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Aim: To characterize the role of orexin‐1 receptors (OX1Rs) in ventrolateral periaqueductal grey matter (vlPAG) on modulation of capsaicin‐induced pulpal nociception in rats. Methodology: Sixty‐six adult male Wistar rats (2 months old) weighing between 230 and 260 g were used. The animals were cannulated for microinjection of drugs into the vlPAG matter. Pulpalgia was induced by intradental application of capsaicin solution (100 μg) into the incisor teeth of the rats. Ten min prior to capsaicin application, orexin‐A (50, 100 and 150 pmol L−1 per rat) was administered. Orexin‐A (150 pmol L−1) was also co‐administrated with SB‐334867 (40 nmol L−1 per rat), an OX1Rs antagonist; or bicuculline (1 μg per rat), a GABAA receptors antagonist. Moreover, treatment effects on the release of pro‐nociceptive modulator substance P (SP) in vlPAG and trigeminal nucleus caudalis (Vc) of rats were explored using an immunofluorescence technique. One‐way analysis of variance was used for the statistical analysis. Results: Orexin‐A dose‐dependently decreased capsaicin‐induced nociceptive behaviour. However, SB‐334867 (40 nmol L−1 per rat) pretreatment (P < 0.05), but not bicuculline (1 μg per rat), attenuated the analgesic effect of orexin‐A (150 pmol L−1). The level of SP was significantly increased in Vc and decreased in vlPAG of capsaicin‐treated rats (P < 0.05). Capsaicin‐induced changes in SP levels, however, were prohibited by orexin‐A treatment (150 pmol L−1) (P < 0.05). Conclusions: Orexin‐A administration into the vlPAG was associated with an inhibitory effect on capsaicin‐induced pulpal nociception and bidirectional effects on the induction of SP in vlPAG and Vc of rats. Central activation of OX1Rs is a potential therapeutic tool for pulpalgia. [ABSTRACT FROM AUTHOR]

Aim: To assess the effects of central administration of α‐pinene alone and in combination with either bicuculline or naloxone, as GABAA and μ‐opioid receptor antagonists, respectively, on capsaicin‐induced dental pulp stimulation in rats. Methodology: Forty‐eight adult male Wistar rats aged 2 months (230–270 g) were cannulated via their lateral ventricles for the central administration of the drugs. α‐Pinene was injected at 0.1, 0.2 and 0.4 μmol L−1. Then, dental pulp stimulation was induced by intradental application of capsaicin solution (100 μg), and nociceptive scores were recorded for up to 40 min. For investigation of the anti‐inflammatory effects of α‐pinene, expression of COX‐2 in the subnucleolus caudalis (Vc) of rats was determined using immunofluorescence staining. Nonparametric repeated measure Friedman and Kruskal–Wallis tests as well as parametric one‐way analysis of variance were used for the statistical analysis. Results: α‐Pinene at 0.2 and 0.4 μmol L−1 was able to decrease capsaicin‐induced nociception. Moreover, there was a significant increase in the expression of COX‐2‐positive cells in the Vc of capsaicin‐treated rats (P < 0.01). This effect was prohibited by α‐pinene (0.4 μmol L−1). Co‐administration of bicuculline (1 μg per rat) or naloxone (6 μg per rat) with α‐pinene (0.4 μmol L−1), however, prevented the inhibitory effects of α‐pinene on both capsaicin‐induced pulp nociception and COX‐2 over‐expression. Conclusions: Pinene exhibited significant curable effects on capsaicin‐induced pulpal nociception and inflammation mainly via pharmacological interfacing with GABAA and μ‐opioid receptors. [ABSTRACT FROM AUTHOR]

Background: The mode of delivery might prompt a long-lasting alteration in physiological and behavioral responsiveness in offspring., Objective: This study was intended to evaluate if the mode of delivery could alter sensitivity to thermal and chemical stimuli in female rats., Materials and Methods: 56 adult female Wistar rats (200-220 gr) that were born by vaginal or cesarean section (C-section) were used (n = 28/each). Inflammatory pain was induced by subcutaneous injection of formalin into the hind paw. The thermal nociceptive threshold was determined by tail-flick and hot plate tests. Besides, the Western blot test was used to evaluate the spinal cord levels of c-Fos and c-Jun proteins., Results: Formalin-induced inflammation was significantly decreased in C-section group as compared to vaginally born rats (p < 0.001). The baseline nociceptive threshed and morphine-induced analgesia were significantly increased in C-section groups in comparison to vaginally born rats. In addition, the levels of c-Fos and c-Jun proteins were significantly decreased in the spinal cord of C-section rats as compared to vaginally born animals (p < 0.01). Morphine treatment could decrease the expression of c-Fos and c-Jun in the C-section group (p < 0.05)., Conclusion: Overall, C-section rats showed lower spinal nociceptive processing and neuronal activity later in life, compared to the vaginal born rats., Competing Interests: The authors declare that there is no conflict of interest., (Copyright © 2024 Nikkhouy et al.)

