C nated, polymodal C-fibers are activated by a variety C Afferent Axons/Fibers of high-intensity mechanical, chemical, hot and cold stimuli. In addition, low threshold fibers (Aβ) that nor- Synonyms mally only transfer innocuous sensations like touch, can CFibers contribute to neuropathic pain following nerve damage. Opioids in the Periphery and Analgesia Definition One kind of fiber in the peripheral nerve; unmyelinated thin fibers. These high-threshold sensory afferents con- duct very slowly (less than 2 m/s), and are thought to be Cachexia responsible for the sensation of deep, burning pain that follows ’first pain’ after injury. Although C fibers ma- Definition β ture earlier than low-threshold A fibers, anatomically General ill health and malnutrition that presents as mus- and neurochemically, other aspects of their function are cle wasting, dehydration and reduced behavioral activ- delayed, for example, the phenomenon of neurogenic ities in untreated diabetic animals. edema, and the development of functional central con- NeuropathicPainModel,DiabeticNeuropathyModel nections within the spinal cord. AFibers(A-Fibers) Alpha(α) 2-Adrenergic Agonists in Pain Treatment Infant Pain Mechanisms CACNA1A Insular Cortex, Neurophysiology and Functional Imaging of Nociceptive Processing Magnetoencephalography in Assessment of Pain in Definition Humans α CACNA1A is a gene encoding the 1A subunit of a Morphology, IntraspinalOrganizationofVisceralAf- voltage sensitive calcium channel abundantly expressed ferents in neuronal tissue. It is activated by high voltage and Nociceptor, Categorization gives rise to P/Q-type calcium currents. Mutations in Nociceptors in the Orofacial Region (Temporo- the human gene are related to diseases like spinocere- mandibular Joint and Masseter Muscle) bellar ataxia type 6, familial hemiplegic migraine and Nociceptor(s) episodic ataxia type 2. In mice, mutations in the or- Opiates During Development thologous gene are responsible for the “leaner” and Spinothalamic Tract Neurons, in Deep Dorsal Horn “tottering” phenotypes. Thalamus, Dynamics of Nociception Calcitonin Gene-Related Peptide and Migraine Vagal Input and Descending Modulation Headaches C and A Fibers Calbindin Definition Definition Nociceptive input is conveyed from the peripheral terminals to the spinal cord, predominantly by two Vitamin D-dependent calcium-binding protein that is classes of primary afferent fibers. Of these, the slowly- present in specific sensory neuronal cell types. conducting, thinly-myelinated Aδ-fibers mediate ther- Spinothalamic Terminations, Core and Matrix mal and mechanical nociception, whereas the unmyeli- Thalamus,ReceptiveFields,ProjectedFields,Human 188 Calbindin D–28k proteins from the blood stream pass into the surround- Calbindin D–28k ing tissue. Release of CGRP from the central terminals of DRG neurons modulates spinal cord neurons, in part Definition by enhancing the actions of substance P. It also plays a A member of the EF-hand family calcium binding pro- role in pain processing. teins, which buffer intracellular calcium concentration Alternative Medicine in Neuropathic Pain and mediate a variety of cellular functions. Calbindin Calcitonin Gene-Related Peptide and Migraine D–28k has six EF-hand domains, but only four of them Headaches bind to calcium. Calbindin D–28k has been used as Clinical Migraine without Aura a marker of nerve cells in neuroanatomical studies, Immunocytochemistry of Nociceptors since it selectively distributes in subpopulations of Migraine, Pathophysiology central nervous system neurons in specific regions. Neuropeptide Release in the Skin In the monkey thalamus, calbindin D–28k antibodies Nociceptor, Categorization selectively label the matrix domain of the medial ven- Nociceptors in the Orofacial Region (Meningeal/ troposterior nucleus of the thalamus, which is related Cerebrovascular) to trigeminothalamic projection from the caudal spinal Opioids in the Periphery and Analgesia trigeminal nucleus subnucleus caudalis. Opioid Modulation of Nociceptive Afferents In Vivo Trigeminothalamic Tract Projections Spinal Cord Nociception, Neurotrophins Thalamus, Visceral Representation Calbindin-Immunoreceptive Matrix Cells Calcitonin Gene-Related Peptide and Definition Migraine Headaches Sensory neurons that stain positively for the presence of KIRSTEN ARNDT,STEFAN JUST,HENRI DOODS vitamin D-dependent calcium-binding protein. CNS Pharmacology, Pain Research, Boehringer Thalamic Nuclei Involved in Pain, Human and Mon- Ingelheim Pharma GmbH & Co. KG, Biberach/Riss, key Germany [email protected] Calcitonin Gene-Related Peptide Synonym CGRP Synonyms CGRP Definition Migraineisacomplex,multi-symptomdiseaseaffect- Definition ing 10–16% of the western population. It has a