Mannion, Richard John; (1999) The survival and growth of sensory neurons following peripheral nerve injury. Doctoral thesis (Ph.D), UCL (University College London).

Text The_survival_and_growth_of_sen.pdf Download (13MB)

Abstract

Primary sensory neurons are a heterogeneous population of cells, designed to inform the central nervous system about distinct stimuli in the periphery. The ability of these neurons to transduce information is a product of their specific phenotypes. The dissociation of sensory neurons from their targets following nerve injury leads to dramatic changes in their chemical phenotype. The regeneration of sensory neurons back to their original targets, while restoring many facets of normal afferent function, is often functionally incomplete and can be associated with many unwanted consequences, such as the generation of neuropathic pain. One consequence of primary sensory neuron injury considered to be maladaptive is the sprouting of low threshold mechanoreceptive Aβ-fibres into lamina II of the spinal cord dorsal horn, a region that under normal circumstances only receives input from nociceptive C-fibres. If dorsal horn neurons that normally receive nociceptive input from C-fibres begin to receive non-nociceptive A-fibre input after nerve injury, it is possible that this novel input concerning innocuous stimuli is misinterpreted as noxious and may represent a substrate for the mechanical allodynia that commonly occurs after nerve injury. The first half of my thesis has focussed on determining the possible mechanisms by which A-fibres can sprout into lamina II, showing that injury to the peripheral axons of A-fibres is not necessary - uninjured sciatic nerve A-fibres demonstrate central sprouting, after both selective sciatic C-fibre injury using the C-fibre specific neurotoxin capsaicin, or following the complete section of an adjacent hindlimb nerve, the posterior cutaneous nerve. A-fibre sprouting is therefore a robust and long lasting example of intact sensory neuron axonal growth in the central nervous system. Many examples of phenotypic changes occurring in sensory neurons after peripheral nerve injury have been documented, but it is likely that some of the key events that occur, such as axonal regeneration, cell survival or death, are mediated by molecules that have not yet been studied in primary afferents. The recent development of molecular biological techniques, such as differential display and subtractive hybridisation, have greatly facilitated the discovery of such molecules. We have developed a subtraction approach aimed at finding molecules upregulated in the DRG after nerve injury. One of the first discoveries was the heat small shock protein HSP27. While this molecule has been well characterised in many other cell populations, its role has never been examined in primary sensory neurons. It is now shown that the expression of HSP27 after nerve injury in vivo and neurotrophic factor withdrawal in vitro, is associated with neuronal survival. Furthermore, the overexpression of human HSP27 in dissociated neonatal sensory neurons dramatically reduces cell death in the absence of neurotrophins, suggesting that HSP27 is an intrinsic sensory neuron survival factor. The final part of my PhD has been to characterise the expression of a novel sodium channel α subunit, SNS2, that was cloned from a DRG cDNA library using a PCR generated pan-specific sodium channel probe. Small diameter sensory neurons, the majority of which are nociceptors, display two types of voltage gated sodium channel (VGSC), those responsible for a very fast current involved in action potential initiation and propagation and sensitive to the puffer fish poison tetrodotoxin (TTX-s), and those that mediate a much slower, TTX resistant (TTX-r) current that is implicated in chronic pain states. The TTX-s current is mediated by a host of VGSCs whereas the TTX-r current has previously been thought to be the product of only one type of channel, SNS/PN3. We now show that another TTX-r sodium channel, SNS2 is co-expressed with SNS in small sensory neurons, and is likely to contribute to the endogenous TTX-r current and may play a role in certain pathological pain states.

Download activity - last month

Export as XMLCSVJSON

Download activity - last 12 months

Export as XMLCSVJSON

Downloads by country - last 12 months

Export as JSONXMLCSV

Archive Staff Only

View Item