35 minutes later, of glutamate combined with ketamine (0, 1, or 10 mmol/L). Evoked pain intensity was scored on a 10-cm electronic visual analog scale (VAS). Distribution of perceived pain was drawn on a lateral view of the face (pain drawing). Masseter muscle pressure pain thresholds (PPT) and pressure-pain tolerances (PPTOL) were determined bilaterally before and at regular time intervals after injections. Analyses of variance (ANOVA) were used to test the data. RESULTS: There were no main effects of ketamine on any of the VAS pain parameters or on the pain drawing (ANOVAs: P > .055). Furthermore, there were no differences in PPT, PPTOL, VAS peak pain, duration, overall VAS pain, or pain drawing when W-OC were compared with W+OC (ANOVAs: P > .087). Repeated injection of glutamate alone significantly decreased PPT and PPTOL (ANOVAs: P < .001); however, this effect was not significantly attenuated by ketamine. CONCLUSIONS: Peripherally administered ketamine had no effect on glutamate-evoked masseter muscle pain and sensitization in healthy young women, which contrasts with recent observations in healthy young men. Further studies will be needed to reveal the mechanisms that underlie this apparent sex-related difference in ketamine-mediated analgesia. [ABSTRACT FROM AUTHOR]

Metformin is classified as a biguanide and is used in the treatment of type 2 diabetes. It is used worldwide and has been investigated in drug repositioning. The present study aims to investigate whether there is sexual dimorphism in the orofacial antinociceptive effect of metformin and the participation of TRP channels. Acute nociceptive behavior was induced by administering cinnamaldehyde or capsaicin to the upper lip. Nociceptive behavior was assessed through orofacial rubbing, and the effects of pre-treatment with metformin (125 or 250 mg/Kg) or vehicle (control) were tested on the behavior. Nociceptive behavior was also induced by formalin injected into the temporomandibular joint. The chronic pain model involved infraorbital nerve transection (IONX) was evaluated using Von Frey electronic filaments. Trpv1 gene expression was analyzed in the nerve ganglion. Docking experiments were performed. Metformin, but not the vehicle, produced antinociception (p < 0.0001) in all acute nociceptive behaviors in both sexes, and these effects were attenuated by the TRPV1 antagonist capsazepine and the TRPA1 antagonist HC-030031. In IONX with better (**p < 0.01, ****p < 0.0001 vs. control) results in females. TRPV1 gene expression was observed in the metformin treated group (*p < 0.05 vs. control). Docking experiments revealed that metformin may interact with TRPV1 and TRPA1 channels. Metformin promotes orofacial antinociception in both sexes in acute pain and is more effective in chronic pain in females than in males, through the modulation of TRPV1 and TRPA1 channels. These preclinical findings suggest a potential repositioning of metformin as an analgesic agent in acute and chronic orofacial pain states., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

In dental sleep medicine several sleep disorders commonly coexist with pain, contributing to complex clinical presentations which might affect the provision of appropriate and timely treatment. There are associations between sleep disorders and pain in general, as well as with specific orofacial pain conditions. As many as five of six patients with orofacial pain can present with sleep problems. The comorbidity of orofacial pain and sleep disorders overlays a complex web of altered neurobiological mechanisms that predispose to the chronification of orofacial pain. This review discusses the relationship between orofacial pain and sleep disorders and highlights their interactions and the neurobiological mechanisms underlying those relationships., (© 2024 Australian Dental Association.)

