Efficacy and mechanism of the antinociceptive effects of cannabidiol on acute orofacial nociception induced by Complete Freund's Adjuvant in male Mus musculus mice.

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.

KCl-induced repetitive cortical spreading depression inhibiting trigeminal neuronal firing is mediated by 5-HT1B/1D and opioid receptors.

BACKGROUND: We aimed to examine the effects of repetitive cortical spreading depression on the responses of nociceptive trigeminal neurons with dural afferents and characterize the role of 5-HT1B/1D and opioid receptors. METHODS: Trigeminocervical complex neurons (n = 53) responsive to nociceptive activation of the dura mater were studied in rats using electrophysiological techniques. RESULTS: A sub-population (n = 32) showed an average inhibition of dural-evoked responses of 65 ± 14% from baseline with cortical spreading depression. This response was reversed by the selective 5-HT1B/1D receptor antagonist, GR127935 (3 mg/kg; n = 6, iv), and a non-selective opioid receptor antagonist, naloxone (1.5 mg/kg; n = 6, iv), five minutes after injection. To determine the role of the nucleus raphe magnus in the trigeminocervical complex inhibitory effect, microinjection of lidocaine (2%, n = 6) or muscimol (100 mM, n = 5) into the nucleus raphe magnus was performed. There was no effect on cortical spreading depression-induced inhibition of neuronal firing in trigeminocervical complex by either. CONCLUSION: The data demonstrate that repetitive cortical spreading depression inhibits a subpopulation of dural nociceptive trigeminocervical neurons, an effect mediated by serotonin and opioid receptors. This inhibition does not involve modulation of nucleus raphe magnus neurons.

Masticatory muscle activity and oral health-related quality of life in patients wearing clear thermoplastic versus wrap-around retainers : A randomized controlled trial.

AIM: To evaluate the surface electromyography (sEMG) activity of the superficial masseter and anterior temporalis muscles at rest, during maximum voluntary clenching (MVC), and mastication, over 6 months of wearing clear thermoplastic or wrap-around retainers. Furthermore, the patients' oral health-related quality of life was assessed using the Oral Impacts on Daily Performance (OIDP) index at 6 months. MATERIALS AND METHODS: Sixty patients aged 14-39 years (19 males/41 females) who received upper and lower retainers after finishing orthodontic treatment were recruited. The patients were randomly divided into a clear thermoplastic retainer group (n = 30) or a wrap-around retainer group (n = 30). The sEMG activity was recorded at retainer delivery (T0), after 3 months (T1), and after 6 months of wearing (T2). The OIDP index was evaluated at T2. RESULTS: None of the sEMG parameters for the masseter and temporalis muscles were different between the two groups at T0, T1, or T2. Over the period of 6 months, both masticatory muscles in both groups demonstrated increased sEMG activity during MVC and mastication; however, only the temporalis muscle demonstrated decreased normalized sEMG activity at rest (P < 0.05). The frequency and severity of the OIDP in the eating aspect at T2 was low and similar in both groups. CONCLUSIONS: sEMG activity of the two masticatory muscles tended to increase during MVC and mastication, while temporalis muscle activity tended to decrease at rest during the observation period, regardless of retainer type. Notably, these sEMG changes did not affect the patients' subjective masticatory function.

PAC1 receptor blockade reduces central nociceptive activity: new approach for primary headache?

Pituitary adenylate cyclase activating polypeptide-38 (PACAP38) may play an important role in primary headaches. Preclinical evidence suggests that PACAP38 modulates trigeminal nociceptive activity mainly through PAC1 receptors while clinical studies report that plasma concentrations of PACAP38 are elevated in spontaneous attacks of cluster headache and migraine and normalize after treatment with sumatriptan. Intravenous infusion of PACAP38 induces migraine-like attacks in migraineurs and cluster-like attacks in cluster headache patients. A rodent-specific PAC1 receptor antibody Ab181 was developed, and its effect on nociceptive neuronal activity in the trigeminocervical complex was investigated in vivo in an electrophysiological model relevant to primary headaches. Ab181 is potent and selective at the rat PAC1 receptor and provides near-maximum target coverage at 10 mg/kg for more than 48 hours. Without affecting spontaneous neuronal activity, Ab181 effectively inhibits stimulus-evoked activity in the trigeminocervical complex. Immunohistochemical analysis revealed its binding in the trigeminal ganglion and sphenopalatine ganglion but not within the central nervous system suggesting a peripheral site of action. The pharmacological approach using a specific PAC1 receptor antibody could provide a novel mechanism with a potential clinical efficacy in the treatment of primary headaches.