higher CGRP is a 37-amino acid peptide that is produced by prevalence in women than in men. Migraine character- tissue-specific processing of the calcitonin gene. It istics are its episodic appearance and symptoms such belongs to the Calcitonin/CGRP family which includes as unilateral headache, phono- and/or photo-phobia, other peptides like calcitonin, amylin, adrenomedullin facial mechanical allodynia and nausea and vomit- and intermedin. CGRP is comprised of at least two ing (Headache Classification Subcommittee of the forms: αCGRP and βCGRP. Whereas αCGRP is found International Headache Society 2004). Preceding the in DRG neurons of all sizes, βCGRP is localized to headache, 20–30% of the patients experience focal neu- small- and medium-sized neurons. CGRP functions rological symptoms termed aura. Based on the presence primarily as a neuromodulator and signals via a het- or absence of an aura, migraines are classified as either erodimeric receptor complex consisting of a G-protein “classical” migraine (migraine with aura), or “com- coupled receptor (calcitonin-like receptor) and a recep- mon” migraine (migraine without aura). Generally, a tor activity modifying protein (RAMP1) and stimulates migraine attack can be subdivided into different phases cAMP formation intracellularly. Release of CGRP from that include the premonitory phase, headache and the the peripheral terminals of DRG neurons contributes to postdrome. The prevalence of the different symptoms neurogenic inflammation. During this process, CGRP varies over the phases with e.g. being tired and weary is the most potent vasodilator in the microcirculation as approximately equally prominent in all phases and identified so far and acts by relaxing small arteries “stiff neck” being most prevalent in the headache and and arterioles. Furthermore, CGRP acts together with postdrome phases. Typically, a migraine attack lasts substance P to potentiate plasma extravasation where from 4 to 72 hours. Calcitonin Gene-Related Peptide and Migraine Headaches 189 Calcitonin gene-related peptide (CGRP) is a neu- tion is coming from observations employing transcra- ropeptide and important vasodilator. It is released niallaserDopplermeasurements,whichsuggestthatmi- during migraine attacks. Blockade of CGRP receptors graine attacks are associated with intracranial large ar- in humans alleviates migraine pain. terial dilatation on the headache side. Together the possible causes described above provide C Characteristics links to the observed migraine symptomatologyand po- tential underlying mechanisms. They deliver thebiolog- Underlying Causes of a Migraine Attack ical “hardware” which contributes to migraine patho- Despite many approaches to understand the initiation genesis. The focus is on the cranial vasculature and the of migraine attacks, “the migraine trigger” or the phys- trigeminal sensory system controlling the vasculature iological starting point has not yet been identified. To and transmitting information to brainstem and midbrain date it is also not possible to come up with a primary un- nuclei,whichinturnmonitorandadjusttheincomingin- derlying cause for migraines and probably there is more formation. During a migraine attack, adjustments made than one. Several genetic factors have been discussed by these systems might be reflected by certain symp- as rendering a person more susceptible to developing toms. As an example, the symptom unilateral throbbing migraines, as well as disturbances of central neuronal pain at the temples seems to be caused by mechanisms function or cranial changes in vasodynamics. Many of like sensitization of sensory afferents in the periphery. these hypotheses evolved from studies of one subtype In addition, facial mechanical allodynia might be initi- of migraine patients, the ones experiencing classical atedbyneuronalsensitizationprocessesadvancingfrom migraines. Potential genetic defects which might cause sensory to central neurons (Burstein et al. 2000). Under- classical migraines include e.g. missense mutations in standing migraine symptoms and the potential mecha- the CACNA1A gene encoding the α1 subunit of the nisms driving an attack is an important basis for under- voltage dependent P/Q type calcium channel, which standing the disease and getting a handle on the essential accounts for 50% of an autosomal disease called famil- molecular drivers that direct the biological systems to- ial hemiplegic migraine (FHM1). Missense mutations wards a migraine attack. in the ATP1A2 gene, which encodes the α2 isoform of the enzyme Na, K-ATPase, have been shown to be The Neuropeptide CGRP, an Important Molecular Player in Mi- responsible for additional cases of FHM. graine Attacks Besides the genetic factors, local disturbances