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Objective: Early life experiences have been found to have a long-lasting effect on brain development in adult life. The purpose of this study was to determine whether neonatal manipulation could alter orofacial pain responsiveness in adult rats METHODS: In the first 21 days of life, male rats were exposed to gentle handling or maternal deprivation (MD) procedures to establish models of handled and MD rats, respectively. The rats were assigned to three of the following experimental groups at the age of two months: intra-dental capsaicin (100 µg), intra-lip formalin (50 µL), and repeated nitroglycerin (NTG) (5 mg/rat/ip) infusion. In addition, there were three drug vehicle groups and three groups that received capsaicin, formalin, or NTG without prior handling or MD procedures. The behaviors were recorded following the pain induction., Results: Spontaneous pain behaviors in the first phase of formalin test was significantly increased in MD (p < 0.01) and handled rats in comparison with the vehicle group (p < 0.05). The second-phase data showed that formalin-induced spontaneous pain behaviors was increased in rats- treated with MD as compared to either vehicle or handled+formalin groups (p < 0.001). Capsaicin-induced dental pulp nociception was increased in the MD group in comparison with the capsaicin (p < 0.001) and capsaicin+handled (p < 0.001) groups. Moreover, NTG-induced migraine-like behaviors symptoms were increased in the MD group as compared to control and handled groups (p < 0.05)., Conclusions: In this study neonatal gentle handling or MD treatment increased orofacial pain in adulthood, showing early life experiences permanent effects on the development of trigeminal circuits in the brain., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to declare., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Objectives: The objectives were to investigate the efficacy and mechanisms of cannabidiol on orofacial nociception induced by Complete Freund's Adjuvant (CFA) in male Mus musculus mice., Design: For the study of efficacy, mice were divided into seven groups: sham; inflammation; and cannabidiol 0.5, 1, 3, 5, and 10 mg. For the study of mechanisms of cannabidiol, mice were divided into six groups: sham, inflammation, calcitonin gene-related peptide (CGRP) antagonist with and without cannabidiol, and vanilloid receptor 1 antagonist with and without cannabidiol. Spontaneous pain-like behaviors, trigeminal nociception, and trigeminal modulating activity were investigated., Results: CFA injected in the right masseter muscle significantly induced spontaneous pain-like behaviors and the trigeminal nociceptive pathway. This effect was inhibited by injection of 1, 3, 5, and 10 mg of cannabidiol. The 50 % inhibitory concentration of cannabidiol on antinociception was found to be 3 mg/kg. In addition, there was no difference in spontaneous pain-like behaviors with vanilloid receptor 1 antagonist injected before treatment with cannabidiol compared to saline control. Reduced c-fos expression was observed in the trigeminal nucleus caudalis and periaqueductal gray in the group injected with CGRP antagonist before treatment with cannabidiol., Conclusion: The antinociceptive effects of cannabidiol induced by acute orofacial nociception is mediated by vanilloid receptor 1 but not by CGRP. Cannabidiol can act with peripheral nonpeptidergic neurons and can be used as an alternative drug or as a synergistic medication in pain treatment., Competing Interests: Declaration of Competing Interest No conflicts of interest with all of the authors., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Objectives: Opiorphin is a recently discovered peptide shown to inhibit the enkephalin-degrading enzymes and prolong the effects of enkephalins. Although opiorphin is found in high concentrations in saliva, the relationship between salivary opiorphin and orofacial pains is not yet fully understood. We aimed to determine salivary opiorphin concentrations in dental pain related to symptomatic irreversible pulpitis (SIP), and symptomatic apical periodontitis (SAP)., Design: 39 patients participated in this study. The participants were categorized into SIP and SAP based on their diagnosis. All the patients were treated with root canal treatment. Saliva specimens were collected, and pain levels were recorded at pre-treatment, 7 days post-treatment and 30 days post-treatment. Saliva opiorphin levels were measured using a commercially available ELISA kit. Pre-treatment and post-treatment opiorphin levels were evaluated using repeated measures ANOVA. Correlations between VAS scores, opiorphin levels and age were evaluated using Spearman's Rank Correlation., Results: The average saliva opiorphin level pre-treatment, 7 days post-treatment and 30 days post-treatment were 31.28 ± 7.10 ng/ml, 20.41 ± 2.67 ng/ml and 18.61 ± 2.05 ng/ml respectively. Significantly higher pre-treatment opiorphin levels were observed in the SIP group compared to the SAP group. A strong correlation was observed between the pre-treatment pain levels and the saliva opiorphin concentrations., Conclusions: Our findings indicate that saliva opiorphin levels increase in inflammation related dental pain. The level of salivary opiorphin is strongly correlated with the reported level of pain. The extent of the inflammation (pulpal vs. periodontal) also affects the opiorphin level., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Objective: To assess changes in orofacial tactile sensitivity and gnawing related to capsaicin-mediated cutaneous, myogenic, and arthrogenic nociception in the rat., Design: After recovery from anesthesia, orofacial tactile sensitivity and gnawing were assessed using operant testing methods following capsaicin application. Twenty female CD-Hairless rats were tested with bilateral capsaicin cream application to the cheek or with isoflurane anesthesia alone. Following several weeks of recovery, animals (n = 20) received either 10 μL unilateral masseter injections of vehicle, or phosphate buffered saline (PBS) to assess injection sensitization. After several weeks, masseter capsaicin (1.0%) injections (10 μL) were assessed compared to vehicle and PBS (n = 13). Weeks later capsaicin TMJ injections were evaluated. Animals (n = 11) received either 10 μL unilateral TMJ injections of capsaicin solution (1%) or vehicle., Results: Capsaicin cream to the skin significantly altered gnawing activity (increased puncture time by 248 s (p = 0.0002)) and tactile sensitivity (decreased tolerated bottle distance by 0.980 cm compared to isoflurane only (p = 0.0001)). Similarly, capsaicin masseter injection increased puncture time (339.6 s, p = 0.07) and decreased tolerated bottle distance (1.04 cm, p = 0.005) compared to vehicle. However, intra-articular capsaicin in the TMJ only modified gnawing (increased puncture time by 133 s), with no changes found in tactile sensitivity compared to vehicle., Conclusion: Application of capsaicin to the skin and masseter had similar behavioral effects; however, intra-articular injections to the TMJ only affected gnawing. These data indicate the behavioral changes in rodent models of myogenic and cutaneous pain may be markedly different than models of arthrogenic pain originating from the TMJ., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Knowledge about how Temporomandibular Disorder (TMD) pain patients regulate masticatory function is still unclear. To investigate the effect of experimental jaw muscle pain as well as texture and size of food on mastication, twelve healthy participants (30.6±7.5 years old) participated in this study. Experimental pain was induced by an infusion of 0.5 M monosodium glutamate (MSG) with isotonic saline (IS) serving as a control. After the infusions, the Jaw Functional Limitation Scale (JFLS) and Pain Catastrophizing Scale (PCS) were filled out. Electromyographic (EMG) activity in the masseter and temporalis muscles, jaw movements and bite force, which was measured by a customized intra-oral device, were recorded simultaneously during mastication of three different types of food. Pain was scored continuously on a visual analog scale. The results demonstrated a trend towards a decrease in the impulse of the bite force, as well as a significant decrease in EMG activity of the masseter muscle during the first five masticatory cycles, in the MSG session. Also, MSG induced increased JFLS and PCS scores compared with IS. On the other hand, the results suggested that the applied levels of pain may not change habitual masticatory movements. This study has revealed that a clinically relevant level of pain in the masseter muscle has only minor impact on the performance of mastication, probably due to a lack of exacerbation of pain during function. In future studies of jaw muscle function during painful conditions, it is important to include patient-based reports of functional limitation and emotional distress., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Objective: Compare pain-related measures and psychosocial variables between glutamate-evoked jaw muscle pain in healthy subjects (HS) and patients with persistent myofascial temporomandibular disorder (TMD) pain., Design: Forty-seven female HS and 10 female patients with persistent myofascial TMD pain participated. The HS received an injection of glutamate into the masseter muscle to model persistent myofascial TMD pain. Participants filled out a coping strategies questionnaire (CSQ), the symptom checklist 90 (SCL-90) and McGill pain questionnaire (MPQ). Pain intensity was assessed on an electronic visual analogue scale (VAS). Pain-drawing areas, numerical rating scale (NRS) scores of unpleasantness, pressure pain thresholds (PPTs) and pressure pain tolerance (PPTOL) were measured. Unpaired t-tests and correlation tests were used for analyses., Results: The groups were significantly different when comparing the CSQ scores of control, decrease, diverting attention, increase of behavioural activities and somatization. The peak VAS pain, NRS of unpleasantness and MPQ scores were not significantly different between groups, but PPT and PPTOL were significantly lower in the TMD patients. Significant positive correlations were found in the TMD patients between peak VAS pain and CSQ catastrophizing score and SCL-90 somatization. The scores of PPTs and PPTOLs, in patients showed positive correlations with CSQ reinterpreting pain sensations scores and PPTs correlated with CSQ praying/hoping scores., Conclusions: Glutamate-evoked pain responses in HS and persistent myofascial TMD pain have similar sensory-discriminative and affective-unpleasantness components but differ in psychosocial features. This study suggests that experimental designs based on glutamate injection into muscle can provide an appropriate model for elucidating persistent myofascial pain conditions.

Objective: Since there is limited information of the effects of orofacial pain on oromotor behaviour, the aim of this study was to test the effects of injection of the algesic chemical glutamate into orofacial tissues on licking behaviour in rats., Design: Male Sprague-Dawley rats were trained to carry out stereotyped licking from a water spout connected to a force transducer, and once they met preset licking motor requirements (peak force of licking of 2-20 g, interlick interval of 0.11-0.19s), their masseter muscle or tongue was injected with either isotonic saline (0.9%, 5 microL) or glutamate (1.0M, 5 microL) and several parameters of their licking performance were re-assessed., Results: There were significant effects (P<0.05; 1-way repeated measures ANOVA) of glutamate injection into the tongue on the number of clusters of licks, the number of licks per cluster, the intercluster period, the peak force of licking and the interlick interval, but there were no significant (P>0.05) effects on licking of isotonic saline injection into the tongue or isotonic saline or glutamate injection into the masseter muscle., Conclusions: These findings provide the first documentation that noxious stimulation of the tongue, but not of the masseter muscle, has a modulatory effect on licking behaviour in the rat and suggest that the neural substrate for licking may be sensitive to selective nociceptive inputs from the orofacial region.