Altered activity in the nucleus raphe magnus underlies cortical hyperexcitability and facilitates trigeminal nociception in a rat model of medication overuse headache.

BACKGROUND: The pathogenesis of medication overuse headache (MOH) involves hyperexcitability of cortical and trigeminal neurons. Derangement of the brainstem modulating system, especially raphe nuclei may contribute to this hyperexcitability. The present study aimed to investigate the involvement of the nucleus raphe magnus (NRM) in the development of cortical and trigeminal hyperexcitability in a rat model of MOH. RESULTS: Chronic treatment with acetaminophen increased the frequency of cortical spreading depression (CSD) and the number of c-Fos-immunoreactive (Fos-IR) neurons in the trigeminal nucleus caudalis (TNC). In the control group, muscimol microinjected into the NRM increased significantly the frequency of CSD-evoked direct current shift and Fos-IR neurons in the TNC. This facilitating effect was not found in rats with chronic acetaminophen exposure. In a model of migraine induced by intravenous systemic infusion of nitroglycerin (NTG), rats with chronic exposure to acetaminophen exhibited significantly more frequent neuronal firing in the TNC and greater Fos-IR than those without the acetaminophen treatment. Muscimol microinjection increased neuronal firing in the TNC in control rats, but not in acetaminophen-treated rats. The number of Fos-IR cells in TNC was not changed significantly. CONCLUSION: Chronic exposure to acetaminophen alters the function of the NRM contributing to cortical hyperexcitability and facilitating trigeminal nociception.

Immediate effects of temporary bite-raising with light-cured orthodontic band cement on the electromyographic response of masticatory muscles.

To assess the immediate effects of temporary bite-raising using light-cured orthodontic band cement on the superficial masseter and anterior temporalis electromyography (EMG) activity in healthy adults. Surface EMG signals were recorded bilaterally from the superficial masseter and anterior temporalis muscles of 30 volunteers with a normal occlusion, before and after having temporary bite-raising. The bite-raising was done by adding light-cured orthodontic band cement (3x5x2 mm WxLxH) on the lingual cusps of both upper first molars. The measurements were recorded (i) at rest, (ii) while clenching in centric occluding position and (iii) while chewing on an artificial test food. The EMG activity at rest and during clenching, the maximum voltage, and the duration of the identified EMG signal burst while chewing the artificial test food before and after temporary bite-raising were statistically compared using the paired t-test or the Wilcoxon signed-rank test based on the normality of the variables. The significance level was set at 5%. After temporary bite-raising, we found no significant change in integral EMG activity at rest position for the superficial masseter (mean difference (MD)=7.5 µVs) and for the anterior temporalis muscle (MD=36.8 µVs); however, the integral EMG activity during clenching was significantly reduced for the superficial masseter (MD=201.2 µVs) and for the anterior temporalis muscle (MD=151.8 µVs). During mastication, the maximum voltage of the identified burst was significantly reduced on the preferred chewing side of the superficial masseter and anterior temporalis muscles (MD=127.9 and 47.7 µV, respectively), while no significant change was found for the duration of the identified burst (MD=-34.1 and 3.4 ms, respectively) after temporary bite-raising. The results point to an altered neuromuscular behavior during clenching and chewing immediately after temporary bite-raising with light-cured orthodontic band cement. This information is relevant for orthodontists to inform their patients what will happen to their masticatory muscle activity when this bite-raising method is used.

Targeted Orexin and Hypothalamic Neuropeptides for Migraine.

