Pharmacological Management of Orofacial Pain.

Orofacial pain is a category of complex disorders, including musculoskeletal, neuropathic and neurovascular disorders, that greatly affect the quality of life of the patient. These disorders are within the fields of dentistry and medicine and management can be challenging, requiring a referral to an orofacial pain specialist, essential for adequate evaluation, diagnosis, and care. Management is specific to the diagnosis and a treatment plan is developed with diverse pharmacological and non-pharmacological modalities. The pharmacological management of orofacial pain encompasses a vast array of medication classes and approaches. This includes anti-inflammatory drugs, muscle relaxants, anticonvulsants, antidepressants, and anesthetics. In addition, as adjunct therapy, different injections can be integrated into the management plan depending on the diagnosis and needs. These include trigger point injections, temporomandibular joint (TMJ) injections, and neurotoxin injections with botulinum toxin and nerve blocks. Multidisciplinary management is key for optimal care. New and safer therapeutic targets exclusively for the management of orofacial pain disorders are needed to offer better care for this patient population.

Devices for Episodic Migraine: Past, Present, and Future.

PURPOSE OF REVIEW: Historically, therapies for migraine have generally involved pharmacological treatments using non-selective or selective analgesics and preventive treatments. However, for many patients these treatments are not effective, while others prefer to use non-pharmacological-based therapies. To fill this need, over the last 15 years, neuromodulatory devices have entered the market for migraine treatment. Here, we will review the most recent findings for the use of these devices in the treatment of migraine. RECENT FINDINGS: Non-invasive vagus nerve stimulation and spring-pulse transcranial magnetic stimulation are both cleared for the treatment of migraine, supported by preclinical studies that validate efficacy and mechanism of action, and complemented with clinical trial data. Other options also authorized for use include transcutaneous supraorbital nerve stimulation and remote electrical neuromodulation. Various options are available to treat migraine using authorized neuromodulatory devices. These data support their efficacy in the treatment of episodic migraine, although further studies are necessary to elucidate their mechanism of action and to provide rigor to clinical trial data.

Comparative effects of traditional Chinese and Western migraine medicines in an animal model of nociceptive trigeminovascular activation.

Background Migraine is a highly prevalent and disabling disorder of the brain with limited therapeutic options, particularly for preventive treatment. There is a need to identify novel targets and test their potential efficacy in relevant preclinical migraine models. Traditional Chinese medicines have been used for millennia and may offer avenues for exploration. Methods We evaluated two traditional Chinese medicines, gastrodin and ligustrazine, and compared them to two Western approaches with propranolol and levetiracetam, one effective and one ineffective, in an established in vivo rodent model of nociceptive durovascular trigeminal activation. Results Intravenous gastrodin (30 and 100 mg/kg) significantly inhibited nociceptive dural-evoked neuronal firing in the trigeminocervical complex. Ligustrazine (10 mg/kg) and propranolol (3 mg/kg) also significantly inhibited dural-evoked trigeminocervical complex responses, although the timing of responses of ligustrazine does not match its pharmacokinetic profile. Levetiracetam had no effects on trigeminovascular responses. Conclusion Our data suggest gastrodin has potential as an anti-migraine treatment, whereas ligustrazine seems less promising. Interestingly, in line with clinical trial data, propranolol was effective and levetiracetam not. Exploration of the mechanisms and modelling effects of Chinese traditional therapies offers novel route for drug discovery in migraine.

Neuroendocrine signaling modulates specific neural networks relevant to migraine.

Migraine is a disabling brain disorder involving abnormal trigeminovascular activation and sensitization. Fasting or skipping meals is considered a migraine trigger and altered fasting glucose and insulin levels have been observed in migraineurs. Therefore peptides involved in appetite and glucose regulation including insulin, glucagon and leptin could potentially influence migraine neurobiology. We aimed to determine the effect of insulin (10U·kg-1), glucagon (100µg·200µl-1) and leptin (0.3, 1 and 3mg·kg-1) signaling on trigeminovascular nociceptive processing at the level of the trigeminocervical-complex and hypothalamus. Male rats were anesthetized and prepared for craniovascular stimulation. In vivo electrophysiology was used to determine changes in trigeminocervical neuronal responses to dural electrical stimulation, and phosphorylated extracellular signal-regulated kinases 1 and 2 (pERK1/2) immunohistochemistry to determine trigeminocervical and hypothalamic neural activity; both in response to intravenous administration of insulin, glucagon, leptin or vehicle control in combination with blood glucose analysis. Blood glucose levels were significantly decreased by insulin (p<0.001) and leptin (p<0.01) whereas glucagon had the opposite effect (p<0.001). Dural-evoked neuronal firing in the trigeminocervical-complex was significantly inhibited by insulin (p<0.001), glucagon (p<0.05) and leptin (p<0.01). Trigeminocervical-complex pERK1/2 cell expression was significantly decreased by insulin and leptin (both p<0.001), and increased by glucagon (p<0.001), when compared to vehicle control. However, only leptin affected pERK1/2 expression in the hypothalamus, significantly decreasing pERK1/2 immunoreactive cell expression in the arcuate nucleus (p<0.05). These findings demonstrate that insulin, glucagon and leptin can alter the transmission of trigeminal nociceptive inputs. A potential neurobiological link between migraine and impaired metabolic homeostasis may occur through disturbed glucose regulation and a transient hypothalamic dysfunction.

