Carr, FB; (2013) A molecular and behavioural analysis of descending facilitation in a model of joint inflammation. Doctoral thesis , UCL (University College London).

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Abstract

Descending facilitation of nociceptive processing via the rostral ventromedial medulla (RVM) has been shown to contribute to behavioural hypersensitivity in a number of models of pain. Pain arising from the joints is a significant clinical problem, and studies to date have focused largely on the underlying peripheral causes. The aim of this study was to investigate the contribution of central mechanisms of descending facilitation to pain in a model of joint inflammation. To determine if the RVM is activated following ankle injection of Complete Freund’s adjuvant (CFA), a model of joint inflammation, pERK immunohistochemistry and labelling of active GABAergic synapses were carried out. At 6h post CFA, pERK labelling was increased, predominantly within 5-HT expressing neurons. Later, at 3d post CFA a decrease in GABAergic transmission was identified. This suggests time dependent changes in neuronal function occur within the RVM following joint inflammation. Selective lesion of descending 5-HT fibres and mu opioid receptor expressing (MOR+) cells of the RVM combined with behavioural studies indicated that both descending pathways contribute to mechanical hypersensitivity of the ipsilateral hindpaw. As the dorsal horn mechanisms underlying descending facilitation are not well understood, microarray analysis was carried out to identify changes in dorsal horn gene expression associated with descending facilitation. This led to the identification of a number of immune system related genes, including the chemokine Cxcl10 and its receptor Cxcr3 suggesting descending facilitation is mediated in part by neuronal - immune system interactions. These findings demonstrate for the first time that behavioural hypersensitivity in joint pain is dependent in part on descending facilitation via the RVM. In addition to peripheral pathology and spinal cord sensitisation, brainstem contributions should also be taken into account in the study and treatment of joint pain.

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