Diss. (sammanfattning) Stockholm : Karol. inst., 2004. / Härtill 6 uppsatser.

Analgésiques opiacés et les antidépresseurs tricycliques (ATC) sont deux grandes classes d'agents thérapeutiques qui sont utilisés pour soulager les symptômes dus au nociception chronique. Mais ces agents chimio thérapeutiques présentent des effets secondaires comme la constipation, dépendance physique plus soulagement de la douleur insuffisante. D'où des complications aggravent la nécessité de concevoir une molécule qui agit sur nouvelle cible en vue de surmonter les effets secondaires causés par la classe dit ci-dessus de médicaments. Pendant ce temps, la distribution du peptide lié au gène de la calcitonine (CGRP), un neuropeptide de 37 acides aminés deux dans le système nerveux central et périphérique et son rôle dans la douleur viscérale a ouvert une nouvelle porte d'entrée pour le traitement de la douleur nociceptive viscérale. Ainsi, l'objectif principal du projet de fusionner propriété antagoniste de CGRP ainsi que la propriété antidépresseur dans une seule molécule, pour fournir un effet de synergie et de traiter les maladies chroniques, inflammatoires et négligées comme le syndrome du côlon irritable (IBS) et la maladie de Crohn. / Opiate analgesics and tricyclic antidepressants (TCAs) are two major classes of therapeutic agents which are used to alleviate symptoms due to chronic nociception. But these chemotherapeutic agents pose side effects like constipation, physical dependence along with insufficient pain relief. Hence these complications aggravate the necessity of designing a molecule which acts on new target in order to overcome the side effects caused by the above said class of drugs. Meanwhile, the distribution of Calcitonin Gene Related Peptide (CGRP), a 37 amino acid neuropeptide both in central and peripheral nervous system and its role in visceral pain has opened up a new gateway for treating visceral nociceptive pain. Thus, the main aim of the project was to merge CGRP antagonist property as well as Antidepressant property in a single molecule, to provide a synergistic effect and to treat Chronic, inflammatory and neglected diseases like Irritable bowel syndrome (IBS) and Crohn’s disease.

No description available.

Migraine patients often demonstrate cutaneous allodynia, defined as a hypersensitivity of the skin to touch or mechanical stimuli that is considered non-noxious under normal circumstances. The allodynia sometimes begins intracranially and spreads, via unknown mechanisms, to extracranial regions. The goal of the study was to develop and validate a model of cutaneous allodynia triggered by dural inflammation for pain associated with headaches, and to explore neuronal and glial mechanisms underlying generalized allodynia. Inflammatory mediators (IM) were applied to the dura of unanesthetized rats via previously implanted cannulas and sensory thresholds of the face and hindpaws were characterized. IM elicited robust and time-related facial and hindpaw allodynia which peaked after approximately three hours as well as FOS expression in the trigeminal nucleus caudalis (TNC), indicative of central sensitization. These effects were reminiscent of cutaneous allodynia seen in patients with migraine or other primary headache conditions, and were reversed by agents used clinically in the treatment of migraine including sumatriptan, naproxen, CGRP-antagonist, and morphine. Consistent with clinical observations, the allodynia was unaffected by an NK-1 antagonist. Having established facial and hindpaw allodynia as a useful animal surrogate of headache-associated allodynia, we next showed that blocking pain-facilitating processes from the rostral ventromedial medulla (RVM) interfered with its expression. Inactivation of the RVM with local anesthetic, destruction of putative pain-facilitation cells, and blockade of cholecystokinin receptors all prevented or significantly attenuated IM-induced allodynia. Electrophysiological studies confirmed activation of pain-facilitating "ON" cells and transient suppression of "OFF" cells in the RVM following IM. Additionally, microinjection of the RVM with a microglial inhibitor or sumatriptan also inhibited the expression of IM-induced cutaneous allodynia as well as microglial activation. Facial and hindpaw allodynia associated with dural stimulation is a useful surrogate of pain associated with primary headache including migraine and may be exploited mechanistically for the development of novel therapeutic strategies for headache pain. The data also demonstrate a requirement for activation of descending facilitation from the RVM, likely reliant on neuronal-glial interactions, for the expression of cranial and extracranial cutaneous allodynia. Consequently, the findings are consistent with a brainstem generator of allodynia associated with headache disorders.

Migraine is a highly prevalent headache disorder imposing a significant burden of disability on human health worldwide. The headache is believed to arise from activation of trigeminal pain pathways, with CNS regions also playing an integral role in attack initiation and progression. Recent genetic associations have been made, but there is a need to convert these into relevant experimental models to study underlying disease mechanisms. Herein, I detail functional analysis of two deleterious variants in the genes KCNK18 and SLC12A3, that segregate with migraine with aura in one large pedigree. Gene function has been studied in a range of cell models, from heterologous expression systems and primary neuronal cultures, to Induced Pluripotent Stem (iPS) cell-derived nociceptors. In this context, the protein products of KCNK18 and SLC12A3 have been shown to modulate parameters of neuronal excitability, including baseline membrane properties and firing patterns. Migraine attacks are not wholly attributable to perturbations in peripheral pathways. I have shown that these genes are also expressed within the CNS in a small number of discreet regions, suggesting a possible role in central processing. Utilizing recently defined genetic variants and physiological cell- based models, will provide a platform for mechanistic insights into migraine pathogenesis and allow for the development of drug screening assays for new migraine therapies.

