Spinal glycinergic neurotransmission in neuropathic pain models

Disruption to inhibitory neurotransmission is commonly associated with the development of chronic neuropathic pain. However, exactly which aspect of inhibition is affected varies between studies with little consensus on the major contributors. I hypothesised that the different neuropathic pain models used in each study contribute to these discrepancies. Thus, the first part of this thesis focused on the following question: Do different neuropathic pain models produce different physiological changes in the spinal cord dorsal horn? Neuropathic pain is poorly treated with existing analgesics, making the need for novel therapeutics paramount. The glycine transporter 2 (GlyT2) is expressed at inhibitory glycinergic synapses in the spinal cord and novel analgesic compounds targeting it have been developed. The second part of this thesis investigated the cellular actions of one of these novel compounds and asked; How does the novel GlyT2 inhibitor, Oleoyl-D-Lysine, effect glycinergic neurotransmission in the spinal cord dorsal horn? Patch-clamp electrophysiology was used in both projects. In project 1, changes to glycinergic neurotransmission were investigated in chronic constriction injury (CCI) or partial nerve ligation (PNL) models. Both produced similar behavioural outcomes, but vastly different physiological changes. Reduced glycinergic neurotransmission was observed in the PNL model, but not the CCI model. In project 2, Oleoyl-D-Lysine displayed a minor effect on synaptic glycinergic currents, but its predominant effect was on tonic glycinergic currents and produced no detrimental effects on presynaptic glycine supply. Overall, these results suggest that each neuropathic pain model should be considered unique and more research should look into the distinct nociceptive circuits involved for a better understanding of neuropathic pain physiology, as well as to identify more novel therapeutic targets. In addition, the findings suggest that despite Oleoyl-D-Lysine’s glycinergic specific mechanism, it may be effective in treating neuropathic pain caused by different injuries because its main effect is to reduce the excitability of the system not just to enhance glycinergic neurotransmission as was previously hypothesised