Neurotrophic Factors and Nociceptor Sensitization

NGF is the most commonly studied growth factor in relation to nociceptor sensitization and serves to promote the survival of DRG neurons during development that express its receptor, trkA (Averill et al. 1995; Huang et al. 2001; Patapoutian and Reichardt 2001). These neurons are generally part of the small and medium diameter DRG population, but some larger cells also express trkA (Wright and Snider 1995; Patapoutian and Reichardt 2001). In addition to its role in development and neuronal survival, it promotes sprouting and regulates innervation density of NGF-responsive neurons in peripheral targets in early post-natal and adult life. For example, it has been shown that ligation of a peripheral nerve induces NGF expression in its target area and these elevated levels are associated with sprouting of adjacent, non-injured afferents into the denervated region (Pertens et al. 1999). Other studies analyzing constitutive overexpression of NGF in the skin (NGF-OEs) report enhanced innervation of the epidermis by both sensory and sympathetic neurons (Albers et al. 1994; Davis et al. 1994, 1996; Goodness et al. 1997). Although NGF appears to be necessary and beneficial for development and maintenance of the peripheral sensory neuron system (Diamond et al. 1992), it has also been shown to participate in the development of thermal and mechanical hyperalgesia (i.e., increased pain in response to normally painful stimuli; Malin et al. 2006; Pertens et al. 1999; Andreev et al. 1995; Lewin et al. 1993) and pain in disorders such as bone cancer and interstitial cystitis (Lowe et al. 1997; Sevcik et al. 2005). Rats chronically treated with NGF are hypersensitive to both mechanical and radiant heat stimulation (Lewin et al. 1993; Andreev et al. 1995; Pertens et al. 1999) in a dose-dependent fashion, and injection of NGF directly into the paw of mice induces a decrease in the paw withdrawal latency to radiant heat (Malin et al. 2006). This NGF sensitization is partially dependent on sympathetic neurons, as sympathectomy partly reduces the effect of NGF in causing hyperalgesia (Andreev et al. 1995). NGF also acts indirectly by activating mast cells and neutrophils, which in turn release additional inflammatory mediators causing hypersensitivity (Lewin et al. 1994; Andreev et al. 1995; Amann et al. 1996; Woolf et al. 1996; Bennett et al. 1998; Bennett 2001). Regardless, it is clear that NGF levels in the target tissue participate in sensitization of nociceptors. For example, NGF-OEs display increases in afferent responses to thermal and mechanical stimulation in a skin-nerve preparation. Stucky and Lewin (1999) found that large diameter Aβ non-nociceptive afferents (typically trkA negative) were unaffected by NGF overexpression, but thermal responsiveness was significantly increased in nociceptive afferents as a result of enhanced cutaneous NGF levels. NGF-sensitive, trkA positive neurons co-label with a variety of other molecules thought to be involved in pain processing. trkA overlaps with neurons containing peptides CGRP and SP (Averill et al. 1995; Molliver and Snider 1997), known mediators of pain behaviors (Koltzenburg et al. 1999; Reeh and Kress 2001; Li et al. 2008) shown to induce hyperalgesia (Oku et al. 1987; Nakamura-Craig and Gill 1991; McMahon, 1996; Sann and Pierau 1998). This population also co-labels with TRPV1, crucial for the development of heat hyperalgesia (Caterina et al. 2000). NGF-induced hyperalgesia may also be mediated by sodium channel, Nav1.8. In mice lacking this channel, NGF does not induce heat hyperalgesia (Kerr et al. 2001), although Nav1.8 knockout mice display indistinguishable thermal thresholds under normal conditions compared to wildtypes (WTs). Since many NGF-responsive neurons contain TRPV1, this channel is suspected of a role in NGF-mediated hypersensitivity (Caterina et al. 1997; Tominaga et al. 1998; Michael and Priestley 1999). Cultured DRG neurons treated with NGF display enhanced inward current in response to application of the TRPV1 agonist capsaicin (Shu and Mendell 1999; Caterina et al. 2000; Zhu et al. 2004). NGF can increase TRPV1 expression (Donnerer et al. 2005; Xue et al. 2007) and promote TRPV1 insertion into the plasma membrane (Zhang et al. 2005). Furthermore, anti-NGF antibodies injected into the hindpaw after peripheral inflammation decrease levels of TRPV1 in DRGs and reduce inflammation-induced hyperalgesia (Ji et al. 2002; Cheng and Ji 2008). Given a clear role for NGF in sensory neuron sensitization and hyperalgesia, anti-NGF treatments may constitute an effective means of treating pain in humans (Anand et al. 1997; Lowe et al. 1997; Saldanha et al. 1999; Sena et al. 2006; Jimenez-Andrade et al. 2007). These hypotheses, however, have not been extensively studied (Abdiche et al. 2008) or verified. Perhaps NGF may only affect a small proportion of nociceptors in the DRG, and other molecules and neurotrophic factors most certainly are involved in hyperalgesia and overall sensory neuron sensitization.