Minett, MS;
(2013)
The role of sensory and sympathetic neurons in distinct pain sensations.
Doctoral thesis , UCL (University College London).
Abstract
Voltage-gated sodium channels are crucial determinants of neuronal excitability. Human genetic mutations show that Nav1.7 is critically important for normal pain processing. Here I show that Nav1.7 expression in different subsets of mouse sensory and sympathetic neurons underlies distinct types of pain sensation. Deleting Nav1.7 in all sensory neurons abolishes mechanical pain, inflammatory pain and reflex withdrawal responses to noxious heat. In contrast, heat-evoked pain is retained when Nav1.7 is deleted specifically in Nav1.8-positive nociceptors. Surprisingly, responses to the hotplate test were unaffected by deleting Nav1.7 in all sensory neurons. However, deleting Nav1.7 in both sensory and sympathetic neurons abolishes these pain sensations and recapitulates the pain-free phenotype seen in humans with Nav1.7 loss-of-function mutations. Previously, Nav1.3, 1.7, 1.8 & 1.9 have all been implicated in neuropathic pain through a plethora of different experimental approaches. Here I show that Nav1.3, 1.7, 1.8 & 1.9 have modality and pathology specific roles. Deleting Nav1.3 or 1.7 in all sensory neurons inhibits both cold and mechanical allodynia specifically following chronic constriction injury. While deleting Nav1.8 or 1.9 only inhibits cold but not mechanical allodynia. Importantly, deleting Nav1.7 in adult mice using AdvillCreERT2 reverses CCI mediated pain, thereby further validating Nav1.7 as a viable analgesic drug target. However, deleting the expression of any of these VGSCs in sensory neurons alone does not attenuate L5 spinal nerve transection induced pain. Instead I show that deleting Nav1.7 expression in sympathetic neurons inhibits SNT pain, as well as sympathetic sprouting into the DRG. Surprisingly, pain induced by the chemotherapeutic agent oxaliplatin does not require the presence of Nav1.7, or the ‘classical’ Nav1.8-positive nociceptors. This demonstrates that identical behavioural outcomes in different neuropathic pain models involve distinct molecular and physiological mechanisms. Rational analgesic drug therapy therefore requires patient stratification in terms of mechanisms, not just phenotype.
| Type: | Thesis (Doctoral) |
|---|---|
| Title: | The role of sensory and sympathetic neurons in distinct pain sensations |
| Language: | English |
| UCL classification: | UCL > Provost and Vice Provost Offices UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Wolfson Inst for Biomedical Research |
| URI: | https://discovery.ucl.ac.uk/id/eprint/1421016 |
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