Photocontrol of pain sensation
Neuropathic pain is a major public health problem, but its cellular and molecular basis is poorly understood, and drugs for neuropathic pain have serious side effects. We have developed a small molecule photoswitch, named QAQ, that can serve a light-regulated analgesic, providing a new scientific tool and a new therapeutic approach for optically controlling pain with high spatial and temporal precision.
QAQ is membrane-impermeant and only affects ion channels from the cytoplasmic side. However. QAQ can be imported into cells through ion channels that have dilating pores; particularly the “capsaicin receptor” (TRPV1) and ionotropic receptor for ATP (P2X). These pore-dilating channels are rare in most neurons, but they are enriched in nociceptors, which are specialized to respond to noxious (i.e. painful) stimuli. We find that QAQ photosensitizes nociceptors 1) at peripheral terminals (by measuring light-sensitive pain-avoidance behavior), 2) at somata (by measuring light-sensitive spiking in dorsal root ganglia, DRG), and 3) at central presynaptic terminals of nociceptors (by measuring light-sensitivity of postsynaptic responses in spinal cord). These results suggest that pore-dilating channels throughout the nociceptor amplify and perhaps prolong pain sensation By enabling rapid photoregulation of nociceptors, QAQ will help identify where chronic pain originates and will aid in evaluating drugs for alleviating chronic pain. Moreover, QAQ may have clinical use as an analgesic that is much more rapidly reversible than currently available drugs.
Our goals are: 1) Develop and test “red-shifted” versions of QAQ to enable more effective photocontrol of nociception in vivo, 2) Measure QAQ-mediated photosensitization in nociceptive neurons from mouse models of neuropathic pain vs. control mice to test whether enhanced TRPV1 or P2X activity is a contributing factor in the disorder . 3) Develop isolated DRG as anin vitro test system for investigating the role dilating pore channels in the development of plastic changes underlying .