How pain and sensorimotor behavior interact has been the subject of research and debate for many decades. This article reviews theories bearing on pain-sensorimotor interactions and considers their strengths and limitations in the light of findings from experimental and clinical studies of pain-sensorimotor interactions in the spinal and craniofacial sensorimotor systems. A strength of recent theories is that they have incorporated concepts and features missing from earlier theories to account for the role of the sensory-discriminative, motivational-affective, and cognitive-evaluative dimensions of pain in pain-sensorimotor interactions. Findings acquired since the formulation of these recent theories indicate that additional features need to be considered to provide a more comprehensive conceptualization of pain-sensorimotor interactions. These features include biopsychosocial influences that range from biological factors such as genetics and epigenetics to psychological factors and social factors encompassing environmental and cultural influences. Also needing consideration is a mechanistic framework that includes other biological factors reflecting nociceptive processes and glioplastic and neuroplastic changes in sensorimotor and related brain and spinal cord circuits in acute or chronic pain conditions. The literature reviewed and the limitations of previous theories bearing on pain-sensorimotor interactions have led us to provide new perspectives on these interactions, and this has prompted our development of a new concept, the Theory of Pain-Sensorimotor Interactions (TOPSMI) that we suggest gives a more comprehensive framework to consider the interactions and their complexity. This theory states that pain is associated with plastic changes in the central nervous system (CNS) that lead to an activation pattern of motor units that contributes to the individual's adaptive sensorimotor behavior. This activation pattern takes account of the biological, psychological, and social influences on the musculoskeletal tissues involved in sensorimotor behavior and on the plastic changes and the experience of pain in that individual. The pattern is normally optimized in terms of biomechanical advantage and metabolic cost related to the features of the individual's musculoskeletal tissues and aims to minimize pain and any associated sensorimotor changes, and thereby maintain homeostasis. However, adverse biopsychosocial factors and their interactions may result in plastic CNS changes leading to less optimal, even maladaptive, sensorimotor changes producing motor unit activation patterns associated with the development of further pain. This more comprehensive theory points towards customized treatment strategies, in line with the management approaches to pain proposed in the biopsychosocial model of pain., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Author(s).)

Pain is a common symptom associated with many disorders affecting the craniofacial tissues that include the teeth and their supporting structures, the jaw, face and tongue muscles, and the temporomandibular joint. Most acute craniofacial pain states are easily recognized and readily treated, but chronic craniofacial pain states (e.g., temporomandibular disorders [TMD], trigeminal neuropathies, and some headaches) may be especially challenging to manage successfully. This chapter provides an overview of the processes that underlie craniofacial pain, with a focus on the pain-modulatory mechanisms operating in craniofacial tissues and in the central nervous system (CNS), including the role of endogenous chemical processes such as those involving opioids. The chapter outlines in particular findings from preclinical studies that have provided substantial information about the neural as well as nonneural (e.g., glial) processes involved in the initiation, transmission, and modulation of nociceptive signals in the trigeminal system, and also draws attention to their clinical correlates. The increased understanding gained from these preclinical studies of how nociceptive signals can be modulated will contribute to improvements in presently available therapeutic approaches to manage craniofacial pain as well as to the development of novel analgesic approaches., (© 2024. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Abstract: The mission of the International Association for the Study of Pain (IASP) is "to bring together scientists, clinicians, healthcare providers, and policymakers to stimulate and support the study of pain and to translate that knowledge into improved pain relief worldwide." The IASP will celebrate its 50th anniversary next year, and the series of articles published in this special issue of its flagship journal PAIN highlights the IASP's achievements over the past 5 decades. This article provides a brief historical overview of the IASP's 50-year journey, including the key "players," events, and initiatives leading to its formation and contributing to its progress. It complements the other articles outlining the contributions that the IASP has made and likely will continue to make to advances in pain education, research, management and advocacy, and its value to the IASP members., (Copyright © 2023 International Association for the Study of Pain.)

The precise control of bite force and gape is vital for safe and effective breakdown and manipulation of food inside the oral cavity during feeding. Yet, the role of the orofacial sensorimotor cortex (OSMcx) in the control of bite force and gape is still largely unknown. The aim of this study was to elucidate how individual neurons and populations of neurons in multiple regions of OSMcx differentially encode bite force and static gape when subjects (Macaca mulatta) generated different levels of bite force at varying gapes. We examined neuronal activity recorded simultaneously from three microelectrode arrays implanted chronically in the primary motor (MIo), primary somatosensory (SIo), and cortical masticatory (CMA) areas of OSMcx. We used generalized linear models to evaluate encoding properties of individual neurons and utilized dimensionality reduction techniques to decompose population activity into components related to specific task parameters. Individual neurons encoded bite force more strongly than gape in all three OSMCx areas although bite force was a better predictor of spiking activity in MIo vs. SIo. Population activity differentiated between levels of bite force and gape while preserving task-independent temporal modulation across the behavioral trial. While activation patterns of neuronal populations were comparable across OSMCx areas, the total variance explained by task parameters was context-dependent and differed across areas. These findings suggest that the cortical control of static gape during biting may rely on computations at the population level whereas the strong encoding of bite force at the individual neuron level allows for the precise and rapid control of bite force., Competing Interests: NH serves as a consultant for BlackRock Neurotech, Inc., the company that sells the multi-electrode arrays used in this study. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Arce-McShane, Sessle, Ram, Ross and Hatsopoulos.)