Transcranial magnetic stimulation and potential cortical and trigeminothalamic mechanisms in migraine.

A single pulse of transcranial magnetic stimulation has been shown to be effective for the acute treatment of migraine with and without aura. Here we aimed to investigate the potential mechanisms of action of transcranial magnetic stimulation, using a transcortical approach, in preclinical migraine models. We tested the susceptibility of cortical spreading depression, the experimental correlate of migraine aura, and further evaluated the response of spontaneous and evoked trigeminovascular activity of second order trigemontothalamic and third order thalamocortical neurons in rats. Single pulse transcranial magnetic stimulation significantly inhibited both mechanical and chemically-induced cortical spreading depression when administered immediately post-induction in rats, but not when administered preinduction, and when controlled by a sham stimulation. Additionally transcranial magnetic stimulation significantly inhibited the spontaneous and evoked firing rate of third order thalamocortical projection neurons, but not second order neurons in the trigeminocervical complex, suggesting a potential modulatory effect that may underlie its utility in migraine. In gyrencephalic cat cortices, when administered post-cortical spreading depression, transcranial magnetic stimulation blocked the propagation of cortical spreading depression in two of eight animals. These results are the first to demonstrate that cortical spreading depression can be blocked in vivo using single pulse transcranial magnetic stimulation and further highlight a novel thalamocortical modulatory capacity that may explain the efficacy of magnetic stimulation in the treatment of migraine with and without aura.

A novel translational animal model of trigeminal autonomic cephalalgias.

OVERVIEW: Trigeminal autonomic cephalalgias (TACs) are highly disabling primary headache disorders that involve severe unilateral head pain coupled with significant lateralized cranial autonomic features. Our understanding of these disorders and the development of novel and more effective treatments has been limited by the lack of a suitable animal model to explore their pathophysiology and screen prospective treatments. DISCUSSION: This review details the development of a novel preclinical model that demonstrates activation of both the trigeminovascular system and parasympathetic projections, thought to be responsible for the severe head pain and autonomic symptoms. CONCLUSION: This model demonstrates a unique response to TAC specific treatments and highlights the importance of the cranial parasympathetic pathway to the pathophysiology of TACs and as a potential locus of action for treatments. The development of this model opens up opportunities to understand the pathophysiology of these disorders further, the likely involvement of the hypothalamus, as well as providing a preclinical model with which to screen novel compounds.

A translational in vivo model of trigeminal autonomic cephalalgias: therapeutic characterization.

Trigeminal autonomic cephalalgias are highly disabling primary headache disorders, characterized by severe unilateral head pain and associated ipsilateral cranial autonomic features. There is limited understanding of their pathophysiology and how and where treatments act to reduce symptoms; this is significantly hindered by a lack of animal models. We have developed the first animal model to explore trigeminal autonomic cephalalgias, using stimulation within the brainstem, at the level of the superior salivatory nucleus, to activate the trigeminal autonomic reflex arc. Using electrophysiological recording of neurons of the trigeminocervical complex and laser Doppler blood flow changes around the ipsilateral lacrimal duct, superior salivatory nucleus stimulation exhibited both neuronal trigeminovascular and cranial autonomic manifestations. These responses were specifically inhibited by the autonomic ganglion blocker hexamethonium bromide. These data demonstrate that brainstem activation may be the driver of both sensory and autonomic symptoms in these disorders, and part of this activation may be via the parasympathetic outflow to the cranial vasculature. Additionally, both sensory and autonomic manifestations were significantly inhibited by highly effective treatments for trigeminal autonomic cephalalgias, such as oxygen, indomethacin and triptans, and some part of their therapeutic action appears to be specifically on the parasympathetic outflow to the cranial vasculature. Treatments more used to migraine, such as naproxen and a calcitonin gene-related peptide receptor inhibitor, olcegepant, were less effective in this model. This is the first model to represent the phenotype of trigeminal autonomic cephalalgias and their response to therapies, and indicates the parasympathetic pathway may be uniquely involved in their pathophysiology and targeted to relieve symptoms.

