Undergraduate Honors Thesis

 

Toll-like 2 and 4 Receptor Antagonism Reverses Neuropathic Pain and Associated Spinal inflammation in Male and Female Dark Agouti Rats in a Model of Multiple Sclerosis Public Deposited

https://scholar.colorado.edu/concern/undergraduate_honors_theses/70795816m
Abstract
  • More than 92% of patients with multiple sclerosis (MS) report frequent and disabling neuropathic pain. In MS, neuropathic pain develops after demyelination, neuroinflammation, and damage to axons in the central nervous system. Although several treatments for MS-related neuropathic pain exist, many patients’ symptoms are refractory to current treatments. Recent research has provided evidence that toll like receptors 2 and 4 (TLR2/TLR4) are implicated in propagating the inflammatory response, raising the potential of TLR2/TLR4 importance in inflammatory conditions such as MS. Moreover, previous research in our lab has shown that TLR2/TLR4 antagonists are effective at reversing neuropathic pain in various rodent models involving peripheral nerve injury. In this study we thus investigated the effects of the non-opioid TLR2/TLR4 antagonist, (+)-naltrexone ((+)-NTX), on mechanical allodynia and transcription levels of spinal TLR2/TLR4-related inflammatory markers (i.e., TLR2/TLR4, nod-like receptor protein 3 (NLRP3) inflammasome, interleukin-1β (IL-1β), Tumor Necrosis Factor (TNF), and NF-kappa-B inhibitor alpha (IκBα)), as well as the Th17 cell signalling molecule, Interleukin-17 (IL-17), using experimental autoimmune encephalomyelitis (EAE), a model of MS and its associated central neuropathic pain. Male and female Dark Agouti rats were induced with EAE and 14 days later began 14 days consecutive treatment with subcutaneous (+)-NTX or saline. (+)-NTX treatment successfully reversed neuropathic pain in both male and female rats compared to the rats receiving saline treatment. Moreover, (+)-naltrexone treatment resulted in significantly lower inflammatory mRNA markers (i.e., TLR2/TLR4, NLRP3, IL-1β, TNF, IκBα, and IL-17) in the spinal cord, relative to the saline-treated animals. XT-203, another TLR2/TLR4 antagonist, reproduced behaviour results, and also reversed mechanical allodynia in male rats. Lastly, administration of intrathecal interleukin-1 receptor antagonist (IL-1ra) on day 15 and 29 post EAE induction demonstrated that ongoing spinal IL-1β signalling is necessary for EAE-induced mechanical allodynia, both early and late in disease development. Collectively, our findings provide the first evidence supporting TLR2/TLR4 and intrathecal IL-1β antagonism as effective interventions against EAE related chronic neuropathic pain in both males and/or females and suggests decreased spinal IL-1β and other related inflammatory signals may be important mechanisms by which (+)-naltrexone exerts its therapeutic effects.
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  • 2019-01-01
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  • 2019-12-02
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