The hypothalamus is involved in the regulation of homeostatic mechanisms and migraine-related trigeminal nociception and as such has been hypothesized to play a central role in the migraine syndrome from the earliest stages of the attack. The hypothalamus hosts many key neuropeptide systems that have been postulated to play a role in this pathophysiology. Such neuropeptides include but are not exclusive too orexins, oxytocin, neuropeptide Y, and pituitary adenylate cyclase activating protein, which will be the focus of this review. Each of these peptides has its own unique physiological role and as such many preclinical studies have been conducted targeting these peptide systems with evidence supporting their role in migraine pathophysiology. Preclinical studies have also begun to explore potential therapeutic compounds targeting these systems with some success in all cases. Clinical efficacy of dual orexin receptor antagonists and intranasal oxytocin have been tested; however, both have yet to demonstrate clinical effect. Despite this, there were limitations in these cases and strong arguments can be made for the further development of intranasal oxytocin for migraine prophylaxis. Regarding neuropeptide Y, work has yet to begun in a clinical setting, and clinical trials for pituitary adenylate cyclase activating protein are just beginning to be established with much optimism. Regardless, it is becoming increasingly clear the prominent role that the hypothalamus and its peptide systems have in migraine pathophysiology. Much work is required to better understand this system and the early stages of the attack to develop more targeted and effective therapies aimed at reducing attack susceptibility with the potential to prevent the attack all together.

Immediate effects of temporary bite-raising with light-cured orthodontic band cement on the electromyographic response of masticatory muscles

Abstract Objective: To assess the immediate effects of temporary bite-raising using light-cured orthodontic band cement on the superficial masseter and anterior temporalis electromyography (EMG) activity in healthy adults. Materials and Methods: Surface EMG signals were recorded bilaterally from the superficial masseter and anterior temporalis muscles of 30 volunteers with a normal occlusion, before and after having temporary bite-raising. The bite-raising was done by adding light-cured orthodontic band cement (3x5x2 mm WxLxH) on the lingual cusps of both upper first molars. The measurements were recorded (i) at rest, (ii) while clenching in centric occluding position and (iii) while chewing on an artificial test food. The EMG activity at rest and during clenching, the maximum voltage, and the duration of the identified EMG signal burst while chewing the artificial test food before and after temporary bite-raising were statistically compared using the paired t-test or the Wilcoxon signed-rank test based on the normality of the variables. The significance level was set at 5%. Results: After temporary bite-raising, we found no significant change in integral EMG activity at rest position for the superficial masseter (mean difference (MD)=7.5 μVs) and for the anterior temporalis muscle (MD=36.8 μVs); however, the integral EMG activity during clenching was significantly reduced for the superficial masseter (MD=201.2 μVs) and for the anterior temporalis muscle (MD=151.8 μVs). During mastication, the maximum voltage of the identified burst was significantly reduced on the preferred chewing side of the superficial masseter and anterior temporalis muscles (MD=127.9 and 47.7 μV, respectively), while no significant change was found for the duration of the identified burst (MD=-34.1 and 3.4 ms, respectively) after temporary bite-raising. Conclusion: The results point to an altered neuromuscular behavior during clenching and chewing immediately after temporary bite-raising with light-cured orthodontic band cement. This information is relevant for orthodontists to inform their patients what will happen to their masticatory muscle activity when this bite-raising method is used.

Evidence for orexinergic mechanisms in migraine.

OBJECTIVE: To examine the effect of the orexinergic blockade with a dual orexin receptor antagonist (DORA) on experimental models of peripheral and central trigeminal as well as cortical activation relevant to migraine and migraine aura. METHODS: In this study we used a precursor of suvorexant, a dual orexin receptor antagonist #12 (DORA-12) in established experimental in vivo models of dural trigeminovascular nociception in rat. Neurogenic dural vasodilation and electrophysiological recordings of second order trigeminocervical neurons were used to study trigeminal nociceptive mechanisms directly. KCl-evoked cortical spreading depression was also used as a surrogate for migraine aura. RESULTS: Neurogenically-induced vasodilation of the middle meningeal artery, caused by nociceptive activation of peripheral afferent projections of the trigeminal nerve, was attenuated by intravenous DORA-12 (1 mgkg(-1)). Second-order trigeminocervical complex neuronal activity was significantly inhibited by intravenous DORA-12 (1 mgkg(-1)). DORA-12 significantly reduced susceptibility to KCl-evoked cortical spreading depression. CONCLUSION: The study provides the first direct evidence, that simultaneous antagonism on both orexin receptors is able to attenuate trigeminal nociceptive activity as well as to induce an elevation of the threshold for the induction of a cortical spreading depression (CSD). In the clinical context, these data imply that targeting the hypothalamic orexinergic system may offer an entirely novel mechanism for the preventive treatment of migraine with and without aura.

