RESUMEN
We attempted to gather information on the pathogenesis of medication-overuse headache, as well as on the neurochemical mechanisms through which symptomatic medication overuse concurs to headache chronification. Transcriptional profiles were therefore evaluated as an index of the homeostasis of the trigeminovascular system in the trigeminal ganglion of female rats exposed for 1 month to daily oral doses of eletriptan or indomethacin. We report that both drug treatments change trigeminal ganglion gene expression to a similar extend. Of note, qualitative transcriptomic analysis shows that eletriptan and indomethacin prompt nearly identical, increased expression of genes coding for proteins involved in migraine pathogenesis and central pain sensitization such as neuropeptides, their cognate receptors, prostanoid, and nitric oxide-synthesizing enzymes, as well as TRP channels. These genes, however, were not affected in thoracic dorsal root ganglia. Of note, lowering of orofacial nociceptive thresholds, as well as forepaw hyperalgesia occurred in both indomethacin- and eletriptan-treated rats. Our study reveals that chronic rat exposure to 2 acute headache medications with completely different mechanisms of action prompts pain sensitization with highly similar induction of pronociceptive genes selectively within the trigeminal ganglion. Data further our understanding of medication-overuse headache pathogenesis and provide hints for specific mechanism-based treatment options.
Asunto(s)
Péptido Relacionado con Gen de Calcitonina/metabolismo , Perfilación de la Expresión Génica , Cefaleas Secundarias/patología , Cefaleas Secundarias/fisiopatología , Umbral del Dolor/fisiología , Ganglio del Trigémino/metabolismo , Animales , Antiinflamatorios no Esteroideos/toxicidad , Modelos Animales de Enfermedad , Femenino , Expresión Génica/efectos de los fármacos , Cefaleas Secundarias/inducido químicamente , Hiperalgesia/radioterapia , Indometacina/toxicidad , Análisis de Secuencia por Matrices de Oligonucleótidos , Umbral del Dolor/efectos de los fármacos , Pirrolidinas/toxicidad , Ratas , Ratas Wistar , Agonistas de Receptores de Serotonina/toxicidad , Factores de Tiempo , Triptaminas/toxicidadRESUMEN
NAD biosynthesis is emerging as a key regulator of immune cell functions. Accordingly, inhibitors of the NAD-synthesizing enzyme nicotinamide phosphoribosyltransferase (NAMPT) have anti-inflammatory effects, counteract hematological malignancies and are being tested in clinical trials. Still, their effect on different cell types still waits to be fully investigated. Here we show that the NAMPT inhibitor FK866 induces NAD depletion in various mouse organs but selectively causes dramatic atrophy of the spleen red pulp. Accordingly, in cultured mouse lymphocytes exposed to FK866, NAD contents drop to 50% of basal values within 2 days, a condition sufficient to prompt complete cell death. Cultures of human lymphocytes are more resistant to FK866 and sustain a 50% NAD reduction for 5 days before dying. Death of both cell types can be prevented by different NAD precursors, indicating critical NAD homeostasis in lymphocytes. Indeed, inhibition of the NAD-consuming enzyme poly(ADP-ribose) polimerase-1 suffices to prevent FK866-induced NAD depletion and death of both lymphocyte types. Poly(ADP-ribose) polymerase-1-null lymphocytes also undergo lower NAD depletion and reduced cell death when exposed to the drug. At variance with other cell types, neither apoptosis nor autophagy are exclusively responsible for lymphocyte death by FK866, consistent with a general impairment of lymphocyte homeostasis following NAD depletion. Data demonstrate a unique sensitivity of resting lymphocytes to NAD-depleting agents, providing new hints of relevance to lymphocyte biology and therapeutic interventions with NAMPT inhibitors.