Self-reported oral moistening disorders in obstructive sleep apnoea: A scoping review.

BACKGROUND: Obstructive sleep apnoea (OSA) is a highly prevalent problem with significant consequences. Continuous positive airway pressure (CPAP) and oral mandibular advancement device (MAD) are considered the standard treatments for OSA. Patients may experience self-reported oral moistening disorders (OMDs) (i.e. xerostomia or drooling) at the beginning, throughout and after treatment. This affects oral health, quality of life and treatment effectiveness. The exact nature of the associations between OSA and self-reported OMD is still unknown. We aimed to provide an overview of the associations between self-reported OMD on the one hand and OSA and its treatment (namely CPAP and MAD) on the other hand. In addition, we sought to determine whether OMD affects treatment adherence. MATERIALS AND METHODS: A literature search in PubMed was performed up to 27 September 2022. Two researchers independently assessed studies for eligibility. RESULTS: In total, 48 studies were included. Thirteen papers investigated the association between OSA and self-reported OMD. They all suggested an association between OSA and xerostomia but not between OSA and drooling. The association between CPAP and OMD was addressed in 20 articles. The majority of studies have indicated xerostomia as a CPAP side effect; however, some have observed that xerostomia diminishes with CPAP therapy. In 15 papers, the association between MAD and OMD was investigated. In most publications, both xerostomia and drooling have been described as common side effects of MADs. These side effects are often mild and transient, and they improve as patients continue to use their appliance. Most studies found that these OMDs do not cause or are not a strong predictor of non-compliance. CONCLUSION: Xerostomia is a common side effect of CPAP and MAD, as well as a significant symptom of OSA. It may be regarded as one of the indicators of sleep apnoea. Moreover, MAD therapy can be associated with OMD. However, it seems that OMD may be mitigated by being adherent to the therapy.

Aging exaggerates pulpal pain sensation by increasing the expression levels of nociceptive neuropeptides and inflammatory cytokines.

BACKGROUND: Dental pain is a main clinical problem in the elderly population and its assessment and treatment make special challenges for health care services. However, the age-induced alteration in dental pain perception and the underlying molecular mechanism(s) has not yet been fully clarified. METHODS: Here, the effect of aging on nociceptive behaviors following inflammatory dental pulp pain was evaluated. Since prostaglandins, nociceptive neuropeptides, and inflammatory cytokines have critical roles in the development of aging as well as pain signaling, the expression levels of COX-2, CGRP, IL-1ß, IL-6, TNF-α and its converting enzyme TACE were assessed in the trigeminal ganglion of young and aged rats with dental pain. Dental pulp pain was induced by intradental application of capsaicin (100 µg). The immunofluorescence (COX-2 and CGRP) and western blot techniques were used. RESULTS: The data showed that aged animals have different pattern of pain. So that, the mean of nociceptive scores was significantly greater in aged rats at 10 and 15 min after capsaicin injection. In aged rats, dental pain was persisting over 7 h, while it was disappeared at 300 min in young rats. Molecular data showed that dental pain significantly increased the expression of COX-2, CGRP, IL-1ß, IL-6, TNF-α and TACE in the trigeminal ganglion of the young and aged rats. In addition, the amount of those parameters, except TACE, in capsaicin-treated aged animals were significantly (p < 0.05) greater than those in capsaicin-treated young rats. CONCLUSION: It seems that the induction of pro-inflammatory cytokines in an acute inflammatory pulpal pain model may contribute, at least in part to the increased nociceptive behaviors and pain perception in aged rats.

Apelin signalling in the periaqueductal grey matter alleviates capsaicin-evoked pulpal nocifensive behaviour and capsaicin-induced spatial learning and memory impairments in rat.

