Faculty Bibliography

Migraine abortives likely target both peripheral-dural and central trigeminovascular mechanisms in mediating their therapeutic effects. However, in preclinical assays, many migraine preventives have little success at inhibiting similar trigeminovascular-mediated peripheral changes within the dural microenvironment. In addition, their effects on central trigeminovascular neuronal responses are largely unknown. Using a validated preclinical model of acute dural-intracranial (migraine-like) head pain, using Sprague Dawley rats, we tested whether migraine preventives suppress ongoing firing of central trigeminocervical neurons, and evoked responses to cranial neurovascular activation. Flunarizine, sodium valproate, propranolol, and amitriptyline, all dose-dependently inhibited ongoing spontaneous firing of dural trigeminovascular neurons, and differentially affected neuronal responses to intracranial-dural and extracranial-cutaneous somatosensory stimulation. Lamotrigine, only effective in the treatment of migraine aura, did not affect responses. These data provide a mechanistic rationale for the clinical effects of migraine preventives in the treatment of migraine, via the modulation of dural-responsive central trigeminovascular neurons. Also, given their limited effect on peripheral dural vasdilatory responses, these data also suggest that migraine preventives specifically target central, rather than peripheral, components of trigeminal neurovascular mechanisms involved in migraine pathophysiology, to mediate their preventive action. Finally, these data further validate this preclinical model of central trigeminovascular activation to screen migraine preventives.

BACKGROUND: Cancer pain is a devastating condition. Pain in the orofacial region, may be present as the single symptom of cancer or as a symptom of cancer in its later stages. This manuscript revises in a comprehensive manner the content of the conference entitled "Orofacial Pain and Cancer" (Dolor Orofacial y Cancer) given at the VI Simposio International "Advances in Oral Cancer" on the 22 July, 2016 in San Sebastioan-Donostia._Material and Methods: We have reviewed (pubmed-medline) from the most relevant literature including reviews, systematic reviews and clinical cases, the significant and evidence-based mechanisms and mediators of cancer-associated facial pain, the diverse types of cancers that can be present in the craniofacial region locally or from distant sites that can refer to the orofacial region, cancer therapy that may induce pain in the orofacial region as well as discussed some of the new advancements in cancer pain therapy. _Results: There is still a lack of understanding of cancer pain pathophysiology since depends of the intrinsic heterogeneity, type and anatomic location that the cancer may present, making more challenging the creation of better therapeutic options. Orofacial pain can arise from regional or distant tumor effects or as a consequence of cancer therapy. _Conclusions: The clinician needs to be aware that the pain may present the characteristics of any other orofacial pain disorder so a careful differential diagnosis needs to be given. Cancer pain diagnosis is made by exclusion and only can be reached after a thorough medical history, and all the common etiologies have been carefully investigated and ruled out. The current management tools are not optimal but there is hope for new, safer and effective therapies coming in the next years.

Temporomandibular disorders (TMDs) are orofacial pains within the trigeminal distribution, which involve the masticatory musculature, the temporomandibular joint or both. Their pathophysiology remains unclear, as inflammatory mediators are thought to be involved, and clinically TMD presents pain and sometimes limitation of function, but often appears without gross indications of local inflammation, such as visible edema, redness and increase in temperature. Calcitonin gene-related peptide (CGRP) has been implicated in other pain disorders with trigeminal distribution, such as migraine, of which TMD shares a significant co-morbidity. CGRP causes activation and sensitization of trigeminal primary afferent neurons, independent of any inflammatory mechanisms, and thus may also be involved in TMD. Here we used a small molecule, selective CGRP receptor antagonist, MK-8825, to dissect the role of CGRP in inducing spontaneous nociceptive facial grooming behaviors, neuronal activation in the trigeminal nucleus, and systemic release of pro-inflammatory cytokines, in a mouse model of acute orofacial masseteric muscle pain that we have developed, as a surrogate of acute TMD. We show that CFA masseteric injection causes significant spontaneous orofacial pain behaviors, neuronal activation in the trigeminal nucleus, and release of interleukin-6 (IL-6). In mice pre-treated with MK-8825 there is a significant reduction in these spontaneous orofacial pain behaviors. Also, at 2 and 24h after CFA injection the level of Fos immunoreactivity in the trigeminal nucleus, used as a marker of neuronal activation, was much lower on both ipsilateral and contralateral sides after pre-treatment with MK-8825. There was no effect of MK-8825 on the release of IL-6. These data suggest that CGRP may be involved in TMD pathophysiology, but not via inflammatory mechanisms, at least in the acute stage. Furthermore, CGRP receptor antagonists may have therapeutic efficacy in the treatment of TMD, as they do with migraine.