When the Journal of Oral Rehabilitation was established in 1973, there was very limited understanding of the mechanisms underlying neurally based functions, including those unique to the face, mouth and jaws (e.g. dental pain, taste, chewing, swallowing and salivation). Since that time, technological and other advances have led to new insights into the structure, connectivity and function of cranial nerves and areas of the central nervous system (CNS) involved in oro-facial functions and disorders or related functions (e.g. cognition, emotion, stress, consciousness, sleep, learning and memory). This review focuses on the advances in understanding of the neural basis of oro-facial pain and its control over the past five decades. The review first briefly considers how oro-facial pain conditions are now classified, diagnosed and managed. It then outlines novel insights that have been gained over this period through neuroscience research into the neural basis of these oro-facial pain conditions and the clinical relevance to these insights to the diagnosis and management of these conditions. The review also identifies promising research directions and gaps in knowledge that still need to be addressed to improve the understanding, diagnosis and management of oro-facial pain conditions., (© 2023 The Author. Journal of Oral Rehabilitation published by John Wiley & Sons Ltd.)

Background: Dental treatment associated with unadaptable occlusal alteration can cause chronic primary myofascial orofacial pain. The serotonin (5-HT) pathway from the rostral ventromedial medulla (RVM) exerts descending modulation on nociceptive transmission in the spinal trigeminal nucleus (Sp5) and facilitates chronic pain. The aim of this study was to investigate whether descending 5-HT modulation from the RVM to the Sp5 is involved in the maintenance of primary myofascial orofacial hyperalgesia after persistent experimental occlusal interference (PEOI) or after delayed removal of experimental occlusal interference (REOI)., Methods: Expressions of 5-HT3A and 5-HT3B receptor subtypes in the Sp5 were assessed by immunofluorescence staining and Western blotting. The release and metabolism of 5-HT in the Sp5 were measured by high-performance liquid chromatography. Changes in the pain behavior of these rats were examined after specific pharmacologic antagonism of the 5-HT3 receptor, chemogenetic manipulation of the RVM 5-HT neurons, or selective down-regulation of 5-HT synthesis in the RVM., Results: Upregulation of the 5-HT3B receptor subtype in the Sp5 was found in REOI and PEOI rats. The concentration of 5-HT in Sp5 increased significantly only in REOI rats. Intrathecal administration of Y-25130 (a selective 5-HT3 receptor antagonist) dose-dependently reversed the hyperalgesia in REOI rats but only transiently reversed the hyperalgesia in PEOI rats. Chemogenetic inhibition of the RVM 5-HT neurons reversed the hyperalgesia in REOI rats; selective down-regulation of 5-HT in advance also prevented the development of hyperalgesia in REOI rats; the above two manipulations did not affect the hyperalgesia in PEOI rats. However, chemogenetic activation of the RVM 5-HT neurons exacerbated the hyperalgesia both in REOI and PEOI rats., Conclusions: These results provide several lines of evidence that the descending pathway from 5-HT neurons in the RVM to 5-HT3 receptors in the Sp5, plays an important role in facilitating the maintained orofacial hyperalgesia after delayed EOI removal, but has a limited role in that after persistent EOI., (© 2023. The Author(s).)

Objective: The aims of this study were to develop a novel rodent model of masticatory muscle ischaemia via unilateral ligation of the external carotid artery (ECA), and to undertake a preliminary investigation to characterize its downstream effects on mechanosensitivity and cellular features of the masseter and temporalis muscles., Design: The right ECA of 18 male Sprague-Dawley rats was ligated under general anaesthesia. Mechanical detection thresholds (MDTs) at the masseter and temporalis bilaterally were measured immediately before ECA ligation and after euthanasia at 10-, 20-, and 35-days (n = 6 rats/timepoint). Tissue samples from both muscles and sides were harvested for histological analyses and for assessing changes in the expression of markers of hypoxia and muscle degeneration (Hif-1α, VegfA, and Fbxo32) via real time PCR. Data were analyzed using mixed effect models and non-parametric tests. Statistical significance was set at p < 0.05., Results: MDTs were higher in the right than left hemiface (p = 0.009) after 20 days. Histological changes indicative of muscle degeneration and fibrosis were observed in the right muscles. Hif-1α, VegfA, and Fbxo32 were more highly expressed in the masseter than temporalis muscles (all p < 0.05). Hif-1α and, VegfA did not change significantly with time in all muscles (all p > 0.05). Fbxo32 expression gradually increased in the right masseter (p = 0.024) and left temporalis (p = 0.05)., Conclusions: ECA ligation in rats induced hyposensitivity in the homolateral hemiface after 20 days accompanied by tissue degenerative changes. Our findings support the use of this model to study pathophysiologic mechanisms of masticatory muscle ischaemia in larger investigations., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

