The effective treatment of chronic pain remains one of the major global health challenges of the 21 st century. Current treatment therapies available include the non-steroidal anti-inflammatory drugs (NSAIDS) e.g. ibuprofen and also opioid based compounds such as morphine sulphate (MST). These drugs have been very useful especially in treating post- operative acute pain states and pain associated with joint diseases such as osteoarthritis. Unfortunately, the long- term use of these drugs has been hampered by the reported unwanted physical side effects such as cardiovascular problems and gastrointestinal disorders, as well as the development of tolerance and addiction, which has made them very unattractive for the treatment of many chronic pain states. Thus, the need to identify new therapeutic targets and substrates for the treatment of chronic pain has become a major goal for pain scientists all over the world. The N-acylethanolamines (NAEs) are endogenous bioactive lipid compounds known to mediate a number of physiological effects including, but not limited to analgesia, through their interactions with a number of receptor systems, notably the inhibitory G-protein coupled cannabinoid receptors and the nuclear receptor peroxisome proliferator activated receptor (PPARα). Elevation in the physiological levels of these compounds, for example anandamide (AEA) and palmitoylethanolamide (PEA) have been shown to produce analgesic effects in animal models of both inflammatory and neuropathic pain, although the cellular and molecular mechanisms involved are not well understood. The physiological levels of NAEs are under tight regulation by hydrolytic enzymes such as fatty acid amide hydrolase (FAAH); as a result, their physiological effects are rather short-lived. Pharmacological inhibition of FAAH using selective inhibitors such as the carbamate compound, URB597, is emerging as a useful approach for overcoming this problem. Previous work in our group comparing the analgesic effects of acute and repeated pharmacological inhibition of F AAH using URB597 has shown that, acute rather than repeated inhibition of F AAH was effective in attenuating inflammatory pain behaviour. Furthermore, the magnitude of elevation in NAE levels was greater following acute treatment with URB597 compared with repeated treatment. These findings suggest that, compounds that target F AAH for the treatment of pain may not be very effective when give repeatedly, as would be the case when treating chronic pain states. The aim of this thesis is to understand the cellular and molecular mechanisms underlying the analgesic effects of NAEs, and also to identify molecular changes associated with both acute and repeated FAAH inhibition which may account for the difference in analgesic effects previously reported. Data presented here suggest that this difference in analgesic effects is not just down to changes in the EC system since both acute and repeated inhibition of F AAH were associated with changes in N APE-PLD (N AE synthetic enzyme) protein expression, but also the ability of the treatment to modulate components of the inflammatory signalling cascade. Thus, I demonstrate here for the first time, that a mechanism underlying the analgesic effects of NAEs involves suppression of the induction of the pronociceptive cyclooxygenase (COX)-2 enzyme, possibly via the activation of the cannabinoid and/or PPARα receptor systems, in the carrageenan model of inflammatory pain. The modulation of COX-2 induction by the PPARα system was further demonstrated by local administration of the endogenous PPARα ligand, PEA into the hindpaw, which suppressed carrageenan-induced COX-2 protein expression as well as protein expression of inducible nitric oxide synthase (iNOS), which also plays a role in the development of inflammatory hyperalgesia. The role of PPARα (a receptor target for some NAEs), as a potential therapeutic target for the treatment of chronic pain states such as neuropathic pain was studied in the rat spinal nerve ligation (SNL) model of neuropathic pain. Systemic administration of the synthetic PPARα ligand, WYI4643, was associated with a rapid decrease in neuronal responses in SNL, but not sham-operated, rats. Taken together these findings suggest that targeted modulation of NAEs could provide a means of activating multiple receptor systems, and consequently offers a unique therapeutic window of opportunity to develop broad-spectrum and robust analgesic drugs that could be used to effectively treat chronic pain.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:580177 |
| Date | January 2012 |
| Creators | Okine, Bright Nii |
| Publisher | University of Nottingham |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
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