Mechanistic studies of the impact of chronic pain on brain, behaviour and cognition in a rodent model of chemically induced osteoarthritis

Chronic pain has been associated with changes in forebrain regions, including the hippocampus and prefrontal cortex, and impairments in cognitive functions associated with these forebrain regions, including impairments in memory and cognitive flexibility. Osteoarthritis (OA) is a major public health burden, and the main symptom of OA is chronic pain. The impact of OA pain on cognitive function is poorly understood. By combining methods from pain research and behavioural integrative neuroscience, in this PhD work, the impact of OA-like chronic knee pain on selected cognitive functions was investigated in a well-characterised rodent model. To investigate clinically relevant cognitive deficits associated with chronic pain caused by knee OA, in this study the rat monosodium iodoacetate (MIA) model was combined with translational tests of clinically relevant cognitive tests, including of hippocampus-dependent everyday type memory function, recognition memory and behavioural flexibility. Previous studies using this model of OA pain behaviour have used juvenile albino strains, which show comparatively poor performance in the cognitive tests. Therefore, the first objective was to transfer the MIA model to young adult Lister hooded (LH) rats, a pigmented strain, which is suitable for these cognitive tests (chapter 3). Pain behaviour and joint pathology phenotypes after a standard 1 mg dose of MIA were not robust in young adult LH rats or age and weight matched SD rats. By contrast, injection of 3mg of MIA caused robust pain behaviour, mainly changes in weight-bearing, accompanied by significant cartilage damage and synovitis. MIA-injected rats showed minor changes in locomotor activity with reduced rearing, which may reflect that they put less weight on their hind legs because of knee pain. This dose of MIA was therefore used throughout the thesis project. To longitudinally assess the impact of OA-related knee pain on hippocampus-dependent place memory, MIA LH rats were tested in the watermaze delayed-matching-to-place (DMP) test, which is highly hippocampus-dependent (chapter 4). There was no evidence of impaired hippocampal memory following induction of the MIA model. No performance parameter on the DMP task was affected by MIA injection up until day 93 after model induction. MIA injected rats showed robust pain behaviour (weight bearing asymmetry), slightly decreased rearing activity and features of knee joint pathology. In this chapter, MIA rats showed some evidence for mildly reduced prepulse inhibition (PPI) at high pulse intensities compared with saline control rats (although this was not replicated in chapter 5 when studied at a later time point following MIA injection). The impact of OA-like pain on recognition memory and behavioural flexibility was also evaluated in the MIA LH rats (chapter 5). This cohort of MIA injected LH rats was tested in the novel object recognition (NOR) test and in an automated set shifting task. Overall, there was no evidence of impaired recognition memory and behavioural flexibility after induction of chronic MIA up until day 59 after model induction. Other factors associated with chronic pain in humans may account for why humans experiencing chronic pain have memory impairments, such as the effects of treatment. To test this, the effects of chronic treatment with morphine (3mg/kg twice daily for 7 days) and subsequent withdrawal was evaluated (chapter 6). Pilot work showed that morphine treatment induced an initial antinociceptive effect in LH rats, followed by tolerance and the development of morphine-induced hyperalgesia. Then, to evaluate the potential impact of chronic morphine treatment on both rapid place learning and NOR memory, MIA-injected LH rats were treated with morphine for 10 days (3mg/kg twice daily) or received control injections and were tested on the watermaze DMP task during treatment and at withdrawal. In addition, they were assessed in the NOR test during morphine withdrawal. Morphine had analgesic effects with no evidence of morphine-induced hyperalgesia in the MIA LH rats. In both naïve and MIA LH rats, acute morphine injection promoted hyperactivity. There was no evidence that repeated morphine treatment induced any impairment in rapid place learning performance or recognition memory in MIA-injected rats. However, in this study, MIA-injected LH rats did not show significant object recognition memory 49 days after model induction, which limits the interpretation the lack of morphine effect, but indicates that MIA-induced pain may disrupt such memory at this stage. Overall, these findings suggest that hippocampus-dependent rapid place learning, NOR memory and behavioural flexibility are not affected by chronic OA-like knee pain in young adult male LH rats. Similarly, sustained treatment with morphine did not affect hippocampal and recognition memory in this model of OA-like knee pain. However, future investigation should be conducted in a wider age range and for longer periods after model induction to exclude the negative impacts of chronic OA pain in cognitive functions