The imbalanced conditions of pronociceptive ON-cells and antinociceptive OFF-cells in the rostral ventromedial medulla (RVM) alter nociceptive transmission and play an important role in the development of chronic pain. This study aimed to explore the neuroplastic mechanisms of the RVM ON-cells and OFF-cells in a male rat model of experimental occlusal interference (EOI)-induced nociceptive behavior reflecting orofacial hyperalgesia and in modified models involving EOI removal at early and later stages. We recorded the mechanical head withdrawal thresholds, orofacial operant behaviors, and the activity of identified RVM ON-cells and OFF-cells in these rats. EOI-induced orofacial hyperalgesia could be relieved by EOI removal around postoperative day 3; this effect could be inhibited by intra-RVM microinjection of the κ-opioid receptor agonist U-69593. EOI removal around postoperative day 8 did not relieve the orofacial hyperalgesia, which could, however, be reversed by intra-RVM microinjection of the NK-1 (neurokinin-1) receptor antagonist L-733060. The activity of ON-cells and OFF-cells did not change during both the initial 3 and 6 d of EOI. When EOI was removed on postoperative day 3, OFF-cell responses decreased, contributing to the reversal of hyperalgesia. When EOI lasted for 8 d or was removed on postoperative day 8, spontaneous activity and stimulus-evoked responses of ON-cell increased, contributing to the maintained hyperalgesia. In contrast, when the EOI lasted for 14 d, OFF-cell responses decreased, possibly participating in the maintenance of hyperalgesia with persistent EOI. Our results reveal that adaptive changes in the RVM were associated with orofacial pain following EOI placement and removal. SIGNIFICANCE STATEMENT A considerable proportion of patients experience chronic orofacial pain throughout life despite the therapies given or removal of potential etiologic factors. However, current therapies lack effectiveness because of limited knowledge of the chronicity mechanisms. Using electrophysiological recording, combined with a behavioral test, we found that the prevailing descending facilitation in the rostral ventromedial medulla (RVM) participates in the maintenance of orofacial hyperalgesia following late removal of nociceptive stimuli, while the prevailing descending inhibition from the RVM may contribute to the reversal of orofacial hyperalgesia following early removal of nociceptive stimuli. Thus, variable clinical outcomes of orofacial pain may be associated with descending modulation, and an optimal window of time may exist in the management of chronic orofacial pain., (Copyright © 2022 the authors.)

This study aimed to test for the possible antinociceptive effect of the naturally occurring terpene citral in rodent models of acute and chronic orofacial pain and to test for the possible involvement of transient receptor potential (TRP) channels in this effect. Acute nociceptive behavior was induced in one series of experiments by administering formalin, cinnamaldehyde, menthol or capsaicin to the upper lip. Nociceptive behavior was assessed by orofacial rubbing, and the effects of pre-treatment with citral (0.1, 0.3 or 1.0 mg/Kg) or vehicle (control) were tested on the behavior. Nociceptive behavior was also induced by formalin injected into the temporomandibular joint or mustard oil injected into the masseter muscle, preceded by citral or vehicle (control) treatment. The chronic pain model involved infraorbital nerve transection (IONX) that induced mechanical hypersensitivity which was assessed by von Frey hair stimulation of the upper lip. Motor activity was also evaluated. Docking experiments were performed using TRPV1 and TRPM8 channels. Citral but not vehicle produced significant (p<0.01, ANOVA) antinociception on all the acute nociceptive behaviors, and these effects were attenuated by TRPV1 antagonist capsazepine, TRPM3 antagonist mefenamic acid and by TRPM8 desensitization, but not by ruthenium red and TRPA1 antagonist HC-030031. The IONX animals developed facial mechanical hypersensitivity that was significantly reduced by citral but not by vehicle. The docking experiments revealed that citral may interact with TRPV1 and TRPM8 channels. These results indicate the potential use of citral as an inhibitor of orofacial nociception in both acute and chronic pain states through TRPV1, TRPM3 and TRPM8 channels. See also Figure 1(Fig. 1)., (Copyright © 2022 Alves Rodrigues Santos et al.)

