Mechanisms by which lipid derivatives and proteinases signal to primary sensory neurons: Implications for inflammation and pain

Certain primary sensory neurons which express the neuropeptides calcitonin gene-related peptide and substance P play important roles in the central transmission of painful stimuli and in inflammation of peripheral tissues. Thermal, chemical and high-threshold mechanical stimuli generate action potentials which induce the release of neuropeptides within the central nervous system, resulting in the transmission of nociceptive signals. These stimuli can also release neuropeptides from peripheral endings of these neurons to initiate neurogenic inflammation that is characterized by arteriolar vasodilatation, extravasation of plasma proteins from gaps between endothelial cells of post-capillary venules, and adhesion of leukocytes to the vascular endothelium. An understanding of the molecular mechanisms of nociception and inflammation is important since primary sensory neurons mediate the pain and inflammation of many diseases, including arthritis, migraine, asthma, and inflammatory diseases of the gastrointestinal tract. Recent progress has been made in the identification of novel membrane proteins on primary sensory neurons that permit them to sense diverse agents and to thereby mediate the central transmission of pain and neurogenic inflammation of peripheral tissues. These membrane proteins include ion channels, G-protein coupled receptors and tyrosine kinase receptors that allow neurons to respond to diverse ligands ranging from protons to lipids and proteinases. This chapter reviews two types of receptor on sensory neurons, vanilloid receptors (VRs) and proteinase-activated receptors (PARs) which play emerging roles in pain and inflammation. VR1 is a non-selective cation channel that responds to vanilloids, such as capsaicin, heat, protons and certain lipid derivatives. PARs are Gprotein coupled receptors that respond to serine proteases derived from the circulation or from pro-inflammatory cells. Although VR1 and PARs are structurally distinct receptors that detect markedly different agonists, there is convergence of function in that agonists of both receptors can release neuropeptides from sensory nerve fibres within the spinal cord and peripheral tissues to induce hyperalgesia and neurogenic inflammation. The identification and characterization of novel membrane proteins on the peripheral and central projections of primary sensory neurons has provided new insights into the regulation of the nervous system, which will have important implications for our understanding and treatment of disease.