AIM: Pulpal pain is a common orofacial health issue that has been linked to cognitive impairment. Because of its prominent role in pain modulation and cognitive impairment, apelin (Apl) is regarded as a promising target for clinical pain management. The role of Apl in orofacial pain, however, is unknown. The purpose of this study was to determine the effects of intra-periaqueductal grey matter (PAG) administrations of Apl-13 on capsaicin-evoked pulpal nocifensive behaviour and capsaicin-induced spatial learning and memory impairments in rats. METHODOLOGY: Forty-nine male Wistar rats (200-250 g) were randomly divided into seven groups (n = 7 per group). The groups included: untreated intact, capsaicin (Caps) only, three Caps+Apl groups that received different dosages of intra-PAG injection of Apl-13 (1, 2 and 3 µg/rat) 20 min prior to capsaicin application, and two Apl+antagonist groups that received Apl receptor antagonist or naloxone (a µ opioid receptor) 20 min before Apl injection. Learning and memory were assessed using the Morris water maze test. One-way analysis of variance followed by Tukey post hoc tests was used for statistical analysis. RESULTS: Intra-PAG administration of Apl-13 significantly reduced the capsaicin-induced nocifensive behaviour (p < .01). This antinociception effect was inhibited by F13A and naloxone. Apl-13 inhibited nociception-induced learning and memory deficits (p < .01). The cognitive effects were also blocked by pre-treatment administration of F13A (3 µg/rat). CONCLUSIONS: These findings indicated that Apl-13, via Apl receptors (AR or APJ) and µ opioid receptors, alleviated capsaicin-induced dental nocifensive behaviour and protected against nociception-induced learning and memory impairments. As a result of our findings, Apl appears to be a promising analgesic option for further research in orofacial pain models and clinical trials.

Blockage of ventrolateral periaqueductal gray matter cannabinoid 1 receptor increases dental pulp pain and pain-related subsequent learning and memory deficits in rats.

Cannabinoid 1 receptor (CB1R) signaling has a pivotal role in the modulation of both pain and cognitive responses. This study aims at investigating the role of CB1R in the ventrolateral periaqueductal gray matter (vlPAG) on both pulpal pain and pain-related subsequent changes in learning and memory performances in rats. The adult male Wistar rats were cannulated in the vlPAG. The rats were pretreated by intra-vlPAG administration of selective CB1R antagonist AM-251 (2, 4 and 8 µg/rat) and vehicle dimethylsulfoxide. The drugs were microinjected 20 min before the induction of capsaicin-induced pulpalgia. The nociceptive behaviors were recorded for 40 min. Then, passive avoidance and spatial learning and memory were assessed using the shuttle box and Morris water maze tests, respectively. Following the administration of intradental capsaicin, there was a significant nociceptive response that increased after an induced blockage of CB1R by AM-251 at 4 and 8 µg. In addition, capsaicin impaired passive avoidance and spatial memory performance of rats. Microinjection of AM-251, prior to capsaicin, could dose-dependently exaggerate capsaicin-related learning and memory deficits in both tests. The present data indicated that the vlPAG endocannabinoid system is involved in the modulation of pain signals from dental pulp. It was also accompanied by learning and memory impairments.

Pain influences food preference and food-related memory by activating the basolateral amygdala in rats.

The amygdala has been demonstrated to contribute to pain-related behavior and food preference. Here, the effect of pain on food preference and food-matched visual-cue memory, in the presence or absence of a basolateral amygdala (BLA) lesion, has been evaluated using a novel innovative apparatus and protocol. Forty adult male Wistar rats were randomly divided into five groups (n = 8) as follows: control, pain, ibuprofen + pain, BLA lesion, BLA lesion + pain groups. Bilateral lesions of the BLA were produced by passing a current of 1.5 mA for 7 s. Pain was induced on the right hind paw of the rats by sub-plantar injection of 50 µl of 2.5% formalin. The animals were encountered with four different meals including wholemeal, wholemeal + sugar, white flour, and biscuit. Each test session consisted of six trials with inter-trial intervals of 15 min. The number of visits to each meal zone and port, the amount of time spent in each food zone and port, traveled distance in each food zone, food consumption per each visit and the total food consumption were recorded. The control group showed a high biscuit preference and low white flour preference. Rats suffering BLA lesion and rats in the BLA lesion + pain group exhibited a shifted preference curve. They had a bias toward eating wholemeal + sugar rather than white flour and biscuit. This group also showed an impaired spatial memory. In conclusion, our findings suggest that the BLA may be involved in pain-induced food preference and food-matched visual-cue memory.

Mode of delivery alters dental pulp nociception and pain-induced changes in cognitive performance in adults male rats.

