Cellular Mechanisms of Neurogenic Inflammation

Abstract

Since the initial observations that stimulation of sensory neurons produces vasodilation, plasma extravasation, and hypersensitivity, much progress has been made in understanding the etiology of neurogenic inflammation. Studies have focused largely on the role of the neuropeptides, substance P and calcitonin gene-related peptide, which are released in the periphery by activation of small diameter sensory neurons. Recent work, however, has begun to emphasize the cellular mechanisms involved in regulating the release of proinflammatory substances from sensory neurons. In this perspective, discussion centers on a number of inflammatory mediators that activate various signal transduction pathways to augment excitability of and transmitter release from sensory neurons. Emphasis is placed on those pathways where multiple lines of evidence support their importance in initiating neurogenic inflammation. Recent studies, however, support the notion that there are novel compounds released during injury that can stimulate or sensitize sensory neurons. Furthermore, only now are intracellular signaling pathways that have been identified in other cell systems being studied in sensory neurons to establish their role in neurogenic inflammation. The challenge remains to ascertain the critical transduction pathways that regulate transmitter release from sensory neurons since this phenomenon triggers neurogenic inflammation. In addition, the cellular mechanisms involved in alterations in neuronal excitability during injury and the cellular pathways that maintain the inflammatory response over time need to be determined. With these advances, we will be able to develop therapeutic interventions to minimize deleterious consequences of neurogenic inflammation. Neurogenic InflammationMore than a century ago, the first observations were made that activation of dorsal root ganglia neurons results in vasodilation, suggesting that these neurons not only conduct afferent information to the spinal cord, but also subserve an efferent function (Bayliss, 1901). Since that time, abundant evidence has accumulated supporting the notion that activation of peripheral terminals of sensory neurons by local depolarization, axonal reflexes, or dorsal root reflexes releases bioactive substances. These substances, in turn, act on target cells in the periphery such as mast cells, immune cells, and vascular smooth muscle producing inflammation, which is characterized by redness and warmth (secondary to vasodilation), swelling (secondary to plasma extravasation), and hypersensitivity (secondary to alterations in the excitability of certain sensory neurons). We call this phenomenon "neurogenic inflammation", that is, inflammatory symptoms that result from the release of substances from primary sensory nerve terminals.Of major importance in the generation of neurogenic inflammation are the small diameter sensory neurons that are sensitive to capsaicin, the vanilloid found in hot peppers (for review, see Holzer, 1988). Intradermal injection of capsaicin ...

Neurokinins enhance excitability in capsaicin-responsive DRG neurons

“…The family of neurokinin receptors NK 1 , NK 2 and NK 3 are G-protein coupled receptors which activate phospholipase C (Maggi, 1995(Maggi, ,1997b. The breakdown of phospholipids into diacylglycerol by PLC, activates PKC (Torrens et al, 1997) to phosphorylate and inhibit a number of K + channels (Boland and Jackson, 1999,Hagiwara et al, 2003,Richardson and Vasko, 2002. We have shown that direct activation of PKC with PDBu did not increase firing in DRG neurons.…”

“…There is growing evidence that neurokinin auto-receptors influence the properties of C-R nociceptive neurons (Hu et al, 1997,Maggi, 1997b,Richardson and Vasko, 2002. In the urinary bladder, neurokinin A released from sensory nerves seems to be involved in both the normal voiding function induced by bladder distension as well as the hyperactive voiding induced by noxious stimuli (Morrison et al, 1999).…”

Inflammation contributes to axon reflex vasodilatation evoked by iontophoresis of an alpha-1 adrenoceptor agonist

“…The local anaesthetic agents in EMLA cream block axon reflexes (Morris and Shore, 1996), and could also prevent intraneural prostaglandin formation (Richardson and Vasko, 2002). Sorbolene pretreatment also inhibited the local vasodilator response to phenylephrine, but not the axon reflex.…”

“…The flare is 4 thought to be mediated by neural discharge that spreads retrogradely through the terminal network of mechano-insensitive nociceptive C-fibres (termed an axon reflex), ultimately releasing neuropeptides that act on mast cells, immune cells and vascular smooth muscle to increase local blood flow (Schmelz et al, 2000;Schmelz and Petersen, 2001;Richardson and Vasko, 2002). Intradermal administration of noradrenaline by microdialysis on the dorsal aspect of the human hand did not induce axon reflex vasodilatation (Zahn et al, 2004).…”

Nociceptors: the sensors of the pain pathway

“…The released substances produce a myriad of autocrine or paracrine effects on endothelial, epithelial, and resident immune cells (Langerhans), which lead to arteriolar vasodilatation ("flare," via CGRP) and/or increased vascular permeability and plasma extravasation from venules (edema, via substance P). Liberated enzymes (e.g., kallikreins) and blood cells (e.g., platelets, mast cells) further contribute to the accumulation of inflammatory mediators and neurogenic inflammation (110,111). A large variety of substances feed back onto nociceptors innervating the injured region and sensitize peripheral terminals by direct and indirect actions at ion channels, receptors, and second messenger cascades (87,102,111,112).…”