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Postsynaptic density protein-95 (PSD-95) as a target for neuropathic pain Approximately
9% of the US population suffer from moderate to severe non-cancer-related
pain, a figure that includes 40-70 million individuals with chronic pain. This
condition precipitates other serious pathologies such as depression and is
associated with an estimated pharmaceuticals market of US$18.7 billion
worldwide. Since chronic pain is notoriously difficult to treat using
currently available therapeutics, the development of analgesics has
represented a major pharmaceutical objective. The origins of pain range
from nociceptive (caused by tissue injury or inflammation) to neuropathic, a
condition that can have many underlying causes. Approximately 26 million
patients worldwide (10 million in the US) suffer from some form of neuropathic
pain, spending an estimated $2-3 billion annually on treatments. Spinal
N-methyl-D-aspartate (NMDA) receptor activation has been demonstrated to play
an important role in the processing of spinal nociceptive information and
indeed a considerable number of NMDA receptor antagonists are in development
for the treatment of pain. The synaptic protein, postsynaptic density
protein-95 binds to and clusters a variety of membrane proteins, including
NMDA receptor NR2 and potassium channel subunits. With respect to NMDA, this
appears to be important in coupling the receptor to pathways that control
synaptic plasticity and learning. Field-leaders
at Johns Hopkins University School of Medicine have investigated the role of
postsynaptic density protein-95 in modulating pain. In early studies this
group found that supression of postsynaptic density protein-95 expression in
the spinal cord significantly attenuated facilitation of the tail-flick reflex
triggered through NMDA receptor activation. More recently it was found that
antisense oligodeoxynucleotide specifically against postsynaptic density
protein-95 dose-dependently delayed the onset of tactile allodynia and thermal
hyperalgesia in a nerve injury-induced model of neuropathic pain. Most recently the effects of oligodeoxynucleotide treatment on established neuropathic pain was investigated. Treatment every 24 h for 4 days from day 7 to day 10 post-surgery exhibited not only a marked decrease in spinal cord postsynaptic density protein-95 protein expression but also a significant reduction in mechanical and thermal hyperalgesia on day 11 post-surgery. The responses to mechanical and thermal stimulation were unaffected in animals free of neuropathic pain. Thus, blocking postsynaptic density protein-95 protein in the spinal cord significantly attenuates nerve injury-induced mechanical and thermal hyperalgesia during both the development and maintenance of chronic neuropathic pain. These results suggest that postsynaptic density protein-95 might be involved in the central mechanisms of chronic neuropathic pain and provide a novel target for development of new pain therapies. Entry date March, 2003 Adapted from Tao et al, Neuroscience 2003;117(3):731-9 - Interested in collaborating with this group? Contact LeadDiscovery or the authors direct.
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