[5] Using anatomical and histological techniques, they showed that the dura of the middle cranial fossa is innervated Tofacitinib purchase by nerve fibers of the mandibular and maxillary trigeminal divisions, while the dura of the anterior cranial fossa and the tentorium cerebelli are innervated by nerve fibers of the ophthalmic division. Due to the seminal intraoperative experiments of Ray and Wolff during

this time, the essential role for the generation of headaches of trigeminal nerve fibers innervating meningeal blood vessels was published and widely accepted,[6] later confirmed by additional studies of other groups.[7, 8] A number of animal experiments during the last decades widened our knowledge about the trigeminovascular system of the meninges as morpho-functional basis for the pathogenesis of headaches. Further studies clarified details of the structure9-12 and the functional characteristics of meningeal afferents innervating the rodent dura mater,13-16 and identified their central projections.[17, 18] Through immunohistochemical examinations, we know that a considerable proportion of these meningeal afferents contains neuropeptides like substance P and calcitonin gene-related peptide.[10, 19, 20] This could also be demonstrated for the human dura mater, confirming the homology of the nociceptive innervation

between mammals.[21] Despite this knowledge, the pathogenesis of headaches is still full of unresolved problems, which applies particularly to primary PD-1/PD-L1 assay headaches such as migraine. While a central origin of primary headaches has been intensely discussed during recent see more years, clinical and experimental observations provide evidence for an essential contribution of peripheral, intracranial

as well as extracranial, nociceptive processes.[22] The intracranial and pericranial trigeminal innervation may partly form a functional unit, a concept that is supported by recent histological and functional data that show collateral afferent connections between the dura mater and deep pericranial tissues in rodents.[23, 24] In the light of these recent findings, old anatomical studies on the primate and human meningeal innervation reporting about nerve fibers that penetrate the skull become again highly important.[2, 3, 5] These nerve fibers, in addition to their originally supposed function to innervate the skull, eg, in the region of the mastoid,[5] can indeed supply extracranial tissues. The present postmortem anterograde tracing study in rat and human skulls completes and extends our recent in vivo anterograde tracings.[24] They show that in the area of the middle cranial fossa, intracranial (meningeal) and extracranial (deep muscular) tissues are innervated by trigeminal nerve fibers passing through the cranial dura mater.