This study examined the effects of delivery mode on the response to inflammatory pulpal pain and pain-induced changes in cognitive performance in adult rats. Experiments were done on rats born by vaginal or caesarean section (C-section) delivery. Dental pulp was irritated by intradental capsaicin (100 µg) application and then nociceptive scores were recorded for 40 min. Spatial and passive avoidance learning and memory were assessed using the Morris water maze (MWM) and shuttle box tools, respectively. Additionally, in vivo recording of field excitatory postsynaptic potential (fEPSP) in the CA1 of the hippocampus was used to verify synaptic plasticity. Capsaicin produced more significant nociceptive behavior in vaginally delivered rats compared to C-section rats (P < 0.01). C-section-delivered rats show better performance in both MWM and shuttle box tests. Likewise, C-section rats had greater fEPSP slopes compared to the vaginally delivered group (P < 0.05). Capsaicin impairs cognitive performance in rats born by each delivery route. However, capsaicin effects were more significant in rats delivered vaginally than by C-section. Overall, C-section-delivered rats show lower sensitivity to capsaicin-evoked pulpal nociception and better cognitive performance than vaginally delivered rats. These effects are in part mediated by reduced neuroinflammation and enhanced neuronal synaptic plasticity following C-section delivery.

Long-term effect of an educational intervention regarding dental trauma first aid: a phase II study.

AIM: Interventions that improve knowledge about emergency management of traumatic dental injuries may be a good way to achieve a more favorable prognosis in such situations. We set out to evaluate the short- and long-term effects of combined educational interventions on health teachers, including lecture presentation, question-and-answer sessions, and informational posters to promote awareness regarding emergency measures for traumatized teeth. Assessment was performed using a three-part questionnaire, including demographic data, knowledge, and self-assessment. Using a census sampling method, 52 health teachers of 68 potential candidates participated in the study. The questionnaires of 38 teachers who participated at all three intervals, including before (T0), immediately after (T1), and 36 months after (T2) the intervention, were analyzed. Statistical analysis involved Cochrane and McNemar's tests. Totally, results revealed an increase in knowledge from T0 to T1 and T2 intervals (P < 0.017). This study shows the positive effect of educational campaigns and, therefore, serves to encourage professionals to embark on innovative educational programs in this field.

Antimicrobial efficacy of different herbal extracts against root canal pathogens - An in vitro study.

Background: The antimicrobial activity exhibited by the plant extracts against various pathogens has previously been demonstrated to a limited extent. However, the antibacterial effects of most of them have not yet been clarified in endodontics. Aim: This study aimed to determine the antimicrobial activity of some medicinal plants' methanolic extracts against some root canal microorganisms. Methods and Materials: In this in vitro study, after gathering the five plants (pomegranate peel, clove, Zhumeria majdae, Eucalyptus galbie and green tea), their methanolic extracts were obtained by the maceration method, and the antimicrobial activity was determined using micro- and macro-dilution methods. The microorganisms tested in this study were Enterococcus (E.) faecalis, Porphyromonas (P.) gingivalis and Fusobacterium (F.) nucleatum. Non-ready-to-use calcium hydroxide (CH), ready-to-use Calcipex II CH and methanol were used as control materials. Statistical Analysis: The nonparametric Kruskal-Wallis and Friedman tests were used to analyse and evaluate the data and variables. Results: In all concentrations and time intervals studied, eucalyptus extract showed the highest antimicrobial activity against E. faecalis. All the extracts showed growth-inhibitory effects against P. gingivalis and F. nucleatum. There were no significant differences between the anti-enterococcus effects of eucalyptus extracts and non-ready-to-use CH (P > 0.05). Conclusion: There was a greater efficacy of Eucalyptus galbie extract than other extracts.

Repeated gentle handling or maternal deprivation during the neonatal stage increases adult male rats' baseline orofacial pain responsiveness.

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.

Age-dependent down-regulation of orexin receptors in trigeminal nucleus caudalis correlated with attenuation of orexinergic analgesia in rats.

