Physiol Rev 92: 1699–1775, 2012 doi:10.1152/physrev.00048.2010 SENSORY AND SIGNALING MECHANISMS OF BRADYKININ, EICOSANOIDS, PLATELET-ACTIVATING FACTOR, AND NITRIC OXIDE IN PERIPHERAL NOCICEPTORS Gábor Peth˝o and Peter W. Reeh Pharmacodynamics Unit, Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Pécs, Pécs, Hungary; and Institute of Physiology and Pathophysiology, University of Erlangen/Nürnberg, Erlangen, Germany Peth˝o G, Reeh PW. Sensory and Signaling Mechanisms of Bradykinin, Eicosanoids, Platelet-Activating Factor, and Nitric Oxide in Peripheral Nociceptors. Physiol Rev 92: 1699–1775, 2012; doi:10.1152/physrev.00048.2010.—Peripheral mediators can contribute to the development and maintenance of inflammatory and neuropathic pain and its concomitants (hyperalgesia and allodynia) via two mechanisms. Activation Lor excitation by these substances of nociceptive nerve endings or fibers implicates generation of action potentials which then travel to the central nervous system and may induce pain sensation. Sensitization of nociceptors refers to their increased responsiveness to either thermal, mechani- cal, or chemical stimuli that may be translated to corresponding hyperalgesias. This review aims to give an account of the excitatory and sensitizing actions of inflammatory mediators including bradykinin, prostaglandins, thromboxanes, leukotrienes, platelet-activating factor, and nitric oxide on nociceptive primary afferent neurons. Manifestations, receptor molecules, and intracellular signaling mechanisms of the effects of these mediators are discussed in detail. With regard to signaling, most data reported have been obtained from transfected nonneuronal cells and somata of cultured sensory neurons as these structures are more accessible to direct study of sensory and signal transduction. The peripheral processes of sensory neurons, where painful stimuli actually affect the nociceptors in vivo, show marked differences with respect to biophysics, ultrastructure, and equipment with receptors and ion channels compared with cellular models. Therefore, an effort was made to highlight signaling mechanisms for which supporting data from molecular, cellular, and behavioral models are consistent with findings that reflect properties of peripheral nociceptive nerve endings. Identified molecular elements of these signaling pathways may serve as validated targets for development of novel types of analgesic drugs. I. INTRODUCTION 1699 and 4) axon interconnecting the above-mentioned ele- II. ROLE OF BRADYKININ IN PERIPHERAL... 1701 ments. Membrane depolarizations induced in the periph- III. ROLE OF PROSTANOIDS IN... 1727 eral terminal by an excitatory effect of thermal, mechanical, IV. ROLE OF LIPOXYGENASE PRODUCTS... 1744 and/or chemical stimuli can evoke action potentials that V. ROLE OF PLATELET-ACTIVATING... 1746 propagate along the peripheral and central axon to the cen- VI. ROLES OF NITRIC OXIDE IN... 1747 tral nervous system. The peripheral ending-preterminal VII. GENERAL CONCLUSIONS 1754 axon region contains three types of receptors/ion channels that mediate the above-mentioned process. First, various I. INTRODUCTION transducer proteins are responsible for conversion of the natural stimuli into locally spreading membrane depolar- Nociceptive primary afferent neurons represent the first izations (receptor or generator potentials) mediated by in- ϩ 2ϩ neuron in the pain pathways. Major parts of these neurons flux of Na and/or Ca . They include several types of are as follows: 1) cell body (soma) located in the sensory heat- or cold-activated ion channels, still largely putative dorsal root, trigeminal, nodose and jugular ganglia where mechanosensitive channels and a big family of G protein- most of the peptides and proteins required by the whole coupled (metabotropic), ion channel-linked (ionotropic), or neuron are synthesized; 2) peripheral terminal specialized tyrosine kinase-linked receptors for various chemical medi- for the detection of heat, cold, mechanical, and chemical ators. Another set of ion channels in the peripheral termi- stimuli that can induce pain; 3) central terminal projecting nal/preterminal axon region is involved in regulation of the to the dorsal horn of the spinal cord or to the brain stem; electrical excitability, i.e., the efficiency of the conversion of 0031-9333/12 Copyright © 2012 the American Physiological Society 1699 GÁBOR PETHO˝ AND PETER W. REEH receptor potentials into propagating action potentials. mediators contains member(s) from both the peptide and These include mainly various types of Kϩ channels (e.g., lipid categories of endogenous locally acting regulatory voltage-gated, Ca2ϩ-activated, or ATP-sensitive channels) substances (autacoids), and also NO that is a unique