Referencies bibliogràfiques

In general, inflammation is a common local response in injured tissues that helps initiate tissue repair (Watkins et al., 1995). However, inflammatory cascades also have the potential to contribute to persistent pain via the release of various chemicals, among which nerve growth factor (NGF) has a major role (Kras et al., 2014a; McMahon, 1996; Woolf et al., 1997). NGF released during inflammation sensitizes nociceptors and increases the excitability of sensory neurons (Dawes et al., 2013; Woolf et al., 1997). NGF is a member of the neurotrophin family of growth factors that has a major role in the growth, development, and survival of sensory neurons through activation of its high affinity receptor, tyrosine receptor kinase A (trkA) (Pezet and McMahon, 2006). In adulthood, NGF is also capable of sensitizing sensory neurons and contributing to pain through post-translational regulation of ion channels as well as increased expression of many pain-associated genes, such as substance P, CGRP, and BDNF (Dawes et al., 2013; Pezet and McMahon, 2006). NGF levels are increased in injured and inflamed tissues

through release from a number of different types of immune cells, such as macrophages (McMahon, 1996). Increased levels of NGF have profound effects on responses to thermal stimuli, via increased expression and phosphorylation of the heat sensitive transient receptor potential vanilloid 1 (TRPV1), and mechanical sensitivity (Figure 1.4) (Amaya et al., 2004; Dawes et al., 2013; Longo et al., 2013; Sah et al., 2003; Woolf, 1996). Both intradermal and intramuscular injections of NGF in human volunteers elicit decreases in the heat pain threshold as well as increased sensitivity to mechanical stimuli (Dyck et al., 1997; Gerber et al., 2011; Rukwied et al., 2010). Similarly, NGF injection induces both thermal and mechanical pain in the rat (Amann et al., 1995; Malik-Hall et al., 2005; Woolf, 1996). Since NGF levels are increased in inflamed tissue, NGF is considered to be a major contributor to inflammatory pain (Amaya et al., 2004; Ma and Woolf, 1997; McMahon, 1996). Recent studies identify upregulation of inflammatory cytokines and prostaglandin E2 in association with loading-induced facet pain in the rat (Kras et al., 2014a; Lee et al., 2008). Moreover, intra-articular injection of the non- steroidal anti-inflammatory drug ketorolac one day after a painful facet joint injury alleviates behavioral hypersensitivity (Dong et al., 2013a). Those findings support a role for joint inflammation in facet-mediated pain. Because inflammation is necessary for persistent pain following facet joint injury, it is likely that NGF contributes to the development of facet pain.

NGF and its receptor have been identified in arthritic joints and degenerative facet joints (Barthel et al., 2009; Surace et al., 2009). Further, systemic anti-NGF therapy has shown success in alleviating osteoarthritis pain in clinical trials (Brown et al., 2012; Lane et al., 2010), demonstrating a role for NGF in that form of joint pain. Although animal

studies implicate NGF as contributing to arthritis pain (Longo et al., 2013; McNamee et al., 2010; Orita et al., 2011), very little is known about the potential relationship between NGF and loading-induced facet joint pain; in addition, the mechanism(s) through which NGF contributes to joint pain is poorly understood.

In parallel with the overall behavioral effects that are induced by NGF exposure, NGF acts on peptidergic afferents to increase expression of the neuropeptides CGRP and substance P, as well as the neurotrophin BDNF, in the rat (Figure 1.4) (McMahon, 1996; Pezet and McMahon, 2006; Woolf, 1996). Because these proteins are transported to, and released in, the spinal cord where they contribute to the activation and sensitization of second order sensory neurons, NGF has a role in central sensitization despite its not reaching the spinal cord itself (Dawes et al., 2013; McMahon, 1996). In fact, peripheral

Figure 1.4. NGF activation of primary afferent neurons innervating peripheral targets.

NGF binds to trkA receptors expressed on the peripheral terminals of peptidergic Aδ- and C-fiber sensory neurons resulting in increased expression of CGRP, substance P (SP) and BDNF. The C-fibers enter the spinal cord and synapse in the superficial dorsal horn; the Aδ-fibers synapse in both the superficial laminae and deeper laminae.

injection of NGF is associated with increased excitability of spinal neurons (Hoheisel et al., 2007). Despite increased expression of neuropeptides and hyperexcitability of spinal neurons after painful facet joint injury (Crosby et al., 2013; Lee and Winkelstein, 2009; Quinn et al., 2010), no study has determined if NGF contributes to that spinal hyperexcitability or altered protein expression in association with facet-mediated pain.

BDNF expression is regulated by NGF and is a central mediator of pain in nerve injury and inflammation induced chronic pain (Li et al., 2006; Mannion et al., 1999; Merighi et al., 2008; Pezet and McMahon, 2006). Peptidergic neurons produce BDNF and transport it to the superficial dorsal horn in the spinal cord where its release activates tyrosine receptor kinase B (trkB) receptors (Merighi et al., 2008; Pezet and McMahon, 2006). BDNF-trkB signaling contributes to central sensitization by facilitating spinal neurotransmission through a combination of increased neuropeptide release and potentiation of ion channels such as glutamate receptors (Merighi et al., 2008; Pezet and McMahon, 2006). BDNF released in the dorsal horn activates pre-synaptic trkB receptors and induces the release of substance P and CGRP into the synaptic cleft (Merighi et al., 2008). Those neuropeptides, in turn, facilitate neurotransmission via their downstream effects on glutamate receptor activation (Seybold, 2009). Increased spinal BDNF expression and release also activates glutamate receptors in association with pain in both neuropathic and inflammatory injury models (Geng et al., 2010; Matayoshi et al., 2005; Slack et al., 2004). Moreover, the increased expression of the glutamate receptor mGluR5, as well as phosphorylation of the NR1 subunit of NMDA glutamate receptors, in the spinal cord that is induced by painful joint injury demonstrates altered glutamate signaling in facet-mediated pain (Crosby et al., 2014; Dong and Winkelstein, 2010).

Because spinal BDNF induces phosphorylation of NR1 (Slack et al., 2004), BDNF might affect spinal glutamate signaling associated with facet-mediated pain. Pharmacological inhibition of BDNF-trkB signaling alleviates behavioral sensitivity in many experimental neural tissue injury models (Coull et al., 2005; Matayoshi et al., 2005; Zhang et al., 2011), further demonstrating a role for spinal BDNF in persistent pain. Although increased BDNF expression has been identified in the synovial tissue of arthritic joints (Grimsholm et al., 2008), the contribution of BDNF to joint pain, particularly from mechanical injury, has not been investigated.

In addition to sensitizing spinal neurons in association with persistent pain, BDNF can also activate supraspinal targets, including those in the thalamus (Merighi et al., 2008; Millan, 1999). A majority of the STT neurons projecting from the superficial and deep laminae of the dorsal horn are sensitive to BDNF, and increased activity of thalamic neurons is associated with elevated thalamic BDNF expression (Millan, 1999; Slack et al., 2005), which supports the potential for thalamic plasticity in painful conditions via BDNF signaling. Moreover, joint inflammation is associated with thalamic plasticity; arthritic rats exhibit altered gene expression in the thalamus as well as increased excitability of thalamic neurons with joint input (Gautron and Guilbaud, 1982; Millan, 1999; Neto et al., 2008). Despite evidence of joint inflammation and increased excitability of neurons in the dorsal horn in response to painful facet joint injury (Crosby et al., 2013; Dong et al., 2013a; Quinn et al., 2010), thalamic plasticity has not been investigated in facet-mediated pain.