Aging is related to a variety of physiological organ changes, including central and peripheral nervous systems. It has been reported that the orexin signaling has a potential analgesic effect in different models of pain, especially inflammatory pulpal pain. However, the age-induced alteration in dental pain perception and orexin analgesia has not yet been fully elucidated. Here, we tested that how aging may change the effect of orexin-A on nociceptive behaviors in a rat dental pulp pain model. The expression levels of orexin receptors and the nociceptive neuropeptides substance P (SP) and calcitonin-related gene peptide (CGRP) were also assessed in the trigeminal nucleus caudalis (TNC) of young and aged rats. Dental pulp pain was induced by intradental application of capsaicin (100 µg). The immunofluorescence technique was used to evaluate the expression levels. The results show less efficiency of orexin-A to ameliorate pain perception in aged rats as compared to young rats. In addition, a significant decrease in the number of orexin 1 and 2 receptors was observed in the TNC of aged as compared to young rats. Dental pain-induced SP and CGRP overexpression was also significantly inhibited by orexin-A injection into the TNC of young animals. In contrast, orexin-A could not produce such effects in the aged animals. In conclusion, the older age-related reduction of the antinociceptive effect of orexin may be due to the downregulation of its receptors and inability of orexin signaling to inhibit the expression of nociceptive neuropeptides such as SP and CGRP in aged rats.

Elementary school staff knowledge and attitude with regard to first-aid management of dental trauma in Iran: a basic premise for developing future intervention.

AIM: The purpose of this study was to evaluate Iranian teachers' knowledge and attitude with regard to emergency management of dental trauma. MATERIAL AND METHODS: A four-part questionnaire, including demographic data, knowledge, attitude, and self-assessment, was given to 422 teachers from 14 schools. Data obtained from 400 completed questionnaires were statistically analyzed using t-test, one-way anova and Pearson correlation coefficient. RESULTS: It was found that there was no statistically significant difference between knowledge and demographic variations (P > 0.05). However, there was a moderate positive association between knowledge and attitude toward emergency management of dental trauma (r = 0.38, P = 0.0001). The outcome indicated completely inadequate knowledge regarding the management of tooth fracture and avulsion. Most participants (94.3%) were unsatisfied with their awareness and suggested that further education on the topic should be offered. CONCLUSIONS: The present study revealed considerably low knowledge of the participants regarding the first-aid management of dental trauma for the study group. As teachers get an opportunity to attend a case of dental trauma, strategies to improve the teachers' knowledge seem crucial.

The ability of orexin-A to modify pain-induced cyclooxygenase-2 and brain-derived neurotrophic factor expression is associated with its ability to inhibit capsaicin-induced pulpal nociception in rats.

Background: The rostral ventromedial medulla (RVM) is a critical region for the management of nociception. The RVM is also involved in learning and memory processes due to its relationship with the hippocampus. The purpose of the present study was to investigate the molecular mechanisms behind orexin-A signaling in the RVM and hippocampus's effects on capsaicin-induced pulpal nociception and cognitive impairments in rats. Methods: Capsaicin (100 g) was applied intradentally to male Wistar rats to induce inflammatory pulpal nociception. Orexin-A and an orexin-1 receptor antagonist (SB-334867) were then microinjected into the RVM. Immunoblotting and immunofluorescence staining were used to check the levels of cyclooxygenase-2 (COX-2) and brain-derived neurotrophic factor (BDNF) in the RVM and hippocampus. Results: Interdental capsaicin treatment resulted in nociceptive responses as well as a reduction in spatial learning and memory. Additionally, it resulted in decreased BDNF and increased COX-2 expression levels. Orexin-A administration (50 pmol/1 µL/rat) could reverse such molecular changes. SB-334867 microinjection (80 nM/1 µL/rat) suppressed orexin's effects. Conclusions: Orexin-A signaling in the RVM and hippocampus modulates capsaicininduced pulpal nociception in male rats by increasing BDNF expression and decreasing COX-2 expression.

α-Pinene Influence on Pulpal Pain-Induced Learning and Memory Impairment in Rats Via Modulation of the GABAA Receptor.

