Pain is a complex experience that not only involves transduction of noxious stimuli, but also emotional and cognitive processing by the brain. In order to avoid painful and potentially harmful stimuli, our bodies instigate coordinated and elaborate responses (Snider and McMahon, 1998). Primary sensory neurons detect pain-producing stimuli in a process called nociception. Nociceptors, excited by different modes of stimuli such as mechanical, thermal, conductive, chemical, and radiant for example, are the mediators of these protective reflexes.
These nociceptors differ from other neurons due to the fact that they have appropriately tuned receptive properties, where they detect stimuli such as noxious heat, intense pressure, or irritant chemicals, but not innocuous stimuli such as light touch or warming (Julius and Basbaum, 2001). Unmyelinated, slowly conducting C Fibers and thinly myelinated, more rapidly conducting A? fibers establish the pain response.C fiber nociceptors are the ones sensitive to noxious chemical stimuli such as capsaicin, the ingredient in hot chili peppers, which gives a burning sensation when eaten; this involves the receptor that is the focus of this paper (Tominaga and Julius, 2000). Nociceptors have a large repertoire of transduction devices in order to detect a wide range of stimulus modalities. Figure 1.
1 shows that different stimuli can activate the TRPV1 receptor; it also illustrates the redundancy of nociception, where a single stimulus can interact with multiple detectors at the same time, such as TRPV1 and ASIC’s (acid sensing ion channels).Fig. 1. 1. This diagram shows how TRPV1 (the light blue ion channel) is activated by various different stimuli and also illustrates the redundancy ion pain sensation showing that ASIC’s (the red ion channel) also respond to pH (Julius and Basbaum, 1998). Nociceptors not only signal acute pain, but also contribute to persistent pathological pain conditions such as rheumatoid arthritis (Julius and Basbaum, 1998). This can occur due to increased responsiveness of pain neurons or because of lowered activation thresholds of nociceptors, which for example occurs in TRPV1 when protons lower the heat activation threshold.Figure 1.
2 shows how, when exposed to products of injury and inflammation, a variety of intracellular signaling pathways alter the sensitivity of the TRPV1 receptor (named VR1 in the diagram). For example, protons and lipid metabolites such as anandamide (AEA) released during tissue acidosis potentate VR1 activation by heat, and NGF and bradykinin bind to cell surface receptors stimulating phospholipase C signaling pathways, which are also known to enhance nociceptor excitability (Julius and Basbaum, 2001). Fig.
1. 2.Diagram illustrating the many different pathways that contribute to the activation of TRPV1 (named VR1 in the diagram) (Julius and Basbaum, 1998).
Nociceptors add to the ‘inflammatory soup’ by releasing peptides, such as substance P, calcitonin gene-related peptide (CGRP) and neurotransmitters when activated, which consequently promote other non-neuronal and vascular tissues to release additional factors such as ATP and protons from damaged tissue, serotonin and prostaglandins released from mast cells, and cytokines and NGF (nerve growth factor) from macrophages (Richardson and Vasco, 2002).This is a phenomenon known as neurogenic inflammation as illustrated in Figure 1. 3. TRPV1 is a key mediator in this process because relatively high levels of CGRP are released by TRPV1 in response to acid (pH 6. 1 – 5. 2) and in experiments done by Reeh et al.
, this response is completely abolished in TRPV1 null mice (Costigan and Woolf, 2000). Fig. 1. 3. This diagram illustrates the ‘inflammatory soup’ that occurs from different substances released from sensory neurons and the subsequent pro-inflammatory mediators that result (Richardson and Vasco, 2002).In contrast to vision, olfaction, or taste, sensory nerve endings that detect painful stimuli are dispersed throughout the body, making the biochemical analysis of these nociceptors even more challenging.
However, combined methods such as electrophysiological testing and pharmacological techniques are constantly teaching us new things about the molecular basis of the pain-signaling pathway.These pathways will be of academic and clinical interest because the treatment of pain remains such a needed and unmet medical need in our ageing society (Snider and McMahon, 1998). Patients for TRPV1 antagonists will have a wide range of diseases such as chronic pain, headache, bladder disorders, irritable bowel syndrome (IBS), gastro-esophageal reflux disease (GORD), and cough among others (Hicks, 2006).