The aim of the study was to evaluate the possible involvement of transient receptor potential (TRP) channels, Acid-sensing ion channels (ASIC) and N-Methyl-D-aspartate receptor (NMDAR) in the orofacial antinociceptive behaviour effect of botulinum toxin type A (BoNT/A) in adult zebrafish. Initially, the open field test was performed to evaluate the effect of BoNT/A on the locomotor activity of zebrafish. Subsequently, the animals were pretreated with BoNT/A (0.05U, 0.1U or 0.5U/masseter) and acute orofacial nociception was induced by cinnamaldehyde, capsaicin, menthol, acid saline or glutamate applied to the lip or masseter muscle. In another group of experiments, animals were pre-treated with capsazepine (TRPV1 antagonist) or ketamine (NMDAR antagonist) to investigate the mechanism of antinociception. The possible involvement of central C-fibre afferents was also investigated using capsaicin desensitized animals. A molecular docking study was performed to observe the in silico interaction of BoNT/A with TRPV1 and NMDA channels. Pretreatment with BoNT/A reduced the nociceptive behaviour induced by capsaicin and glutamate. Antinociception was effectively inhibited by capsazepine and ketamine, as well as by capsaicin-induced desensitization. Consistent with these in vivo findings, the molecular docking study indicated that BoNT/A can interact with TRPV1 and NMDAR. The results indicate the involvement of TRP and NMDAR mechanisms in the orofacial antinociceptive behaviour effect of BoNT/A. The results also confirm the pharmacological relevance of BoNT/A as an inhibitor of orofacial nociception behaviour., (Copyright © 2022. Published by Elsevier Ltd.)

Background: Astrocytes in the rostral ventromedial medulla (RVM) contribute to descending pain modulation, but their role in oro-facial pain induced by persistent experimental dental occlusal interference (PEOI) or following EOI removal (REOI) is unknown., Objective: To explore the involvement of RVM astrocytes in PEOI-induced oro-facial hyperalgesia or its maintenance following REOI., Methods: Male rats were randomly assigned into five groups: sham-EOI, postoperative day 6 and 14 of PEOI (PEOI 6 d and PEOI 14 d), postoperative day 6 following REOI on day 3 (REOI 3 d) and postoperative day 14 following REOI on day 8 (REOI 8 d). The nociceptive head withdrawal threshold (HWT) and activities of RVM ON- or OFF-cells were recorded before and after intra-RVM astrocyte gap junction blocker carbenoxolone (CBX) microinjection. RVM astrocytes were labelled immunohistochemically with glial fibrillary acidic protein (GFAP) and analysed semi-quantitatively., Results: Persistent experimental dental occlusal interference-induced oro-facial hyperalgesia, as reflected in decreased HWTs, was partially inhibited by REOI at day 3 but not at day 8 after EOI placement. Increased GFAP-staining area occurred only in REOI 8 d group in which CBX could inhibit the maintained hyperalgesia; CBX was ineffective in inhibiting hyperalgesia in PEOI 14 d group. OFF-cell activities showed no change, but the spontaneous activity and responses of ON-cells were significantly enhanced that could be suppressed by CBX in REOI 8 d group., Conclusion: Rostral ventromedial medulla astrocytes may not participate in PEOI-induced oro-facial hyperalgesia or hyperalgesia inhibition by early REOI but are involved in the maintenance of oro-facial hyperalgesia by late REOI., (© 2021 John Wiley & Sons Ltd.)