Background: This study investigated the effect of central administration of α-pinene and the interaction of α-pinene with GABAA receptor on pulpal nociception-induced changes in learning and memory performances in rats. Materials and Methods: Sixty-six adult male Wistar rats were used. Pulpal nociception was induced by intradental application of capsaicin (100 µg/rat). α-pinene (0.1, 0.2, and 0.4 µg/rat) was injected centrally 10 min before the administration of capsaicin. In addition, α-pinene (0.4 µg/rat) was co-injected with bicuculline (0.5 µg/rat). Spatial and passive avoidance learning and memory were assessed using Morris water maze (MWM) and shuttle box tasks, respectively. Results: Experimental results of the MWM test showed that capsaicin increases escape latency and distance traveled to the hidden platform (P < 0.01). The effect was prohibited by α-pinene at the dose of 0.4 µg/rat. Moreover, capsaicin-treated animals spent less time in the target zone than capsaicin + α-pinene (0.4 µg/rat)-treated rats (P < 0.05). In the shuttle box test, α-pinene (0.2 µg and 0.4 µg) prevented an increased number of acquisition trials and time spent in the dark chamber induced by capsaicin, whereas it increased step-through latency (P < 0.01). However, the effects of α-pinene (0.4 µg/rat) in both tests were prohibited by bicuculline (0.5 µg/rat). Conclusion: The data showed that central administration of α-pinene might reduce pulpalgia-induced learning and memory impairment, at least partially, via modulation of GABAA receptors.

Clinical, radiological, and histological correlation in diagnosis of pulpitis.

Background: To establish an endodontic diagnosis, a clinician should consider a variety of factors. Various studies have failed to demonstrate a strong correlation between histological findings with clinical and radiographic assessments. This study sought to evaluate the histopathological features of reversible and irreversible pulpitis diseases and their correlation with clinical diagnosis in extracted human molar teeth. Materials and Methods: In this experimental ex vivo study, 75 molars with caries and three intact molars were used. According to the radiographic findings and clinical criteria and the need for root canal therapy, samples were categorized as having normal/reversible pulpitis and irreversible pulpitis. Immediately after extraction, an exposure was made at 2 mm below the cementoenamel junction. Formalin-fixed specimens were decalcified, sectioned and stained with hematoxylin and eosin for histological examinations using light microscopy. Variables including the type and severity of the inflammation, hyperemia, necrosis, fibrosis and the existence of an odontoblastic layer and dentin bridge were evaluated. The Fisher's exact test and the Chi-squared test were used for statistical analysis. P <0.05 was considered as significant. Results: Acute inflammation, hyperemia and pulp exposure were significantly more common among subjects with irreversible pulpitis (P < 0/005). However, fibrosis was significantly higher in the reversible group (P < 0/005). There were no statistically significant differences between the groups regarding the other variables. Conclusion: Some discrepancies between clinical, radiographic and histological findings were observed in our experimental study. Indeed, effective clinical practice requires consideration of all discrepancies found.

The role of basolateral amygdala orexin 1 receptors on the modulation of pain and psychosocial deficits in nitroglycerin-induced migraine model in adult male rats.

BACKGROUND: Migraine headaches have been associated with sensory hyperactivity and anomalies in social/emotional responses. The main objective of this study was to evaluate the potential involvement of orexin 1 receptors (Orx1R) within the basolateral amygdala (BLA) in the modulation of pain and psychosocial dysfunction in a nitroglycerin (NTG)-induced rat model of migraine. METHODS: Adult male Wistar rats were injected with NTG (5 mg/kg, intraperitoneal) every second day over nine days to induce migraine. The experiments were done in the following six groups (6 rats per group): untreated control, NTG, NTG plus vehicle, and NTG groups that were post-treated with intra-BLA microinjection of Orx1R antagonist SB-334867 (10, 20, and 40 nM). Thermal hyperalgesia was assessed using the hot plate and tail-flick tests. Moreover, the elevated plus maze (EPM) and open field (OF) tests were used to assess anxiety-like behaviors. The animals' sociability was evaluated using the three-chamber social task. The NTG-induced photophobia was assessed using a light-dark box. RESULTS: We observed no change in NTG-induced thermal hyperalgesia following administration of SB-334867 (10, 20, and 40 nM). However, SB-334867 (20 and 40 nM) aggravated the NTG-induced anxiogenic responses in both the EPM and OF tasks. The NTG-induced social impairment was overpowered by SB-334867 at all doses. Time spent in the dark chamber of light-dark box was significantly increased in rats treated with SB-334867 (20 and 40 nM/rat). CONCLUSIONS: The findings suggest a role for Orx1R within the BLA in control comorbid affective complaints with migraine in rats.

