Abdalla, Rayan Haroun Mohammed; (2023) Exploring potential analgesic targets and tools for chronic pain treatment. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

This thesis investigated two main topics. The first was the preclinical evaluation of various analgesic modalities for cancer-induced bone pain (CIBP). The second involved the potential application of chemogenetic tools for pain research. I optimised and used an in vivo model of CIBP involving the injection of Lewis Lung Carcinoma cells into the intramedullary space of the femur of C57BL/6 mice or transgenic mice with C57BL/6 background. In this model, mice gradually reduce the use of the affected limb resulting in altered weight bearing. Symptoms of secondary cutaneous cold, heat, and mechanical sensitivity also manifest. Three potential analgesic modalities were assessed, which can be divided into three categories; targeting the NaV1.7 voltage-gated Na+ channel, targeting neuronal subsets (namely the µ-opioid receptor-expressing neurons and the sensory neurons that express NaV1.8 channels), and finally, the dual targeting of two of the tumour-derived products (nerve growth factor (NGF) and tumour necrosis factor (TNF)). Results from these experiments indicated the congenital deletion or chemogenetic-based silencing of the NaV1.8 expressing neurons reduced pain-like behaviour associated with CIBP. Moreover, dual inhibition of NGF and TNF resulted in an impressive reduction in CIBP-driven weight-bearing and prevented the development of secondary cutaneous heat hyperalgesia. The second half of this work focused on modified ligand-gated ion channels, namely PSAM4-GlyR and PSAM4-5HT3. This work showed that expressing PSAM4-GlyR in dorsal root ganglia (DRG) neurons and agonism with varenicline silences DRG neurons and elevates the withdrawal thresholds of mice in various sensory tests. Additionally, PSAM4-GlyR activation in the NaV1.8+ neurons reversed signs of mechanical, thermal, and cold sensitivity associated with neuropathic pain. Moreover, chemogenetic-based activation of specific neurons in the central amygdala was shown to increase pain thresholds. These techniques will be useful for studies investigating the effects of manipulating neuronal subsets.

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