Objectives: Active plant ingredients have been successfully used in modern medicine to control appetite and energy hemostasis. This study was designed to evaluate the efficacy of the phytohormone methyl jasmonate (MJ) on food-related behaviors in rats., Materials and Methods: Adult male Wistar rats were randomly divided into different groups (7 rats) and infused intracerebroventricularly ( i.c.v. ) with MJ vehicle (DMSO) or MJ (2.5, 5 and 10 μg/rat). Then, the individual rats were placed in an automated open field-like apparatus to assess a 12-h food-related activity in light and dark times. After behavioral tests, immunofluorescence staining of the orexin 1 receptor (Orx1R) was studied in the hypothalamus of rats., Results: MJ (2.5, 5, and 10 μg/rat) administration significantly decreased food intake in the light and dark phases compared with the control group. Moreover, all the MJ-treated groups exhibited a decrease in visits to food containers at the light and dark times ( p < 0.001). In addition, rats infused with MJ at 5 μg and 10 μg spent less time in the ports of food containers in the light and dark phases in comparison with control rats. Time in zone-related to food and locomotor activity was significantly decreased in the MJ (5 μg) groups during the light time and in all MJ-injected groups in the dark time. Moreover, hypothalamic expression of Orx1R in rats treated with MJ (5 μg) was significantly lower as compared to the control group., Conclusion: Overall, the results indicated the potential of MJ to modulate feeding-related behavior and Orx1R expression in the hypothalamus of rats., Competing Interests: Conflict of Interest: No conflict of interest was declared by the authors., (©2023 The Author. Published by Galenos Publishing House on behalf of Turkish Pharmacists’ Association.)

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., (© 2023 John Wiley & Sons Ltd.)

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.)

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 GABA A receptors., Competing Interests: There are no conflicts of interest., (Copyright: © 2022 Advanced Biomedical Research.)

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., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

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., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

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.

Objectives: This study explored the possible role of orexin one receptors (Orx1R) in the basolateral amygdala (BLA) on the modulation of nitroglycerin (NTG)-induced migraine-like symptoms. In addition, pain-induced subsequent alteration in learning and memory competence was evaluated in the adult male Wistar rats., Methods: The rats were given NTG (5 mg/kg, i.p.) every two days (for nine-day) to induce a migraine-like state. The migraine animals were treated with intra-BLA infusion of an Orx1R antagonist SB 334,867 (10, 20, and 40 nM/rat) or its vehicle DMSO. The NTG-induced migraine symptoms were recorded for 90 min. Spatial and passive avoidance performances were assessed by Morris water maze (MWM) and shuttle box tasks, respectively., Results: In comparison with control, NTG produced significant migraine-like symptoms characterized by a decrease in cage climbing and an increase in head-scratching, freezing, and facial grooming behavior. Intra-BLA infusion of SB 334,867 (40 nM/rat) significantly decreased cage climbing and increased facial grooming responses in NTG-treated rats. Moreover, all administrated doses of SB 334,867 increased NTG-evoked head-scratching and freezing behavior. Besides, NTG impaired learning and memory performances in both tests, which were exaggerated by post-injection of SB 334,867 (40 nM/rat)., Conclusions: Overall, the data provided an emerging role for the orexin system within BLA in the modulation of cognitive decline comorbid with migraine in 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., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective: This study intended to evaluate if central administration of abscisic acid (ABA) alone or in combination with GW9662, a peroxisome proliferator-activated receptor γ (PPAR-γ) antagonist, could modulate learning and memory as well as hippocampal synaptic plasticity in a rat model of streptozotocin (STZ)-induced diabetes., Materials and Methods: Intraperitoneal injection of STZ (65 mg/kg) was used to induce diabetes. Diabetic rats were than treated with intracerebroventricular (i.c.v.) administration of ABA (10, 15 and 20 µg/rat), GW9662 (3 µg/rat) or GW9662 (3 µg/rat) plus ABA (20 µg/rat). Animals' spatial and passive avoidance learning and memory performances were assessed by Morris water maze (MWM) and shuttle box tasks, respectively. Further, in vivo electrophysiological field recordings were assessed in the CA1 region., Results: STZ diabetic rats showed diminished learning and memory in both MWM and shuttle box tasks. The STZ-induced memory deficits were attenuated by central infusion of ABA (10 and 20 µg/rat). Besides, STZ injection impaired long-term potentiation induction in CA1 neurons that was attenuated by ABA at 20 μg/rat. Central administration of GW9662 (3 µg/rat) alone did not modify STZ-induced spatial and passive avoidance learning and memory performances of rats. Further, GW9662 prevented ABA capacity to restore learning and memory in behavioral and electrophysiology trials., Conclusion: Altogether, ABA ameliorates cognitive deficits in rats via activation of PPAR-γ receptor in diabetic 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., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