The effects of neonatal maternal deprivation and chronic unpredictable stresses on migraine-like behaviors in adult rats.

BACKGROUND: Stress is known to cause migraine. This study investigates the effects of neonatal maternal deprivation (MD) and chronic unpredictable stress (CUS) on migraine in rats. METHODS: Seventy rats were randomly divided into ten groups (five groups of each sex, and seven rats/group). The groups included: untreated intact, nitroglycerin (NTG) only, NTG + MD, NTG + CUS (10 weeks after birth), and NTG + MD + CUS. For the induction of MD, pups were separated from their mothers from postnatal day 2 to day 14. The CUS was conducted by daily exposure to different stressors for 2 weeks. For the induction of migraine after stress, NTG (5 mg/kg/IP) was administered every second day for 9 days. Afterward, NTG-related symptoms, including climbing behavior, facial rubbing, body grooming, freezing behavior, and head-scratching, were recorded for 90 min. Statistical differences between the groups were analyzed by one-way and two-way ANOVA followed by the Newman-Keuls test. RESULTS: Migraine symptoms, including increased head-scratching, facial rubbing, and decreased climbing behavior, were more significant in females than in males. Head scratching and facial rubbing increased in stressed females, but not in males as compared to NTG-treated rats. Body grooming was significantly decreased in MD males compared to the NTG group. The effects of NTG in MD + CUS on the rats did not differ from those in the MD or CUS groups. CONCLUSIONS: MD and CUS had a sex-related aggravating effect on the development of migraine, while the combination of MD and CUS had no additive migraine-aggravating effect.

The involvement of orexin 1 and cannabinoid 1 receptors within the ventrolateral periaqueductal gray matter in the modulation of migraine-induced anxiety and social behavior deficits of rats.

Orexin 1 receptors (Orx1R) and cannabinoid 1 receptors (CB1R) are implicated in migraine pathophysiology. This study evaluated the potential involvement of Orx1R and CB1R within the ventrolateral periaqueductal gray matter (vlPAG) in the modulation of anxiety-like behavior and social interaction of migraineurs rats. A rat model of migraine induced by recurrent administration of nitroglycerin (NTG) (5 mg/kg/i.p.). The groups of rats (n = 6) were then subjected to intra-vlPAG microinjection of orexin-A (25, 50 pM), and Orx1R antagonist SB334867 (20, 40 nM) or AM 251 (2, 4 µg) as a CB1R antagonist. Behavioral responses were evaluated in elevated plus maze (EPM), open field (OF) and three-chambered social test apparatus. NTG produced a marked anxiety like behaviors, in both EPM and OF tasks. It did also decrease social performance. NTG-related anxiety and social conflicts were attenuated by orexin-A (25, 50 pM). However, NTG effects were exacerbated by SB334867 (40 nM) and AM251 (2, 4 µg). The orexin-A-mediated suppression of NTG-induced anxiety and social conflicts were prevented by either SB334867 (20 nM) or AM251 (2 µg). The findings suggest roles for Orx1R and CB1R signaling within vlPAG in the modulation of migraine-induced anxiety-like behavior and social dysfunction in rats.

The rostral ventromedial medulla orexin 1 receptors and extracellular signal-regulated kinase in hippocampus are involved in modulation of anxiety behavior induced by dental pulp nociception in adult male rats.

