Investigating the Contribution of the Inflammasome to Persistent Pain States
type: CreativeWork
description: Neuropathic pain, a debilitating condition, occurs as a consequence of nerve injury with symptoms such as spontaneous pain, hyperalgesia, and allodynia commonly reported. In animal models of peripheral nerve injury, there is accumulation and proliferation of microglial cells in the injured spinal cord and macrophages within the injured nerve and dorsal root ganglion (DRG), contributing to the development of pain-like behaviours. The pro-inflammatory cytokine interleukin-1β (IL-1β) plays a key role in acute and chronic inflammation. It causes potent mechanical and thermal hyperalgesia when injected into peripheral tissues, and increased expression of IL-1β in the spinal cord, DRG, and injured nerve is seen in several animal models of inflammatory and neuropathic pain. A key step in the release of active IL-1β is the cleavage of pro-IL-1β by active caspase-1, generating mature IL-1β. Activation of this enzyme requires assembly of the inflammasome, a multi-protein complex. The active complex contains a central scaffold protein (eg nod-like receptor-1 (NLRP1), NLRP3), the adaptor protein apoptosis-associated speck-like protein containing a CARD (ASC), and pro-caspase-1. It is known to assemble in response to a variety of exogenous and endogenous danger signals (eg adenosine-5’-triphosphate (ATP), monosodium urate (MSU) crystals). Data presented in this thesis demonstrates that, following L5 Spinal Nerve Transection (SNT), an animal model of neuropathic pain, inflammasome components NLRP3, ASC, and caspase-1 are upregulated in the injured DRG and the ipsilateral lumbar dorsal horn. Immunohistochemical analysis reveals that ASC and caspase-1 are both highly co-localised with macrophage and microglial marker ionised calcium-binding adaptor molecule-1 (IBA1), but not with astrocytic marker glial fibrillary acid protein (GFAP) or neuronal marker NeuN. While daily intrathecal administration of Ac-YVAD-CMK, a cell-permeant caspase-1 inhibitor, significantly attenuated establis…
abstract: Neuropathic pain, a debilitating condition, occurs as a consequence of nerve injury with symptoms such as spontaneous pain, hyperalgesia, and allodynia commonly reported. In animal models of peripheral nerve injury, there is accumulation and proliferation of microglial cells in the injured spinal cord and macrophages within the injured nerve and dorsal root ganglion (DRG), contributing to the development of pain-like behaviours. The pro-inflammatory cytokine interleukin-1β (IL-1β) plays a key role in acute and chronic inflammation. It causes potent mechanical and thermal hyperalgesia when injected into peripheral tissues, and increased expression of IL-1β in the spinal cord, DRG, and injured nerve is seen in several animal models of inflammatory and neuropathic pain. A key step in the release of active IL-1β is the cleavage of pro-IL-1β by active caspase-1, generating mature IL-1β. Activation of this enzyme requires assembly of the inflammasome, a multi-protein complex. The active complex contains a central scaffold protein (eg nod-like receptor-1 (NLRP1), NLRP3), the adaptor protein apoptosis-associated speck-like protein containing a CARD (ASC), and pro-caspase-1. It is known to assemble in response to a variety of exogenous and endogenous danger signals (eg adenosine-5’-triphosphate (ATP), monosodium urate (MSU) crystals). Data presented in this thesis demonstrates that, following L5 Spinal Nerve Transection (SNT), an animal model of neuropathic pain, inflammasome components NLRP3, ASC, and caspase-1 are upregulated in the injured DRG and the ipsilateral lumbar dorsal horn. Immunohistochemical analysis reveals that ASC and caspase-1 are both highly co-localised with macrophage and microglial marker ionised calcium-binding adaptor molecule-1 (IBA1), but not with astrocytic marker glial fibrillary acid protein (GFAP) or neuronal marker NeuN. While daily intrathecal administration of Ac-YVAD-CMK, a cell-permeant caspase-1 inhibitor, significantly attenuated establis…
author: Ellis, Amanda
language: eng
date published: 2013-7-1
date modified: 2026-07-24T02:44:37Z
provider: King's College London
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: King's College London