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.

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.

Objectives: Natural products have a potential role on food intake in mammals. It has been reported that phytohormone abscisic acid (ABA) has a regulatory role on metabolic processes. Here, the effects of ABA on feeding behavior and brain oxidative stress were investigated in male Wistar rats. Methods: ABA was injected intracerebroventricularly. Experimental groups were included ( n = 9): control (received no injection), ABA vehicle (received normal saline), and ABA-treated groups were injected with different doses of ABA (2.5, 5, and 10 μg/rat for 7 days). Daily cumulative daytime and nighttime food consumption, meal frequency, meal duration, and alteration in body weight were recorded. At the end of behavioral experiment, catalase and peroxidase activity and malondialdehyde (MDA) and hydrogen peroxide (H 2 O 2 ) levels were assayed. Results: The results showed that ABA (5 and 10 μg) increased the meal frequency. Moreover, ABA could decrease body weight and MDA and H 2 O 2 levels and increased the catalase and peroxidase activities in diencephalon. It also decreased the MDA concentration in the brain stem. Discussion: Taken together, ABA has an important effect on feeding behavior and body weight in rats likely via increasing antioxidant capacity. However, further studies are still required to determine the underlying mechanisms of ABA on the feeding behavior.

Different types of trigeminal pains are frequently associated with psychophysiological concerns. Orexin-A and orexin 1 receptor (OX1R) are involved in modulation of both trigeminal pain and anxiety responses. Ventrolateral periaqueductal gray matter (vlPAG), a controlling site for nociception and emotion, receives orexinergic inputs. Here, the role of vlPAG OX1Rs and their interaction with cannabinoid 1 (CB1) receptor was evaluated in anxiety-like behavior following capsaicin-induced dental pulp pain. Rats were cannulated in the vlPAG and orexin-A was injected at the doses of 0.17, 0.35 and 0.51 μg/rat prior to the induction of pain. The elevated plus maze (EPM) and open field (OF) tests were used for assessing the anxiety responses. In addition, the induction of c-fos, in the vlPAG, was investigated using immunofluorescence microscopy. Capsaicin-treated rats displayed significantly higher anxiogenic behavior on EPM and OF tests. Pretreatment with orexin-A (0.51 μg/rat) attenuated capsaicin-mediated nociception, while exaggerated anxiogenic responses (p < 0.05). In addition, orexin-A effects were diminished by the administration of OX1R (SB-334867, 12 μg/rat) and cannabinoid 1 (AM251, 4 μg/rat) receptor antagonists. Intradental capsaicin induced a significant increase in c-fos expression in the vlPAG that was exaggerated by orexin-A (0.51 μg/rat). Blockage of OX1R and CB1 receptors attenuated the effect of orexin-A on c-fos expression in capsaicin-treated rats. In conclusion, the data suggest that manipulation of OX1R and CB1 receptors in the vlPAG alters capsaicin-evoked anxiety like behaviors and c-fos induction in rats., (Copyright © 2018. Published by Elsevier Ltd.)