Thèse médecine Paris, 1875, numéro 77.

Thèse médecine Paris, 1884, numéro 35.

Cortical Spreading Depression (CSD) is characterized by a wave of neuronal and glial depolarization followed by depression of bioelectrical activity that slowly propagates through the cortex of many species, including humans. CSD is associated with brain disorders such as stroke, head trauma and migraine. Many earlier studies have provided compelling evidence that CSD is the underlying mechanism of aura in migraine; however, whether CSD can elicit headache associated with migraine is not fully understood. Cutaneous allodynia is highly prevalent in the peri-orbital area and extracephalic sites of migraine patients, suggesting that sensitization of primary afferents and central trigeminovascular neurons in these patients could be initiated by the underlying mechanism of aura.Unlike previous reports on the interaction between CSD and the trigeminal system, in which nociceptive behavior could not be measured since they employed anesthetized animals, we designed a model in which freely moving rats could be monitored for both CSD events and behavior responses due to pinprick plus KCl injection to the occipital cortex. We show that significant tactile hypersensitivity of the periorbital region of the face and hindpaws develop in a time-dependent manner following CSD. Enhanced expression of Fos protein and increased mRNA levels of the inflammatory cytokines IL-1beta and IL-6 are found within the trigeminal nucleus caudalis (TNC) two hours following cortical injection. We further show that systemic administration of anti-migraine drugs such as sumatriptan, naproxen and CGRP(8-37) (a CGRP antagonist) attenuate the generalized allodynia that ensue following cortical stimulation by KCl. Microinjection of bupivacaine in the ipsilateral trigeminal ganglion or in the rostral ventromedial medulla (RVM) prior to cortical pinprick plus KCl injection reversibly diminishes tactile hypersensitivity, suggesting that RVM pain-facilitating cells become activated by a trigeminal-RVM pathway following CSD. In addition we demonstrate that cortical pinprick plus KCl injection induced CSD events in 24/28 (85%) rats, among which 66% and 87% developed allodynia in the face and hindpaw, respectively.These studies suggest a potential association between CSD and development of hypersensitivity in rats, indicating that this model can be used to investigate the role of CSD-evoked migraine-related pain and to explore novel therapeutic strategies.

Thesis (Ph.D.)--Ohio University, November, 2003. / Title from PDF t.p. Includes bibliographical references (leaves 133-149)

Background: Migraine trigger factors are precipitating factors that can contribute to an attack by increasing the probability of a migraine occurring. For some migraineurs, the headache phase is preceded by a transient disturbance in neurological function (an aura). An aura could be visual or sensory in nature. There are medications that can be used to treat a migraine attack when it occurs (acute medication) and medication that can be used to reduce frequency and severity of migraine attacks (prophylactic medication). Objectives: The primary aim of the study was to identify if there was a relationship between migraine trigger factors, auras and treatment. Methods: The study was conducted in 2014 in Port Elizabeth and consisted of two self-administered questionnaire-based surveys, one for pharmacists and one for migraine patients. Migraine patient questionnaires were distributed to migraine patients who frequented pharmacies, physiotherapy practices and health shops. A total of 18 pharmacist questionnaires and 173 migraine patient questionnaires were analysed. Results: Experiencing an aura before a migraine attack was reported by 43.9% of respondents and only “sometimes” by 22.5% of respondents. Visual auras were experienced by 92.0% of respondents who indicated that they suffered from migraine with aura and sensory auras were experienced by 71.5% of respondents, with 62.8% of respondents experiencing both visual and sensory auras. Trigger factors were experienced by 89.0% of respondents. There was no statistical relationship between aura and trigger factors, but there was a statistical relationship between trigger factors and visual aura at the 5% level (Chi-square = 7.966, d.f. = 1, p-value = 0.005). Cramér’s V showed a small practical significance at 0.218. About 80.0% of respondents used over-the-counter (OTC) medication and only 12.6% used migraine specific medication to abort a migraine attack. There was no statistical relationship between aura (visual or sensory) and abortive medication. There was a statistical relationship between abortive medication and the presence of trigger factors (Chi-square = 8.775, d.f. = 3, p-value = 0.032). Cramér’s V showed a small practical significance at 0.244. There was no statistical relationship in the presence of trigger factors between aura and abortive medication. Conclusion: Migraine is a complex disease which affects people of all ages. There appears to be a statistical relationship between visual auras and trigger factors and between abortive medication and trigger factors. There was, however, no statistical relationship between aura and abortive medication in the presence of trigger factors. Further studies need to be conducted to substantiate these findings.