The rostral ventromedial medulla (RVM) plays a key role in the endogenous modulation of nociceptive transmission in the central nervous system (CNS). The primary aim of this study was to examine whether the activities of RVM neurons were related to craniofacial nociceptive behaviour (jaw-motor response, JMR) as well as the tail-flick response (TF). The activities of RVM neurons and TF and JMR evoked by noxious heating of the tail or perioral skin were recorded simultaneously in lightly anaesthetized rats. Tail or perioral heating evoked the TF and JMR, and the latency of the JMR was significantly shorter (P < 0.001) than that of the TF. Of 89 neurons recorded in RVM, 40 were classified as ON-cells, 27 as OFF-cells, and 22 as NEUTRAL-cells based on their responsiveness to heating of the tail. Heating at either site caused an increase in ON-cell and decrease in OFF-cell activity before the occurrence of the TF and JMR, but did not alter the activity of NEUTRAL cells. Likewise, noxious stimulation of the temporomandibular joint had similar effects on RVM neurons. These findings reveal that the JMR is a measure of the excitability of trigeminal and spinal nociceptive circuits in the CNS, and that the JMR as well as TF can be used for studying processes related to descending modulation of pain. The findings also support the view that RVM ON- and OFF-cells play an important role in the elaboration of diverse nociceptive behaviours evoked by noxious stimulation of widely separated regions of the body., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Chronic orofacial pain conditions can be particularly difficult to diagnose and treat because of their complexity and limited understanding of the mechanisms underlying their aetiology and pathogenesis. Furthermore, there is considerable variability between individuals in their susceptibility to risk factors predisposing them to the development and maintenance of chronic pain as well as in their expression of chronic pain features such as allodynia, hyperalgesia and extraterritorial sensory spread. The variability suggests that genetic as well as environmental factors may contribute to the development and maintenance of chronic orofacial pain. This article reviews these features of chronic orofacial pain, and outlines findings from studies in animal models of the behavioural characteristics and underlying mechanisms related to the development and maintenance of chronic orofacial pain and trigeminal neuropathic pain in particular. The review also considers the role of environmental and especially genetic factors in these models, focussing on findings of differences between animal strains in the features and underlying mechanisms of chronic pain. These findings are not only relevant to understanding underlying mechanisms and the variability between patients in the development, expression and maintenance of chronic orofacial pain, but also underscore the importance for considering the strain of the animal to model and explore chronic orofacial pain processes.

This article reviews the major features and events that have characterized the 40-year history of the Canadian Pain Society/Société canadienne de la douleur, which is a chapter of the International Association for the Study of Pain (IASP). The review first describes its early formative years in the 1970s as eastern and western chapters of IASP and then its evolution as a Canada-wide chapter and society. Also highlighted is the formulation in this period of its purpose to foster pain research, education, and management and the many activities in which the Society has been engaged to reinforce this purpose over the ensuing decades. These include its annual scientific meetings and the establishment of publications, guidelines, and other educational material as well as awards to support research and trainees. Many of these activities have included engagement with key partners who have also collaborated with the Society in national and international advocacy for pain. The review also outlines some of the features and factors underpinning the Society's national and international reputation and impact resulting from the many contributions that its members have made to the advances in pain research, education, and management over the past 40 years. The review concludes by noting that by way of its rich history and its past and present experiences, the Society is well positioned to continue its many activities and contributions to address the many challenges still facing the pain field in Canada and around the world., (© 2020 The Author(s). Published with license by Taylor & Francis Group, LLC.)

To investigate neuronal activity involved in responses to noxious stimuli in conscious monkeys, the animals were subjected to a task that required them to detect a small change in facial skin temperature or light (second temperature: T2, second light: V2) relative to an initial condition (T1 or V1), and to detect changes in V2 along with a heat task. Recordings were obtained from 57 neurons in the ventral premotor cortex (PMv) during the heat or light detection task. T1 neurons and T2 neurons showed increased activity only during T1 or T2, and T1/T2 neurons were activated by both T1 and T2 stimuli. T1/T2 neurons showed an increase in firing at higher T1 temperatures, whereas T1 neurons did not. About half of the non-light/heat-sensitive T1/T2 neurons showed increased firing at higher T2 temperatures, whereas T2 neurons showed no such increase. The heat responses of heat-sensitive PMv neurons were significantly suppressed when monkeys shifted their attention from heat to light. The present findings suggest that heat-sensitive PMv neurons may be involved in motor responses to noxious heat, whereas light/heat-PMv neurons may be involved in emotional and motivational aspects of pain and inappropriate motor responses to allow escape from noxious stimuli.