Objective: The neuropeptide orexin-A and its receptors are widely distributed in both hippocampal circuitry and pain transmission pathways. Involvement of the CA1 orexin 1 receptor (OX1R) on the modulation of orofacial pain and pain-induced changes in hippocampal expression of cyclooxygenase-2 (COX-2) and brain-derived neurotrophic factor (BDNF) was investigated., Methods: Orofacial pain was induced by an intra-lip injection of capsaicin (100 μg). Reverse transcription polymerase chain reaction and immunoblot analysis were used to indicate changes in hippocampal BDNF and COX-2 expression, respectively., Results: Capsaicin induces a significant pain response, which is not affected by either orexin-A or SB-334867-A, an OX1R antagonist. However, an increased expression of COX-2 and decreased expression of BDNF was observed in the hippocampus of animals that received capsaicin or SB-334867-A (80 nM) plus capsaicin. Meanwhile, orexin-A (40 pM) attenuated the effects of capsaicin on the expression of COX-2 and BDNF., Conclusions: CA1 OX1R activation moderates capsaicin-induced neuronal inflammation and neurotrophic deficiency.

Background: The trigeminal nucleus caudalis (Vc) is a primary central site for trigeminal transmitting. Noxious stimulation of the trigeminal nociceptors alters the central synaptic releases and neural expression of some inflammatory and trophic agents. Orexin-A and the orexin 1 receptor (OX1R) are expressed in pain pathways including trigeminal pain transmission. However, the the mechanism(s) underling orexin-A effects on trigeminal pain modulation have not been fully clarified., Methods: Trigeminal pain was induced by subcutaneous injection of capsaicin in the upper lip in rats. The effect of trigeminal pain on cyclooxygenase-2 (COX-2) and brain-derived neurotrophic factor (BDNF) expression in the Vc of animals was determined by immunofluorescence. Subsequently, OX1R agonist (orexin-A) and antagonist (SB-334867-A) was administrated in the Vc to investigate the possible roles of the Vc OX1R on changes in COX-2 and BDNF levels following pain induction., Results: The data indicated an increase in COX-2 and decrease in BDNF immuno-reactivity in the Vc of capsaicin, and capsaicin- pretreated with SB-334867-A (80 nM), groups of rat. However, the effect of capsaicin on COX-2 and BDNF expressions was reversed by a Vc microinjection of orexin-A (100 pM)., Conclusions: Overall, the present data reveals that orexin-A can attenuate capsaicin-induced trigeminal pain through the modulation of pain effects on COX-2 and BDNF expressions in the Vc of rats., Competing Interests: CONFLICTS OF INTEREST: The authors declared that they have no conflict to interest.

Objective: Chronic stress can alter nociceptive sensitivity. However, the effect of stress exposure on dental nociception has been less addressed. Therefore, the present study investigated the effects of chronic exposures to some social and psychological stresses on pulpal nociceptive responses., Design: The stress groups were constructed as follows: forced swimming (n=6), restraint (n=6), and mild (n=10) and severe (n=15) crowding stresses. Rats were subjected to stress for 1h per day for a week. At the end of the stress session, pulp irritation was induced by intradental application of capsaicin (100μg). There were another capsaicin or capsaicin plus stress training groups that received articaine 5min before the administration of capsaicin. Nociceptive responses were recorded for 40min. The time (ins) of continuous shaking of the lower jaw and excessive grooming and rubbing of the mouth near the procedure site was measured as nociceptive behaviors. Data was analyzed using one-way analysis of variance (ANOVA) followed by post hoc Tukey's test., Results: Significant nociceptive responses were evoked by the administration of capsaicin. Exposures to forced swimming (p<0.01), restraint (p<0.001), and both mild and severe crowding stresses (p<0.05) exaggerated capsaicin-induced nociceptive reaction. There was, however, no significant difference in nociceptive reaction time between the different stress groups. Articaine buccal infiltration attenuated nociceptive time in capsaicin and capsaicin plus stress training groups (p<0.001)., Conclusions: The current data support the association between chronic stress exposures and nociceptive behavior following intradental capsaicin administration., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: Pulpal pain is one of the most common and severe orofacial pain conditions with considerable adverse effects on physiological processes including learning and memory. Regular exercise is known to be effective on cognitive function as well as pain processing in the central nervous system. Here, the possible effects of regular exercise on pulpal pain response as well as pain-induced changes in learning and memory efficiency in rats were investigated., Methods: Twenty-four male Wistar rats were randomly assigned to the control, capsaicin, exercise, and exercise plus capsaicin groups. Rats in exercise groups were forced to run on a treadmill with a moderate exercise protocol for 4 weeks. Capsaicin was used to induce dental pulp pain. Passive avoidance learning and memory performance was assessed by using a shuttle box apparatus., Results: According to the results, regular exercise could decrease the time course of capsaicin-induced pulpal pain ( P < 0.001). Moreover, in capsaicin-treated rats, passive avoidance acquisition was impaired as compared to the control ( P < 0.05) and exercise ( P < 0.001) groups. Additionally, regular exercise before capsaicin injection could attenuate capsaicin-induced memory impairments ( P < 0.05)., Conclusions: Taken together, the present data showed that regular exercise has inhibitory effects on capsaicin-induced pulpal pain as well as pain-induced cognitive dysfunction in rats.