OBJECTIVES: To explore the role of rostral ventromedial medulla (RVM) orexin 1 receptors (OX1R) on orofacial nociception -induced anxiety and locomotion in rats. DESIGN: Forty two adult male Wistar rats (220-270 gr) were randomly divided into 7 groups (n = 6) as follows: untreated control, capsaicin, capsaicin vehicle-treated group (sham operation), capsaicin groups pretreated by intra-RVM administration orexin 1 receptor (OX1R) agonist (orexin A) or antagonist (SB-334867) and the capsaicin groups treated by drugs vehicles (DMSO or aCSF). Orofacial nociception was induced by intradental application of capsaicin (100 µg) into the incisors of rats. Anxiety level and locomotor activity were measured by the elevated plus maze (EPM) and open field (OF) tests, respectively. Hippocampal levels of phosphorylated extracellular signal regulated Kinase (p-ERK) was also assessed by western blotting. RESULTS: Intradental application of capsaicin significantly increased anxiety and decreased locomotion behaviors. Intra-RVM microinjection of orexin-A significantly prevented capsaicin-induced anxiety-like behavior and increased locomotor activity in the EPM and OF tests. These effects were inhibited by SB-334867. Furthermore, orexin-A significantly increased p-ERK levels in capsaicin-treated rats. This effect was inhibited by pretreatment of the rats with SB-334867. CONCLUSIONS: The results suggest that both OX1R signaling in the RVM and hippocampal p-ERK signaling are involved in orofacial nociception-induced anxiety as well as locomotor activity.

Physical exercise enhances vulnerability to migraine headache associated with CGRP up-expression in trigeminal nucleus caudalis of stressed rats.

OBJECTIVES: There is conflicting evidence on the effect of physical exercise on migraine development. Present study investigated the impact of treadmill exercise on migraine - associated symptoms and changes in calcitonin gene-related peptide (CGRP) expression in rats with and without maternal deprivation stress (MD). METHODS: Two days after birth, the male Wistar pups were randomly divided into four groups (n = 6) as follows: intact, exercise, MD, and MD plus exercise. The animals in the MD groups were separated from their dams 4 h per day for 2 weeks. At 8 weeks of age, the rats were exercised on a motor-driven treadmill for 4 weeks. Then, nitroglycerin (NTG) (5 mg/kg/IP) was used to induce migraine and pain-related symptoms were recorded for 90 min. NTG-related thermal hyperalgesia was measured by tail flick and hot plate methods. Finally, immunofluorescence staining of CGRP in trigeminal subnucleus caudalis (Vc) was performed. RESULTS: NTG - produced a significant headache symptoms and thermal hypersensitivity, which were aggravated following physical exercise in stressed or unstressed groups. Besides, NTG administration increased CGRP expression in the Vc of rats. Such effect was overpowered by treadmill running only in rats exposed to MD stress. CONCLUSION: These findings highlight the worsening effects of treadmill exercise for migraine in rats with and without MD stress. However, inflammatory response can further exacerbate in stressed rats.

Activation orexin 1 receptors in the ventrolateral periaqueductal gray matter attenuate nitroglycerin-induced migraine attacks and calcitonin gene related peptide up-regulation in trigeminal nucleus caudalis of rats.

This study aims to explore whether orexin 1 receptors (Orx1R) in the ventrolateral periaqueductal gray matter (vlPAG) play a role in the modulation of migraine headaches in adult male Wistar rats. To model chronic migraine-associated pain, nitroglycerin (NTG) (5 mg/kg/IP) was administered to test subjects every second day for 9 days. After the last NTG injection, rats were randomly separated into the following groups (n = 6): orexin-A (OrxA) groups that received intra-vlPAG OrxA (25, 50, and 100 pM), an Orx1R antagonist group, a SB-334867 (20 µM) group; and a SB-334867 (20 µM) + OrxA (100 pM) group. After 10 min, migraine-associated behavioral symptoms were recorded in all animals for up to 90 min. Light-dark chamber and hot plate tests were used for assessing light aversion and thermal hyperalgesia, respectively. Calcitonin gene-related peptide (CGRP)-positive cells were detected in the trigeminal nucleus caudalis (Vc) by immunofluorescence microscopy. NTG caused significant freezing behavior, which was prevented by all OrxA doses. Moreover, OrxA (100 pM) could obstruct NTG-induced increases in facial rubbing and decreases in climbing and body grooming. Furthermore, NTG-induced light aversion and thermal hyperalgesia were attenuated by OrxA at doses of 50 and 100 pM. The effects of OrxA were significantly blocked by SB-334867 (20 µM). Besides, OrxA (100 pM) decreased NTG-induced CGRP upregulation. The data revealed that the activation of Orx1Rs in the vlPAG is effective in relieving NTG-induced migraine symptoms mainly by the downregulation of CGRP in the Vc of rats.