| Summary: | Whilst pain serves a physiological function, chronic diseases such as osteoarthritis and cancer of the bone involve central neurones and peripheral nociceptors becoming sensitised to heighten or extend the pain experience temporally, which is detrimental to the quality of life. Mechanisms underlying central sensitization of neurones are examined in this thesis in two rodent models of pain: osteoarthritis (OA) and cancer-induced bone pain (CIBP) using pharmacology, mapping of receptive field size for lamina I neurones in OA animals and TENS. Pharmacological studies focused on NMDA and P2X3 and P2X2/3 receptors using ketamine, ifenprodil and a novel agent: AF-353. Ketamine reduced the neuronal responses to noxious stimuli in OA animals to levels observed in naïve animals. However effects were significantly stronger in CIBP animals where doses 10-fold lower produced the same effect suggesting post-synaptic NMDA receptors have a significant role in the maintenance of CIBP. Ifenprodil, which acts at NR2B subunit containing receptors, which are presynaptically located and may thus control release of neurotransmitters from the afferent terminal, more strongly inhibited electrical stimuli evoked responses in OA animals. Inhibition of natural stimuli evoked neuronal responses were similar in both models suggesting the importance of primary afferent drive in maintenance of central sensitization in OA and CIBP. AF-353 which inhibits the actions of ATP on pre-synaptically located P2X3 and P2X2/3 receptors was found to profoundly inhibit neuronal responses to noxious thermal stimuli in CIBP suggesting that thermal-stimuli induced hyperalgesia has a central component driven by the purinergic system. Finally, TENS a nonpharmacological intervention was found to have no significant effect on evoked responses of lamina V neurones in CIBP animals questioning its suitability in managing chronic pain. Differing pharmacology appears to contribute to the maintenance of central sensitization in OA and CIBP suggesting that more targeted therapy may be more clinically appropriate.
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