Interplay between the nervous and immune systems has been the subject of research for several decades. One important aspect of this work is neuronal signaling in inflammatory states, particularly the direct responsiveness of neurons to immune mediators. Multiple techniques have been utilized to understand the increasingly complex physiology and functional role(s) of the plethora of proteins expressed at sites of inflammation, in sensory ganglia and central sites of sensory afferent termination. Consequent to the recent explosion in pharmacogenomics, the number of proteins with as yet undefined function has exponentially increased. This has created the ‘luxury’ of an over-abundance of potential drug targets, necessitating rational and focussed validation studies.1 From an analgesic drug discovery perspective, the identification of receptors or channels expressed exclusively by sensory nociceptive neurons makes these attractive targets; hypothetically, a drug working through such a receptor or channel population would block the transmission of nociceptive signals in a manner unlikely to be blighted with centrally-mediated side effects. Currently available analgesics typically act non-selectively at ion channels (for example, sodium channel blockers) or at neurotransmitter receptors, typically of the G-protein-coupled receptor (GPCR) superfamily (for example, opioids). Though efficacious, they have considerable adverse effect liability. A highly restricted distribution to sensory neurons has not yet been observed for many ion channels or GPCRs, although the capsaicin receptor, VR1, a ligand-gated cation channel, and SNS/PN3, a voltage-gated Na channel are notably localized to sensory ganglion neurons.2,3 The recent discovery of the involvement of the GPCR, proteinase-activated receptor-2 (PAR2) in the generation of hyperalgesia, and the observation that its mechanism of action is through sensory neuropeptide regulation is therefore interesting and potentially important.4
The PAR family has four members, which are self-activated by innate tethered ligands following proteinase-mediated cleavage of the extracellular amino terminal domain of the receptor.5 The proteinases involved in this activation are more commonly associated with protein degradation and include thrombin (cleaves PAR1, PAR3 and PAR4), trypsin (PAR2 and PAR4) and tryptase (PAR2). The evidence for a role of PARs, and particularly PAR2, in inflammation is convincing. For example, activation of PAR2 leads to smooth muscle relaxation, leukocyte marginalization and infiltration, increased vascular permeability, systemic hypotension and bronchoconstriction (for a review, see Vergnolle et al5). There is also good reason to suggest an emerging function for PAR2 in neurogenic inflammation. For example, PAR2-immunoreactivity has been demonstrated on enteric neuronal, endothelial and epithelial cells and PAR2 and PAR1 are expressed on primary afferent neurons.5 Sixty percent of dorsal root ganglia (DRG) neurons express PAR2-immunoreactivity, significant percentages of which also express calcitonin gene-related peptide (CGRP) and substance P (SP), the two major neuropeptides contained in nociceptive C-fibers innervating superficial laminae of the spinal cord. Activation of these PARs causes rapid intracellular neuronal Ca2+ mobilization.6 Trypsin, tryptase and PAR2-selective agonists, corresponding to cognate tethered ligand sequences, cause the release of CGRP and SP from C-fibers in peripheral tissues and in spinal cord.6 Finally, CGRP1 and NK1 receptor antagonists inhibit PAR2 agonist-induced edema. In conclusion, PAR2 agonists mediate neurogenic inflammation via CGRP and SP release and local release of proteinases (eg mast cell tryptase) may result in activation of neuronal PAR2, thereby exacerbating extravasation and edema.
This is a preview of subscription content, access via your institution
