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dc.contributor.authorAlrashdi, Ibrahim Awadh H-
dc.descriptionPhD Thesisen_US
dc.description.abstractThe histaminergic system is an interesting target for the development of new antipruritic and analgesic medications as all four histamine receptors (H1R - H4R) are expressed in regions concerned with itch and pain transmission. Recent advances in itch and pain research have elucidated the potential role of histamine and its receptors in the initiation and maintenance of both conditions. This fast-emerging knowledge about the role of histamine system in a variety of physiological and pathological processes led to the hypothesis that blocking histamine action may have beneficial therapeutic approaches in wide range of pathological conditions, including acute itch (pruritis) and chronic neuropathic pain. Both neuropathic pain resulting from nerve damage as well as itch where histamine has been a well-known mediator have limited therapeutic strategies due to incomplete understanding of the mechanisms underlying these major clinical problems. Both conditions seem to have a significant negative impact on healthrelated quality of life and daily functioning, including physical, emotional and social well-being. Pharmacological management remains the most common therapeutic option for both itch and chronic neuropathic pain, but therapeutic outcomes are still poorly achieved. Moreover, systemic therapy is commonly associated with side effects that can also lead to medication safety issues and discontinuation of treatment. Therefore, more effective, and safer treatments for itch and chronic pain are urgently needed. Indeed, local peripheral administration of medications can be a viable alternative to systemic delivery with a lower rate of systemic side effects, reduced interactions with other systematically acting substances, and allow direct targeting of the affected area/s. In line with this therapeutic strategy, peripheral targeting of the histamine system has provided interesting tools for further investigation of the role of histamine and its receptors in itch and chronic pain. Therefore, here I hypothesized that scavenging of peripherally released endogenous histamine or selective blocking of specific type of histamine receptor result in both anti-itch and anti-nociceptive effects. To test this hypothesis, adult male mice were subjected to histaminergic itch, as well as peripheral nerve injury that resulted in neuropathic pain. I investigated the role of peripheral histamine receptors (HRs) and evaluated the anti-pruritic and anti-nociceptive efficacy of two novel ligands targeting the peripheral histamine system. Specifically, I worked with Votucalis (rEV-131) that is a novel centrally sparing highly affinity histamine scavenger protein as well as PF0868087 that is a selective and peripherally-acting / centrally-sparing H3R antagonist. The uniqueness of these novel ligands lies in their chemical structure that restricts penetration to the central nervous system. Thus, these drugs have been ideal candidates to test our hypothesis and to validate peripheral HRs as a potential target for therapeutic intervention in both acute itch and neuropathic pain. Using behavioural in vivo models of acute itch and neuropathic pain, I showed for the first time that both Votucalis and PF-0868087 had a significant effect on attenuating acute itch induced in mice by injection of compound 48/80 ( is N-methyl-pmethoxyphenethylamine and formaldehyde used to induce mast cell degranulation and histamine release), and peripheral neuropathy induced by chronic constriction injury (CCI) of the sciatic nerve, respectively. Based on the mechanisms of nerve injury-induced hypersensitivity it is possible that PF-0868087 and Votucalis targeted peripheral histamine receptors expressed on subpopulation of A-delta. In addition, I investigated the role of peripheral histamine receptors in acute itch using photoswitchable ligands to control pharmacological activity using a specific wavelength of light. For the first time, I used VUF-16129 a photo-switchable compound which can be reversibly switched via light between two isomers (trans-cis) corresponding to high and low pharmacological activity showing the importance of H4R in the regulation of histaminergic itch. Taken together, our findings further emphasize the key role for histamine system in the regulation of itch and chronic pain. Importantly, I provide the first evidence that peripheral targeting of the histaminergic system either by scavenging of histamine or blocking the specific type of receptors support the importance of the histamine system in the modulation of peripheral itch and neuropathies and represent a novel therapeutic strategy in the treatment of both conditionsen_US
dc.description.sponsorshipSaudi Arabian culture bureau ministry of interioren_US
dc.publisherNewcastle Universityen_US
dc.titleValidating the peripheral histamine system for therapeutic interventions in pre-clinical in vivo models of acute itch and chronic neuropathic painen_US
Appears in Collections:Translational and Clinical Research Institute

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