Townson, LD; (2016) Descending controls and peripheral contribution to pain in the monosodium iodoacetate model of osteoarthritis. Doctoral thesis , UCL (University College London).

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Abstract

This thesis sets out to elucidate whether, in a lower dose MIA model of osteoarthritis (OA), the previously observed adaptations in descending noradrenaline and serotonin (5hydroxytrptamine, 5HT) are present. We similarly aimed to ascertain whether these adaptations were reflected in the firing patterns of ON cells in the Rostral Ventromedial Medulla (RVM), as has been seen in other chronic pain models. Finally, the role of Nav1.8 containing peripheral sensory afferents and a subset of mechanically sensitive TRPC ion channels were assessed by modeling osteoarthritis (OA), using a 0.5mg dose of MIA, in knock-out and genetically manipulated mouse lines. in vivo electrophysiology was performed in rats following the injection of 1mg MIA to the left knee to induce OA. Following behavioural assessment, single unit recordings compared the effects of spinal ondansetron or spinal atipamezole on evoked responses of dorsal horn neurones to electrical, mechanical and thermal stimuli in MIA or control rats under isoflurane anaesthesia. Separately, single-unit recordings characterized the response of ON cells in the RVM to a range of ipsilateral and contralateral mechanical stimulation to the areas of primary and secondary hypersensitivity in MIA or sham animals. Given the absence of effect of either drug on evoked responses of dorsal horn neurones during the 1mg MIA model, it seems possible that modifications to the extent of descending facilitation or inhibition during the MIA model are dose and time dependent. Recordings in the brainstem, the majority of which appear to be taken from the NGC, exhibited no significant adaptations, further suggesting a lack of recruitment of descending control in this 1mg MIA model. This work adds to a growing body of evidence suggesting that the descending control of pain is highly adaptive, depending upon both the extent and profile of the insult during the initiation and maintenance of chronic pain conditions. No clear or significant sparing effect was observed through the KO of either TRPC3, TRPC6, the double TRPC3/6 KO, or through the sensory ablation of Nav1.8 containing neurones. This may indicated a role for redundancy within the mechano-sensory system of the periphery, rendering these channels poor targets of analgesia in OA.

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