Research Projects

Background and Rationale: Neuropathic pain (NP) is defined as pain arising from damage or disease affecting the somatosensory nervous system. Clinically, it presents with spontaneous pain, hyperalgesia, and altered sensory perception, significantly reducing quality of life. It affects an estimated 7–10% of the general population and is particularly prevalent in individuals with HIV, where sensory neuropathy impacts 25–50%, making it one of the most common neurological complications. The gp120-induced neuropathic pain model in rodents replicates key features of HIV-associated neurodegeneration and sensitization, providing a valuable platform for mechanistic and therapeutic studies. Current treatments—including α2δ-ligands (e.g., pregabalin), SNRIs, and tricyclic antidepressants—offer symptomatic relief but are often limited by suboptimal efficacy and adverse effects such as sedation and dizziness. These agents do not target the underlying mechanisms of nerve injury, underscoring the need for novel, mechanism-based therapies that are both effective and well tolerated. Recent findings implicate Wnt signalling and glutamatergic systems, particularly NMDA receptors, in the development and maintenance of neuropathic pain. Activation of Wnt ligands (e.g., Wnt3a, Wnt5a) and downstream effectors like β-catenin and GSK3β contributes to synaptic plasticity and inflammation—hallmarks of pain hypersensitivity. Concurrently, NMDA receptor activation, especially via the NR1 subunit, amplifies nociceptive signaling through calcium-mediated excitotoxicity. Brain-Derived Neurotrophic Factor (BDNF), regulated by Wnt pathways and known to potentiate NMDA receptor activity, may serve as a key link between these systems. Elevated BDNF levels have been consistently associated with central sensitization and pain persistence in neuropathic states. Novelty This study uniquely investigates the mechanistic crosstalk between Wnt signalling and NMDA receptor activity in neuropathic pain, using a gp120-induced model relevant to HIV-associated neuropathy. While both pathways have been implicated independently, their interaction and the potential role of BDNF-TrkB as a molecular link remain largely unexplored. By integrating behavioural, molecular, and pharmacological approaches, this work aims to identify novel targets for intervention. The dual evaluation of Wnt and glutamate receptor antagonists highlights a translational focus, with potential to inform more effective and mechanism-based therapies for neuropathic pain—a condition with substantial clinical burden and limited treatment options. Hypothesis Modulation of the Wnt signalling pathway alters neuropathic pain by regulating NMDA receptor expression and function. We hypothesize that this effect may be mediated through downstream signalling involving BDNF-TrkB, and aim to determine whether this pathway links Wnt activity to glutamatergic mechanisms in gp120-induced neuropathic pain.