Neuropathic components of CLBP
CLBP is characterized in many cases by a combination of inflammatory and neuropathic mechanisms (Baron 2009) (see also Chapter 25). This may be a salient reason for the difficulties of finding effective pharmaco-therapies for this kind of chronic pain (see Chapter 25). Neuropathic alterations can be due to mechanical forces, i.e. chronic pressure on nerve roots, but chemical mediators are probably more important, e.g. by the action of the material from disc hernia on the conductile axons. However, also in the absence of a ruptured nucleus pulposus inflammatory cytokines, in particular TNFa released from macrophages, can induce ectopic spike activity from injured and also from uninjured nerve fibres (Sommer 2003; Sorkin et al. 1998). Interestingly, macrophages may accumulate in DRG even when the nerve lesion is located at a distance (Lu et al. 1993).
While chronic inflammatory pain is due to alterations of the transduction and transformation process at the nociceptor terminals, neuropathic changes occur along the conductile membrane of the axons. Several animal models of neuropathic pain have been developed and the results have been described in recent comprehensive reviews (Decosterd and Woolf 2000; Woolf and Salter 2000; Decosterd and Berta 2009; Ossipov and Porreca 2009). In the context of this chapter models of mononeuropathies are most important including loose ligature of a nerve (Bennett and Xie 1988) and partial nerve transection (Decosterd and Woolf 2000).
A large number of cellular changes are the consequence of sustained alterations of the conductile axonal membrane. Partial nerve injury leads to increased levels of messenger RNA for membrane receptors and channels. In particular, sodium channels NaV 1.8 and 1.9 are accumulated at the site of a nerve lesion, and in addition an embryonic channel NaV 1.3 can be expressed (Wood et al. 2004; Omana-Zapata et al. 2005. This can lead to ectopic action potentials. Not only at the lesion site, but also in the cell bodies in the DRG channel expressions are changed. Even more important, altered channel expressions are also found in unaffected neurons. After traumatic nerve injury, redistribution of NaV 1.8 to the axons of uninjured neighbouring nociceptors plays a major role in mechanical hypersensitivity (Amir et al. 2006). The expression of TRPV1 channels at the nerve terminals distal to the lesion site is downregulated after partial nerve lesion but novel expression of TRPV1 in uninjured neighbouring axons has been observed even in myelinated afferents and their ganglion cells (Hudson et al. 2001; Ma et al. 2005). Also receptors which are normally not expressed in primary afferent nociceptive neurons may be produced in spared axons and cell bodies. After a traumatic lesion of a nerve or root, for example, cold sensing TRPM8 (transient receptor potential cation channel, subfamily M, member 8) channels (Obata et al 2005) and alpha adrenoreceptors (Sato and Perl 1991) are expressed in the terminal membrane. There is evidence that the impaired capacity of lesioned axons to take neurotrophins up (e.g. NGF) which are produced in the tissue surrounding the nociceptor terminals leads to ‘overfeeding’ of spared axons. Since these neurotrophins are taken up by their endings and transported to the cell bodies in the DRG, they can alter the genetic programming in the nucleus leading to the production of increased amounts of mRNA and even altered mRNA fostering the production of signal proteins and their transport to the nerve terminals (Wu et al. 2001).
