Sensory and Signaling Mechanisms of Bradykinin, Eicosanoids, Platelet-Activating Factor, and Nitric Oxide in Peripheral Nociceptors

Abstract

Peripheral mediators can contribute to the development and maintenance of inflammatory and neuropathic pain and its concomitants (hyperalgesia and allodynia) via two mechanisms. Activation or 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, mechanical, 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.

The G Protein–Coupled Receptor–Transient Receptor Potential Channel Axis: Molecular Insights for Targeting Disorders of Sensation and Inflammation

“…TRP channels amplify or sustain these painful processes, and GPCRs transduce signals to activate or sensitize TRP channels through several mechanisms. GPCR-stimulated second messenger kinases (e.g., cAMP-dependent protein kinase A [PKA], PKC) phosphorylate TRPs to reduce activation thresholds in response to endogenous channel agonists (Peth} o and Reeh, 2012). GPCRs stimulate phospholipase activity to release tonic inhibitory effects of PIP 2 on ion channels .…”

“…Evidence indicates that each of these GPCR classes functionally interacts with TRP channels to induce painful, inflammatory, or pruritic cellular outcomes and an extensive summary of these pathways is provided (Tables 1 and 2). Key sensitizing receptors, such as the tyrosine kinase receptor TrkA, 5-HT, purinergic, and the prostaglandin-activated EP receptors, have been reviewed (Peth} o and Reeh, 2012;McKelvey et al, 2013;Bannwarth and Kostine, 2014;Bautista et al, 2014). The best studied sensory GPCR-TRP channel regulatory pathways include the protease-activated receptor and bradykinin receptor families, and these are discussed in greater detail below.…”

“…b. Bradykinin receptors. The contributions of bradykinin (BK) receptors (B 1 R and B 2 R) to pain, inflammation, and TRP channel activation has been the subject of multiple reviews (Peth} o and Reeh, 2012;Regoli et al, 2012;Blaes and Girolami, 2013). Proteases of the kallikrein-kininogen system cleave propeptides to produce painful ligands of the kinin family.…”

“…Known as receptor-operated channel theory, this mechanism describes how GPCRs stimulate cell signaling and lipid metabolism pathways, which converge on TRP channels to lower their activation threshold and initiate rapid ion flux across the cell surface or internal membranes (Montell, 2005b). In mammals, the GPCR-TRP axis is enriched by the coexpression of GPCRs and TRPs in select cell types (e.g., subpopulations of sensory neurons) and by an abundance of signaling intermediates (e.g., adaptor proteins, kinases, lipid metabolites) that functionally link GPCRs to TRPs (Peth} o and Reeh, 2012). These intermediates afford Fig.…”

Anti-inflammatory, analgesic, and immunostimulatory effects of Luehea divaricata Mart. & Zucc. (Malvaceae) bark

“…These inflammatory and activated cells release vasoactive mediators such as nitric oxide, bradykinin, and metabolites of arachidonic acid, all of which increase regional blood flow and promote microvascular permeability (Suffredini et al, 1999). Several inflammatory mediators, mainly bradykinin and metabolites of arachidonic acid, are potent pain-producing agents that can excite and sensitize nociceptive primary afferent neurons (Petho, Reeh, 2012). Several plant extracts have been studied for their anti-inflammatory properties, by using in vitro and in vivo models (Ojewole, 2006;Siriwatanametanon et al, 2010;Areej et al, 2013), and existing data suggest that L. divaricata may also have similar characteristics.…”