Introduction: Cognitive impairment is commonly associated with pain. The modulatory role of orexin 1 receptor (OX1R) in pain pathways as well as learning and memory processes is reported in several studies. The current study was designed to investigate the possible role of CA1-hippocampal OX1R on spatial learning and memory of rats following capsaicin-induced orofacial pain., Methods: Orofacial pain was induced by subcutaneous intra lip injection of capsaicin (100 μg). CA1 administration of orexin A and its selective antagonist (SB-334867-A) were performed 20 minutes prior to capsaicin injection. Learning and spatial memory performances were assessed by Morris Water Maze (MWM) task., Results: Capsaicin treated rats showed impairment in spatial learning and memory. In addition, pretreatment with orexin A (20 and 40 nM/rat) significantly attenuated learning and memory impairment in capsaicin-treated rats. Conversely, blockage of OX1R via SB-334867-A (40 and 80 nM/rat) significantly exaggerated learning and memory loss in capsaicin-treated rats., Conclusion: The obtained results indicated that CA1 OX1R may be involved in modulation of capsaicin -induced spatial learning and memory impairment., Competing Interests: Conflict of Interest The authors declared no conflicts of interest.

It is widely accepted that the spinal trigeminal nuclear complex, especially the subnucleus caudalis (Vc), receives input from orofacial structures. The neuropeptides orexin-A and -B are expressed in multiple neuronal systems. Orexin signaling has been implicated in pain-modulating system as well as learning and memory processes. Orexin 1 receptor (OX1R) has been reported in trigeminal nucleus caudalis. However, its roles in trigeminal pain modulation have not been elucidated so far. This study was designed to investigate the role of Vc OX1R in the modulation of orofacial pain as well as pain-induced learning and memory deficits. Orofacial pain was induced by subcutaneous injection of capsaicin in the right upper lip of the rats. OX1R agonist (orexin-A) and antagonist (SB-334867-A) were microinjected into Vc prior capsaicin administration. After recording nociceptive times, learning and memory was investigated using Morris water maze (MWM) test. The results indicated that, orexin-A (150 pM/rat) significantly reduced the nociceptive times, while SB334867-A (80 nM/rat) exaggerated nociceptive behavior in response to capsaicin injection. In MWM test, capsaicin-treated rats showed a significant learning and memory impairment. Moreover, SB-334867-A (80 nM/rat) significantly exaggerated learning and memory impairment in capsaicin-treated rats. However, administration of orexin-A (100 pM/rat) prevented learning and memory deficits. Taken together, these results indicate that Vc OX1R was at least in part involved in orofacial pain transmission and orexin-A has also a beneficial inhibitory effect on orofacial pain-induced deficits in abilities of spatial learning and memory., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Orexin 1 receptor signaling plays a significant role in pain as well as learning and memory processes. This study was conducted to assess the changes in orexin 1 receptor expression levels in hippocampus following learning and memory impairment induced by tooth inflammatory pulpal pain. Adult male Wistar rats received intradental injection of 100 µg capsaicin to induce pulpal pain. After recording the pain scores, spatial learning and memory were assessed using Morris Water Maze test. The hippocampal levels of orexin 1 receptor mRNA and protein were determined by semiquantitative reverse transcriptase polymerase chain reaction (RT-PCR) and immunoblotting respectively. The data showed that capsaicin-induced tooth inflammatory pulpal pain was correlated with learning and memory impairment. Intra-hippocampal injection of orexin A inhibited pain-induced learning and memory impairment. However, orexin 1 receptor antagonist, SB-334867, had no effect on learning and memory impairment. Moreover, capsaicin-induced pain significantly decreased hippocampal orexin 1 receptor mRNA and protein levels. Meanwhile, reversed changes took place in the ibuprofen-pretreated group (p < 0.05). It seems that decrease in orexin 1 receptor density and signaling could be involved in tooth pain-induced learning and memory impairment., (Copyright © 2015 Elsevier Ltd. All rights reserved.)