Trigeminocervical complex responses after lesioning dopaminergic A11 nucleus are modified by dopamine and serotonin mechanisms.

Both serotonergic and dopaminergic receptor modulation can alter trigeminal nociceptive processing, and descending A11 dopaminergic projections can affect trigeminal nociceptive transmission. Here we aimed to test the interaction between dopamine D(2) and serotonin 5-HT(1B/1D) receptors and their individual and combined effects in order to better understand the relationship of the descending influences of these systems on nociceptive trigeminovascular afferents. Extracellular recordings were made in the rat trigeminocervical complex in response to electrical stimulation of the dura mater and mechanical noxious and innocuous stimulation of the ipsilateral ophthalmic dermatome. The A11 nucleus was lesioned, and following the resultant facilitation of neuronal firing, one of a selective 5-HT(1B/1D) receptor agonist (naratriptan), selective 5-HT(1B/1D) receptor antagonist (GR127935), a selective D(2)-like receptor agonist (quinpirole), and a selective D(1)-like receptor agonist (dihydrexidine), or a combination of the above, were administered. Both quinpirole and quinpirole with naratriptan inhibited firing in the trigeminocervical complex evoked by noxious stimuli, reducing it below prelesion baseline, while the response to innocuous stimuli was reduced back to baseline. Both naratriptan alone, and quinpirole combined with GR127935, inhibited firing in the trigeminocervical complex evoked by noxious stimuli, returning it to prelesion baseline, while the response to innocuous stimuli remained facilitated. Immunohistochemical staining demonstrated D(2)-receptor and 5-HT(1B/1D)-receptor colocalization in the trigeminocervical complex. The data suggest that the serotonergic and dopaminergic antinociceptive pathways act simultaneously on neurons in the trigeminocervical complex, and both amine systems need to be functioning for trigeminal sensitization to be reversed.

Dopamine: what's new in migraine?

PURPOSE OF REVIEW: Dopamine has been implicated in the pathophysiology of migraine, although its exact role remains unclear. Recent data offer some new perspective on a possible role for dopaminergic mechanisms in migraine. This review aims to summarize our current understanding of dopamine in migraine. RECENT FINDINGS: Direct application of dopamine and dopamine receptor agonists onto trigeminocervical complex neurons inhibits their activation after nociceptive stimulation. The dopaminergic A11 nucleus of the hypothalamus has been identified as the likely source of this dopamine. Recent evidence has shown that the genes for dopamine beta-hydroxylase and the dopamine transporter SLC6A3 may play a role in migraine pathophysiology, and dopamine has also been implicated in menstrual migraine. SUMMARY: Dopamine is currently considered to contribute to the pathophysiology of migraine, and dopamine receptor antagonists are prescribed in the treatment of acute migraine. Laboratory data suggest that the role of dopamine in migraine is more complex, perhaps due to the multiple receptors and levels of the brain involved in the disorder. These data suggest a reappraisal of dopaminergic therapeutic targets in migraine as our understanding of the role of this important biogenic amine is better characterized.

The role of histamine in dural vessel dilation.

The pain of migraine is often throbbing suggesting an important role for the cranial blood vessels and their innervation by the trigeminal nerve. It is proposed that clinically effective anti-migraine compounds, such as 5-HT(1B/1D) agonists, have actions that include inhibiting calcitonin gene-related peptide (CGRP) release from trigeminal nerves. Human studies suggest that histamine can induce migraine possibly by activating nitric oxide (NO) synthase to promote endogenous NO production. The present studies investigated the effect of histamine and its antagonists on the cranial blood vessels using intravital microscopy to assess directly the diameter of dural arteries in sodium pentobarbitone anaesthetised rats. Electrical stimulation of a closed cranial window produces, by local depolarisation of nerves, dural vessel dilation that is monitored continuously on-line using video-microscopy and a video dimension analyser. Histamine infusion caused immediate and reproducible dilation of meningeal blood vessels (103.5+/-6%; n=40) that could be blocked by H(1)- (mepyramine) and H(2) (famotidine)-receptor antagonists (P<0.05), as well as a nitric oxide synthase inhibitor (N(G)-nitro-L-arginine methylester; P<0.05). Neurogenic dural vasodilation was not inhibited by H(2)-receptor antagonists, but was significantly inhibited by a H(1)-receptor antagonist at the high dose of 10 mg/kg. The present studies demonstrate that histamine is likely to activate NO synthase to promote NO production. There is also evidence that H(1)-receptors may be present on trigeminal neurones as the H(1)-receptor antagonist inhibited neurogenic vasodilation, albeit at a large dose.