RESUMEN
During a migraine attack capsaicin-sensitive trigeminal sensory nerves release calcitonin gene-related peptide (CGRP), producing cranial vasodilatation and central nociception; hence, trigeminal inhibition may prevent this vasodilatation and abort migraine headache. This study investigated the role of spinal α2-adrenoceptors and their subtypes (i.e. α(2A), α(2B) and/or α(2C)-adrenoceptors) in the inhibition of the canine external carotid vasodilator responses to capsaicin. Anaesthetized vagosympathectomized dogs were prepared to measure arterial blood pressure, heart rate and external carotid conductance. The thyroid artery was cannulated for one-min intracarotid infusions of capsaicin, α-CGRP and acetylcholine. A cannula was inserted intrathecally for spinal (C1-C3) administration of 2-amino-6-ethyl-4,5,7,8-tetrahydro-6H-oxazolo-[5,4-d]-azepin-dihydrochloride (B-HT 933; a selective α2-adrenoceptor agonist) and/or the α2-adrenoceptor antagonists rauwolscine (α(2A/2B/2C)), 2-[(4,5-dihydro-1H-imidazol-2-yl)methyl]-2,3-dihydro-1-methyl-1H-isoindole maleate (BRL44408; α(2A)), imiloxan (α(2B)) or acridin-9-yl-[4-(4-methylpiperazin-1-yl)-phenyl]amine (JP-1302; α(2C)). Infusions of capsaicin, α-CGRP and acetylcholine dose-dependently increased the external carotid conductance. Intrathecal B-HT 933 (1000 and 3100 µg) inhibited the vasodilator responses to capsaicin, but not those to α-CGRP or acetylcholine. This inhibition, abolished by rauwolscine (310 µg), was: (i) unaffected by 3,100 µg imiloxan; (ii) partially blocked by 310 µg of BRL44408 or 100 µg of JP-1302; and (iii) abolished by 1,000 µg of BRL44408 or 310 µg of JP-1302. Thus, intrathecal B-HT 933 inhibited the external carotid vasodilator responses to capsaicin. This response, mediated by spinal α2-adrenoceptors unrelated to the α(2B)-adrenoceptor subtype, resembles the pharmacological profile of α(2C)-adrenoceptors and, to a lesser extent, α(2A)-adrenoceptors.
Asunto(s)
Antagonistas de Receptores Adrenérgicos alfa 2/uso terapéutico , Arteria Carótida Externa/efectos de los fármacos , Modelos Animales de Enfermedad , Trastornos Migrañosos/tratamiento farmacológico , Receptores Adrenérgicos alfa 2/metabolismo , Médula Espinal/efectos de los fármacos , Vasoconstrictores/uso terapéutico , Acetilcolina/metabolismo , Antagonistas de Receptores Adrenérgicos alfa 2/administración & dosificación , Antagonistas de Receptores Adrenérgicos alfa 2/química , Analgésicos no Narcóticos/administración & dosificación , Analgésicos no Narcóticos/antagonistas & inhibidores , Analgésicos no Narcóticos/uso terapéutico , Animales , Péptido Relacionado con Gen de Calcitonina/metabolismo , Capsaicina/antagonistas & inhibidores , Capsaicina/toxicidad , Arteria Carótida Externa/fisiología , Vértebras Cervicales , Perros , Hemodinámica/efectos de los fármacos , Infusión Espinal , Masculino , Trastornos Migrañosos/inducido químicamente , Trastornos Migrañosos/metabolismo , Isoformas de Proteínas/antagonistas & inhibidores , Isoformas de Proteínas/metabolismo , Receptores Adrenérgicos alfa 2/química , Flujo Sanguíneo Regional/efectos de los fármacos , Médula Espinal/metabolismo , Vasoconstrictores/administración & dosificación , Vasoconstrictores/antagonistas & inhibidores , Vasodilatadores/antagonistas & inhibidores , Vasodilatadores/toxicidadRESUMEN
The postictal state is generally followed by antinociception. It is known that connections between the dorsal raphe nucleus, the periaqueductal gray matter, and the locus coeruleus, an important noradrenergic brainstem nucleus, are involved in the descending control of ascending nociceptive pathways. The aim of the present study was to determine whether noradrenergic mechanisms in the locus coeruleus are involved in postictal antinociception. Yohimbine (an α(2)-receptor antagonist) or propranolol (a ß-receptor antagonist) was microinjected unilaterally into the locus coeruleus, followed by intraperitoneal administration of pentylenetetrazole (PTZ), a noncompetitive antagonist that blocks GABA-mediated Cl(-) influx. Although the administration of both yohimbine and propranolol to the locus coeruleus/subcoeruleus area resulted in a significant decrease in tonic or tonic-clonic seizure-induced antinociception, the effect of yohimbine restricted to the locus coeruleus was more distinct compared with that of propranolol, possibly because of the presynaptic localization of α(2)-noradrenergic receptors in locus coeruleus neurons. These effects were related to the modulation of noradrenergic activity in the locus coeruleus. Interestingly, microinjections of noradrenaline into the locus coeruleus also decrease the postictal antinociception. The present results suggest that the mechanism underlying postictal antinociception involves both α(2)- and ß-noradrenergic receptors in the locus coeruleus, although the action of noradrenaline on these receptors causes a paradoxical effect, depending on the nature of the local neurotransmission.