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In epilepsy, synaptic glutamate release acting through AMPA receptors is a trigger factor and synaptic activity is required (in most instances) for propagation. In migaine, synaptic glutamate acting through NMDA receptors is a trigger factor. Once established, synaptic activity may no longer be necessary and glutamate release from glia is the predominant factor that drives the advancing front of spreading depression. The spreading depression wave triggers the release of mediators that activate the trigeminovascular system, resulting in headache pain. Voltage-gated Na⁺ channel dependence (tetrodotoxin-sensitivity) implies the involvement of synaptic mechanisms. CGRP, calcitonin gene-related peptide.

Protease cleavage and activation of PAR₂ on primary spinal afferent neurons to cause neurogenic inflammation and pain. (1) Injury and inflammation trigger the generation and release of proteases from mast cells (tryptase), epithelial cells, and neurons (trypsins), and the circulation (FVIIa, FXa) that can cleave PAR₂ at the peripheral projections of primary spinal efferent neurons. (2) Cleavage exposes the tethered ligand domain (SLIGRL in mice and rats), which binds conserved regions of the extracellular loop II to activate the receptor. (3) PAR₂ activation increases [Ca²⁺]_i and releases CGRP and SP in peripheral tissues. (4) CGRP interacts with the type 1 CGRP receptor (a heterodimer of calcitonin receptor-like receptor, CLR, and receptor activity modifying protein 1, RAMP1) on arterioles to induce dilation and hyperemia. (5) SP interact with the neurokinin 1 receptor (NK1R) on endothelial cells of postcapillary venules to induce gap formation and plasma extravasation. Together, these induce neurogenic inflammation. (6) The same stimuli release SP and CGRP in the spinal cord dorsal horn to induce pain transmission. (7) PAR₂ sensitize TRPV1 and TRPV4 channels, which causes hyperalgesia to thermal and mechanical stimuli, respectively.

Vasomotor control mechanisms operant in skeletal muscle in the endothelium and vascular smooth muscle cells in the walls of arteries and arterioles (upper panel). Lower panel illustrates some of the more prominent receptors, ion channels, and signaling pathways that operate to modulate vascular smooth muscle tone in skeletal muscle as these emphasize the complex nature of the neurohumoral and metabolic regulatory systems involved in the control of vascular resistance in skeletal muscle at rest and during exercise. The illustration is not meant to be all-inclusive. Pericytes are not depicted, but are discussed in the text, as these contractile cells may also participate in vasomotor control. Modified from reference [365]. In both panels, the internal elastic lamina (basement membrane) between the endothelium and vascular smooth muscle is omitted for clarity.
Abbreviations: K_Ca, calcium-activated K⁺ channel; K_ATP, ATP-sensitive K⁺ channel; K_v, voltage-gated K⁺ channel; K_IR, inward rectifying K⁺ channel; Trp, transient receptor potential channels; O₂, oxygen; ATP, adenosine triphosphate; NO, nitric oxide; TXA₂, thromboxane A₂ and receptor; 5HT, 5-hydroxytryptamine and receptor; PMNs, polymorphonuclear leukocytes; O₂^-, superoxide anion radical; H₂O₂, hydrogen peroxide; TNF, tumor necrosis factor α; LTC₄, leukotriene C₄; MMP, matrix metalloproteinases; P2, purinergic type 2 receptor; M, muscarinic receptor; MEJ, myoendothelial junction; H₁ and H₂, histamine receptors; B₂, bradykinin receptor; TNFR, tumor necrosis alpha receptor; LTR, leukotriene receptor; ECE, endothelin-converting enzyme; bET-1, big endothelin-1; ET-1, endothelin-1; eNOS, endothelial nitric oxide synthase; L-Arg, L-arginine; COX-1, cyclooxygenase 1; CYP450, cytochrome P450 epoxygenase; ACE, angiotensin-converting enzyme; AI, angiotensin I; AII; angiotensin II; AT₁, angiotensin type 1 receptor; AT₂, angiotensin type 2 receptor; ET_A, endothelin type A receptor; ET_B, endothelin type B receptor; PG, prostaglandins; AA, arachidonic acid; EDHF, endothelium-derived hyperpolarizing factor; VGCC, voltage-gated calcium channels; IP, prostacyclin receptor; EETs, epoxyeicosatrienoic acids; HETEs, hydroxyeicosatetraenoic acids; α₁, α₁-adrenergic receptor; α₂, α₂-adrenergic receptor; β₂, β₂-adrenergic receptor; ACh, acetylcholine; NE, norepinephrine; NPY, neuropeptide Y; P1, purinergic type 1 receptor; Y₁, neuropeptide Y receptor; IL, interleukin-6 receptor; CGRP, calcitonin gene-related peptide; CLR, calcitonin-like receptor.