Trigeminal Nociception-Induced Cerebral Fos Expression in the Conscious Rat

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Abstract
Little is known about trigeminal nociception-induced cerebral activity and involvement of cerebral structures in pathogenesis of trigeminovascular headaches such as migraine. Neuroimaging has demonstrated cortical, hypothalamic and brainstem activation during the attack and after abolition with sumatriptan. This has led to the conclusion that the dorsal raphe and locus coeruleus may initiate events that generate migraneous headache. Using a conscious rat model of trigeminal nociception and cerebral Fos expression as histochemical markers of neuronal activity, we characterized the pattern of brain activity after noxious trigeminal stimulation with capsaicin (250 and 1000 nm). A significantly increased Fos immunoreactivity was found in the trigeminal nucleus caudalis (layers I and II), the area postrema, the nucleus of the solitary tract, the parvicellular reticular nucleus, the locus coeruleus, the parabrachial nucleus and the raphe nuclei. In addition, the ventrolateral periaqueductal grey, the intralaminar thalamic and various hypothalamic areas, showed an enhanced Fos expression after the intracisternal administration of capsaicin. Other responding areas were the amygdala, the upper lip and forelimb regions of the primary somatosensory cortex, and the insula. Many of these areas participate in (anti)-nociception, although we cannot exclude the possibility that in conscious animals the pain-associated physiological and behavioural responses that are an intrinsic and necessary part of coping with pain have generated the increased Fos expression. Trigeminal stimulation-induced locus coeruleus, dorsal raphe and hypothalamic activation are opposed to a suggested pathogenic role of these nuclei in migraine and cluster headache, respectively.