Orofacial pain may be a symptom of diverse types of cancers as a result of local or distant tumor effects. The pain can be presented with the same characteristics as any other orofacial pain disorder, and this should be recognized by the clinician. Orofacial pain also can arise as a consequence of cancer therapy. In the present article, we review the mechanisms of cancer-associated facial pain, its clinical presentation, and cancer therapy associated with orofacial pain.

Migraine is a severe and debilitating disorder of the brain that involves a constellation of neurological symptoms alongside head pain. Its pathophysiology is only beginning to be understood, and is thought to involve activation and sensitization of trigeminovascular nociceptive pathways that innervate the cranial vasculature, and activation of brain stem nuclei. Much of our understanding of migraine pathophysiology stems from research conducted in animal models over the last 30 years, and the development of unique assays in animals that try to model specific aspects of migraine pathophysiology related to particular symptoms. This review will highlight some of the latest findings from these established animal models, as well as discuss the latest in the development of novel approaches in animals to study migraine.

Some of the most prevalent and debilitating pain conditions arise from the structures innervated by the trigeminal system (head, face, masticatory musculature, temporomandibular joint and associated structures). Orofacial pain (OFP) can arise from different regions and etiologies. Temporomandibular disorders (TMD) are the most prevalent orofacial pain conditions for which patients seek treatment. Temporomandibular disorders include a number of clinical problems that involve the masticatory musculature, the temporomandibular joint (TMJ) or both. Trigeminal neuropathic pain conditions can arise from injury secondary to dental procedures, infection, neoplasias, or disease or dysfunction of the peripheral and/or central nervous system. Neurovascular disorders, such as primary headaches, can present as chronic orofacial pain, such as in the case of facial migraine, where the pain is localized in the second and third division of the trigeminal nerve. Together, these disorders of the trigeminal system impact the quality of life of the sufferer dramatically. A multidisciplinary pain management approach should be considered for the optimal treatment of orofacial pain disorders including both non-pharmacological and pharmacological modalities.

Migraine is one of the most severe and debilitating brain disorders. Most scientists accept that it involves activation and sensitization of the trigeminovascular system, which includes the sensory peripheral projections to the pain-producing dura mater, and a central projection to the trigeminal nucleus caudalis and its cervical extension, the trigeminocervical complex (TCC). The development of the anti-migraine therapeutics, triptans-5-HT1B/1D receptor agonists, had originally targeted the craniovasculature to exert therapeutic effects, and this locus of action seemed to predict efficacy in the clinic. However, subsequent development of novel targets, using the same strategy failed to replicate this early success and as a consequence central mechanisms of action away from the dural vasculature were thought to be responsible for these therapeutic effects. Coupled to this, migraine has been hypothesized to involve a dysfunction of areas of the brainstem and diencephalon, which seem to mediate the activation, or perception of activation, of the trigeminovascular system as well as sensitization of neuronal pathways that drive trigeminovascular activation. Therefore, drug targets that act in the brain, specifically on the central component of the trigeminovascular system, the TCC, would seem to be ideally placed to modulate this nociceptive pathway and relieve migraine, but particularly the headache phase. This review will discuss how the TCC, rather than other more craniovascular sites, may be the anatomical target of some of the current and emerging therapies to relieve migraine symptoms, and why this should prove to be a fruitful area for drug development for the treatment of migraine.

BACKGROUND: Physiological studies have been determinant for the understanding of migraine pathophysiology and the screening of novel therapeutics. At present, there is no animal model that translates fully the clinical symptoms of migraine, and generally these studies are conducted on anesthetized animals. METHODOLOGY: Pain as well as non-painful symptoms such as photophobia, need to have a conscious individual to be experienced; therefore, the new development and adaptation of behavioral assays assessing pain and other non-painful symptomatology in conscious animals represents a great opportunity for headache research and it is exciting that more and more researchers are using behavioral paradigms. SUMMARY: This review will describe the different behavioral models for the study of headache that are performed in non-anesthetized conscious animals. The pearls and challenges for measuring hypersensitivity in rodents such as the common tests for measuring mechanical allodynia and thermal hyperalgesia have been the landmark for the development of assays that measure hypersensitivity in the craniofacial region. Here we describe the different behavioral assays that measure hypersensitivity in the craniofacial region as well as the established behavioral models of trigeminovascular nociception and non-nociceptive migrainous symptoms.