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Past Research
Mechanisms of HIV viral envelope protein gp120-induced painful neuropathy
Painful peripheral neuropathy affects approximately 30% of HIV patients. Although the precise aetiology of HIV-associated painful neuropathy is unknown, direct invasion of cells of the nervous system by HIV is unlikely. There is evidence however that the presence of the HIV-1 envelope glycoprotein, gp120, in the peripheral and central nervous systems can initiate a cytokine-driven neurotoxic cascade involving glia and immune cells (Herzberg & Sagen 2001; Milligan et al., 2000;2001). In addition gp120 may directly activate sensory neurons (Oh et al., 2001). Gp120 binds primarily to the CD4 receptor allowing entry of HIV into immune cells. However, gp120 is also a ligand at the chemokine receptors; CXCR4 and CCR5. There is increasing evidence that chemokine receptors are expressed by neurons and glia and that their activation results in pathological responses which may be involved in the development of persistent pain. This project aims to establish a gp120-associated model of peripheral and central neuropathic pain in rodents and to investigate the anatomical and functional basis for this interaction.

Proposed studies
1: Establishment of Behavioural Models of gp120-associated pain.

Behavioural hypersensitivity has been shown to occur in rodents following either intrathecal, or periaxonal administration of gp120 (Minami et al., 2003; Milligan et al.,2001; Herzberg & Sagen, 2001). Based upon these studies, rodent models of HIV related, gp120-induced painful neuropathy are currently being developed involving delivery of gp120 either intrathecally to the spinal cord or perineurally to the sciatic nerve. Initially, behavioural correlates of chronic pain will be assessed in each model employing hind paw withdrawal reflex tests to mechanical, thermal and cold stimulation. Once characterized behaviouraly, the mechanisms of the pain associated with these models will investigated via pharmacological, immunohistochemical and electrophysiological approaches.

2: Development of integrative measurements of chronic pain
In addition to reflex limb withdrawal tests, we are investigating more sophisticated outcome measures for the analysis of integrative pain behaviours. Such paradigms include;
-Place preference and avoidance behavior to mechanical stimuli (LaBuda & Fuchs 2000).
-Weight bearing and paw pressure of injured and contralateral limbs.
-Ultrasound vocalization in response to noxious and innocuous stimuli
-Open field activity to assess exploratory and locomotor behaviour.
-Brush evoked Fos expression (Catheline et al. 1999) which is probably a correlate of the phenomenon of brush evoked dynamic mechanical allodynia, a common feature of clinical neuropathic pain. We will use this approach and ascertain whether such Fos expression can be activated in gp120 treated animals and prevented by pharmacological perturbation.

3: Gene profiling
Dorsal root ganglia and spinal cords from GP120 treated animals will probably be used for studies of differentially expressed genes measured using the microarray facility available to the Consortium. The results will be compared to those obtained from other neuropathic pain models with the intention of identifying differentially expressed genes which are common to neuropathic pain.