Animal models of chronic migraine.

Many animal models of migraine have been described. Some of them have been useful in the development of new therapies. All of them have their shortcomings. Animal models of chronic migraine have been relatively less frequently described. Whether a rigid distinction between episodic and chronic migraine is useful when their underlying pathophysiology is likely to be the same and that migraine frequency probably depends on complex polygenic influences remains to be determined. Any model of chronic migraine must reflect the chronicity of the disorder and be reliable and validated with pharmacological interventions. Future animal models of chronic migraine are likely to involve recurrent activation of the trigeminal nociceptive system. Valid models would provide a means for investigating pathophysiological mechanism of the transformation from episodic to chronic migraine and may also be used to test the efficacy of potential preventive medications.

New onset migraine with aura after treatment initiation with ivabradine.

BACKGROUND: Migraine with aura is a complex neurological disorder modeled in animals by cortical spreading depression. It is less usual to find complete animal models for the disease so any opportunity to test a human effect back at the bench is welcome. FINDINGS: We report the case of a 24 year old woman who developed new onset episodic migraine with visual aura shortly after treatment initiation with the If ion channel blocker ivabradine for frequency control in hypertrophic cardiomyopathy. We studied whether ivabradine could alter cortical spreading depression in a suitable animal model. Sixteen rats received either ivabradine or saline, and the number of depolarization shifts and blood flow changes induced by cortical spreading depression were measured in both groups. No significant differences between the ivabradine and saline group were detected. CONCLUSIONS: Ivabradine is an interesting substance since it is known to produce migraine-like phosphenes frequently and the patient we report developed de novo migraine with aura. However, we were unable to demonstrate that the drug influences the susceptibility of the brain to cortical spreading depression with acute administration. The combined data show the relationship of migraine aura to cortical spreading depression may have some nuances yet to be identified.

Olvanil acts on transient receptor potential vanilloid channel 1 and cannabinoid receptors to modulate neuronal transmission in the trigeminovascular system.

The transient receptor potential vanilloid channel 1 (TRPV1) is a nociceptive transducer located on nociceptive neurons. TRPV1 channels located on peripheral neurons mainly transduce the sense of heat and are also activated by low pH or capsaicin. The role of centrally located TRPV1 channels is not fully understood. Likewise their importance in pain syndromes of central origin, such as migraine, is not known. Experimental data suggest a relationship to migraine. However, experimental studies with TRPV1 receptor antagonists indicate that the receptor may not be a useful target for new acute migraine treatments. Any potential role for the receptor in the chronification of migraine has not been investigated. The present study aimed at analyzing the use of the TRPV1 channel as a target to desensitize trigeminal neurons and thereby inhibit neuronal activity in the trigeminocervical complex. The TRPV1 receptor agonist olvanil was used for desensitization because, as compared with capsaicin, it is non-noxious and lacks capsaicin's pungency and CGRP release potential. We further investigated a possible effect of olvanil on cannabinoid (CB(1)) receptors, as an interaction between both receptor systems has been described previously. The results show that olvanil dose-dependently inhibited spontaneous and stimulus-induced activity within the trigeminocervical complex, whereas it had no effect on CSD susceptibility. We further demonstrated that the inhibiting effect of olvanil is mediated by vanilloid and cannabinoid receptor systems, thereby using the synergistic effects this dual mechanism offers. Curiously, TRPV1 receptor agonism may have anti-nociceptive properties through central mechanisms that would be of considerable interest to elucidate.