medi- whose hyperpolarizing activity opposes the depolarizing ef- ator both chemically and functionally. In accord with the fect induced by transducer protein activation. The preter- recognition that inflammation (e.g., Wallerian degenera- minal axon is equipped with voltage-gated Naϩ channels tion) is a critical element of the pathological processes fol- that are acivated by membrane depolarization of sufficient lowing nerve injury, contribution of these mediators to neu- magnitude and are responsible for the generation of action ropathic pain is also discussed. The quasi-efferent tissue potentials. One subtype of these channels, Nav1.9, how- responses secondary to inflammatory mediator-induced re- ever, appears not to be involved in spike generation; it lease of neuropeptides such as substance P (SP) or calcitonin rather contributes a depolarizing influence to resting poten- gene-related peptide (CGRP) from peptidergic nociceptors tial and thereby regulates electrical excitability. are not covered here, although this (measurable) neurose- cretion can be used as an index of activation. A huge array of endogenous chemicals contribute to sen- sory phenomena including pain and hyperalgesia that de- Although the major site where painful stimuli excite noci- velop during inflammation and after tissue as well as nerve ceptors in vivo is the peripheral terminal, this structure is injury. Most of these mediators are not stored preformed inaccessible to direct investigation of membrane currents but synthesized de novo at the site of injury. The agents and intracellular signaling processes owing to its minute contribute to pain via two principal mechanisms. Excita- size. In contrast, somata of the primary afferent neurons are tion of nociceptive nerve endings or fibers implicates gener- suitable for such examinations explaining why the bulk of ation of action potentials which then travel to the central data concerning inflammatory mediator effects on sensory nervous system and may directly induce pain sensations or, neurons have been obtained studying the cultured cell bod- at least, “central sensitization” of spinal nociceptive trans- ies, assuming that they are reliable models of their periph- mission resulting in secondary hyperalgesia and allodynia, eral terminals. This assumption has suffered a first major in particular to mechanical stimulation (625). Sensitization setback when mice with a targeted deletion of the heat- of nociceptors refers to their increased responsiveness to activated ion channel and capsaicin receptor TRPV1 (tran- heat/cold, mechanical, or chemical stimulation that gives sient receptor potential vanniloid type 1) showed the ex- rise to primary hyperalgesia to these stimuli. If, for example, pected loss of heat-activated current in capsaicin-sensitive the threshold to noxious heat drops to 37°C or lower, a dorsal root ganglion (DRG) neurons but almost normal decrease by only 3–4°C, normal body temperature can be- nocifensive behavior and completely normal primary affer- come a driving force of nociceptor discharge and pain, and ent discharge in response to moderate noxious heat (90, the discrimination between excitatory and sensitizing 777, 803). Another example is the functional expression of mechanisms becomes vain (431, 599). In fact, in most in- GABAA receptor channels in all DRG neurons as opposed flammatory and neuropathic disease states, both ongoing to their lack in peripheral nerve axons and terminals (199). activity in sensory nerves and sensitization or hyperalgesia Thus selective trafficking, variable heteromerization, post- (to heating) are found in vivo. All three types of receptors/ translational modifications of proteins may create relevant ion channels in the sensory nerve endings and preterminal differences between the cellular model and the real nerve axons (see above) are molecular targets for the intracellular endings. In addition, biophysical parameters, e.g., surface- signaling mechanisms underlying inflammatory mediator- to-volume ratio, are entirely different, resulting in different induced spike generation and sensitization. mechanisms underlying (electrical) excitability (802). Even the ultrastructure is essentially different with cell bodies in Bradykinin is one of the most potent pain-producing agents the DRG being rich in endoplasmic reticulum and calcium formed under inflammatory conditions, and a multitude of store capacity, while in nerve endings, bare of endoplasmic its excitatory and sensitizing effects on peripheral nocicep- reticulum, calcium-operated mechanisms such as neurose- tors have been described supporting its role as a prototype cretion depend entirely on influx from extracelluar space. of peripheral pain mediators. A number of bradykinin ef- fects