Background: Adenosine triphosphate (ATP) and glutamate are associated with some headache conditions, and purinergic (P2X) and glutamatergic N-methyl-D-aspartate (NMDA) receptor-related processes in the medulla can modulate the effects of trigeminal nociceptive afferent inputs into the brainstem on craniofacial sensorimotor circuits. This study aimed to test whether neck muscle activity can be induced in rats by noxious stimulation of the frontal dura or superior sagittal sinus that involves P2X or NMDA receptor-dependent mechanisms., Methods: While electromyographic activities of neck and craniofacial muscles were being recorded in anesthetized rats (n = 46), the inflammatory irritant mustard oil (0.2 µL, 20% MO) or vehicle (mineral oil) was topically applied to the dura or sinus, preceded by 10 µL of the ATP antagonist 2',3'-O-(2,4,6- trinitrophenyl) adenosine 5'-triphosphate (TNP-ATP, 0.1 mmol/L; n = 8) or 2-amino-5-phosphonopentanoic acid (APV, 0.05 mmol/L; n = 7) or phosphate-buffered saline (PBS as vehicle control; n = 10)., Results: Application of MO but not vehicle to the frontal dura significantly increased (P < .05) neck electromyographic activity whereas MO application to the superior sagittal sinus did not significantly increase neck electromyographic activity unless MO had previously been applied to the dura. Pre-treatment (i.t.) with TNP-ATP or APV but not vehicle control significantly reduced neck electromyographic activity evoked by MO application to the dura., Conclusions: These data suggest that noxious stimulation of the frontal dura (but not superior sagittal sinus) may enhance neck muscle activity that is P2X and NMDA receptor-dependent. These effects may contribute to neck muscle stiffness that occurs in some headache conditions., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The aims of this study were to investigate if Toll-like receptor 4 (TLR4) is expressed in the medullary dorsal horn (MDH) and if medullary application of a TLR4 antagonist (lipopolysaccharides from Rhodobacter sphaeroides , LPS-RS) can attenuate changes in nociceptive sensorimotor responses or TLR4 expression that might be evoked by mustard oil (MO) application to the right maxillary first molar tooth pulp. Of 41 adult male Sprague-Dawley rats used in the study, 23 received intrathecal application of the TLR4 antagonist LPS-RS (25 μg/10 μl; LPS-RS group) or isotonic saline (10 μl; vehicle control group) 10 min before pulpal application of MO (95%; 0.2 μl). Bilateral electromyographic (EMG) activities of the anterior digastric and masseter muscles were recorded continuously before and until 15 min after the MO application to the pulp. In 6 of these 23 rats and an additional 18 rats, the caudal medulla containing the ipsilateral and contralateral MDH was removed after euthanasia for subsequent Western Blot analysis of TLR4 expression in LPS-RS ( n = 8) and vehicle ( n = 8) groups and a naïve group ( n = 8). The % change from baseline in the MO-evoked EMG activities within the anterior digastric muscles were significantly smaller in the LPS-RS group than the control group (two-way ANOVA, post hoc Bonferroni, P < 0.0001). Western Blot analysis revealed similar levels of TLR4 expression in the caudal medulla of the naïve, vehicle and LPS-RS groups. These novel findings suggest that TLR4 signaling in the caudal medulla may mediate MO-induced acute dental inflammatory pain in rats., (Copyright © 2020 Filippini, Molska, Zanjir, Arudchelvan, Gong, Campos, Avivi-Arber and Sessle.)

Aims: To test for the possible antinociceptive effect of nifedipine in rodent models of acute and chronic neuropathic orofacial pain and the possible involvement of TRP- and NMDA-related processes in this effect., Methods: Acute nociceptive behavior was induced by administering formalin, cinnamaldehyde, glutamate, capsaicin, or acidified saline to the upper lip or hypertonic saline to the cornea of Swiss mice. Acute nociceptive behavior was also induced by formalin injected into the TMJ or mustard oil injected into the masseter muscle of Wistar rats. The chronic pain model involved infraorbital nerve transection (IONX) in Wistar rats to induce mechanical hypersensitivity, which was assessed with von Frey hair stimulation of the upper lip. The effects of pretreatment with nifedipine or vehicle (control) were tested on the nociceptive behaviors. Docking experiments were also performed. Statistical analysis included one-way ANOVA followed by Tukey post hoc test and two-way ANOVA followed by Bonferroni post hoc test (statistical significance P < .05)., Results: Nifedipine produced significant antinociceptive effects in all of the acute nociceptive behaviors except that induced by capsaicin. The antinociceptive effects were attenuated by NMDA, TRPA1, or TRPM3 receptor antagonists. The IONX animals developed facial mechanical hypersensitivity, which was significantly reduced by nifedipine. The docking experiments suggested that nifedipine may interact with TRPM3 and NMDA receptors., Conclusion: The present study has provided novel findings in a variety of acute and chronic orofacial pain models showing that nifedipine, a selective inhibitor of L-type Ca 2+ channels, can suppress orofacial nociceptive behavior through NMDA, TRPA1, and TRPM3 receptor systems.