Axonal sprouting

Anatomical and electrophysiological studies (reviewed in Hefti, 1997) provide support for the hypothesis that axonal branching exists in cervical and lumbar dorsal root ganglia (DRGs) of the cat or the rat. Moreover, injury-induced sprouting of A-, C- or sympathetic fibers has been suggested to be responsible for the generation of intractable pain at the level of the peripheral nociceptor or within affected DRGs (Ramer et al., 1999). Since neuropathic pain is often exacerbated by increased activity of the sympathetic nervous system, the coupling of sympathetic and sensory axons may play an important role in the development of neuropathic pain. It is now well established that sympathetic fibers form abnormal terminal arborizations (baskets) around DRG neurons after axotomy, and the molecules involved in this sprouting response are currently being identified.

The neurotrophins nerve growth factor (NGF) and brain derived neurotrophic factor play a major role in facial nerve (Streppel et al., 2002) and sympathetic sprouting (Ramer et al., 1999), because treatment with neutralizing antibodies significantly reduces collateral branching of facial axons and basket formation in DRGs. In addition to the neurotrophins, the cytokines LIF and IL-6 enhance axonal sprouting in lesioned ganglia (Thompson and Majithia, 1998) possibly via up-regulation of the neuropeptides galanin or PACAP/VIP. Recently, we identified the neuropeptides galanin and PACAP38, which are utilized as modulators of synaptic transmission under normal conditions (for review see Klimaschewski et al., 1996b), as potent inducers of peripheral axon sprouting in both, motor and sensory neurons, after axotomy (Suarez et al., 2006). Treatment of DRG neurons with either peptide increases the number of axonal branch points in vitro and application of galanin or PACAP38 to the transected facial nerve dramatically elevates the number of facial neurons with axon collaterals in different branches. Functional analysis revealed that the peptides negatively affect the re-innervation of the whisker pad.

We speculate that endogenous galanin or PACAP38 are released from axotomized neurons and directly activate intracellular signaling pathways involved in collateral axon branching. Confirming the assumption that axon collateralization is induced in axotomized DRG neurons Tsuyoshi et al. (2006) by retrograde labeling revealed axonal sprouting from the vicinity of the neuronal perikaryon in response to peripheral nerve transection. Since the above mentioned cytokines and neuropeptides are only slightly induced after nerve root injury, the sprouting response may be considerably less prominent following this type of lesion. We are investigating this hypothesis by reconstructing the course of myelinated axons through the L5 DRG at the highest microscopical magnification.