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Paton, Kenneth (2015) Role of the GPR55 receptor in the modulation of joint afferent mechanosensitivity. PhD thesis, University of Nottingham.

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Abstract

Deep somatic pain originating from synovial joints is a major clinical problem as it is the primary reason for loss of joint mobility and function in musculoskeletal disorders. Musculoskeletal disorders, including osteoarthritis (OA), are the most prevalent cause of disability worldwide with an estimated 1 in 3 adults affected. Current therapies for the treatment of joint pain have limited effectiveness and certain drugs produce unwanted side effects, preventing their long-term use. Targeting pain at the level of the joint may have the potential to maximise treatment efficacy, whilst reducing possible non- specific side effects associated with systemic drug treatment. Identification of novel analgesic targets that inhibit peripheral mechanical sensitization during joint pain states will be critical to the development of improved analgesics for these conditions. Based on recent preclinical findings, the orphan G protein- coupled receptor GPR55 has controversially been suggested to be the novel third cannabinoid receptor and has been identified as a potential novel target for the treatment of pain. Very few studies have investigated the effects of GPR55 activation on nociceptive processing in vivo and only one at the level of the joint during acute inflammatory arthritis. The aim of this thesis was to investigate the role of GPR55 in the modulation of joint afferent mechanosensitivity in vivo, and whether this role is altered in an experimental model of OA during established pain.

Electrophysiological recordings of joint afferent nociceptors, taken from the saphenous nerve, which innervates the knee joint via the medial articular nerve, were carried out in anaesthetised rats under non-pathological conditions (naïve rats) and in a model of OA following the development of pain behaviour, 14 days following knee joint injection of monosodium iodoacetate (MIA) and compared to saline control rats. Effects of peripheral administration of the putative endogenous GPR55 agonist L-α-lysophosphatidylinositol (LPI) on the mechanically-evoked responses of joint nociceptors were studied in naïve rats and in MIA and saline rats. An involvement of GPR55 in the effects of LPI was investigated using pre-administration of the GPR55 antagonist cannabidiol. Further, the role of GPR55 in endogenously modulating joint afferent mechanosensitivity was investigated following the peripheral administration of cannabidiol alone. GPR55 expression in knee innervating L3- L5 rat DRGs was studied by immunohistochemistry.

Joint nociceptors in MIA rats were mechanically sensitized compared to the saline rats at 14 days post-injection confirming the development of peripheral sensitization during established pain behaviour. LPI (150, 250μM) inhibited joint nociceptor mechanically-evoked responses in naïve and saline rats and inhibited peripheral sensitization in MIA rats. Cannabidiol blocked the LPI- induced inhibition of joint nociceptor mechanosensitivity in all groups of rats confirming an involvement of GPR55 in these effects. Cannabidiol alone had no effect on mechanically-evoked responses of joint nociceptors in naïve, saline and MIA rats indicating that any endogenous GPR55 tone does not modulate joint afferent mechanosensitivity. GPR55 expression was detected in small, medium and large neurones (and possibly satellite glial cells) of L3-L5 DRG.

The findings of this thesis provide compelling evidence that activation of GPR55 in vivo modulates the mechanosensitivity of joint afferent nociceptors and this inhibitory effect is maintained during established peripheral sensitization and pain behaviour following OA development. GPR55-mediated control of joint afferent mechanosensitivity during established OA pain and expression of GPR55 in sensory neurones at the level innervating the joint highlights GPR55 as a potential new peripheral target for the modulation of joint pain including during OA. The findings of this thesis support further studies aimed at investigating the clinical utility of GPR55 agonists for the treatment of OA pain.

Item Type:	Thesis (University of Nottingham only) (PhD)
Supervisors:	Kelly, S. Harris, J.
Keywords:	Joint pain, Nociceptors, GPR55 in nociception, Receptor activation
Subjects:	Q Science > QP Physiology
Faculties/Schools:	UK Campuses > Faculty of Science > School of Biosciences
Item ID:	28303
Depositing User:	Paton, Kenneth
Date Deposited:	21 Aug 2015 12:16
Last Modified:	13 Oct 2017 17:20
URI:	https://eprints.nottingham.ac.uk/id/eprint/28303

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