Maie, I.A.S.; (2007) Nociceptin and the ORL-1 receptor: analgesic mechanisms and interactions with dorsal horn neurones in rat spinal cord. Doctoral thesis , University of London.

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Abstract

There is a need to improve our understanding of the mechanisms of pain, especially neuropathic pain in order to develop new analgesic drugs based on opioids. In recent years, the cloning of the novel opioid receptor like-1 (ORLi/NOP) receptor and studies on the effectiveness of opioids in pain models provides a basis for potential novel therapy. This thesis is based on nociceptin/orphanin FQ and its receptor ORLi, which represent a novel peptide/receptor system pharmacologically different from classical opioid systems. Nociceptin regulates several biological functions, both at the peripheral and central levels therefore, the ORLi receptor may be viewed as a novel target for drug development. However, the pharmacology of this receptor is still under study, with few molecules selectively acting on this receptor. Little is known about the physiological roles of this new opioid system. Using an in vivo electrophysiology study, spinal effects of nociceptin were investigated on deep dorsal horn neurones in normal, sham operated and neuropathic rats. Nociceptin induced a greater dose-dependent inhibition in normal animals when compared with the neuropathic and sham operated animals which were the least inhibited. Additionally to clarify the role of nociceptin and its receptor in the spinal processing of pain a non peptide antagonist and agonist of nociceptin were studied. Another objective of this thesis was to study the interaction between nociceptin and cholecystokinin (CCK), an anti-opioid peptide. CCK enhanced the inhibitory effect of nociceptin in sham operated and neuropathic animals, whereas in normal animals CCK had the expected antiopioid action. Furthermore, this thesis emphasizes the importance of opioid receptors located on lamina I expressing NK1 receptors in the modulation of spinal analgesia of nociceptin when compared to D-Pen2, D-Pen5 enkephalin (DPDPE), a delta-opioid agonist. Finally, this thesis suggests a potential therapeutic value of oxytocin in the treatment of neuropathic pain.

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