PROJECT SUMMARY
Millions of Americans suffer from unrelenting chronic pain conditions that are resistant to existing
treatments, and those who turn to opioid medication can develop dependencies that are devastating and
life threatening. There is essential need for more effective, non-addictive analgesics with limited side
effects. Voltage-gated calcium (CaV) channels are potential targets for improved pain therapeutics. CaV
channels are critical in altering sensory neuron sensitivity and in transmitting information about noxious
stimuli. Changes in sensitivity of sensory neurons to stimuli – such as heat and touch - can result in
transient forms of hypersensitivity and, if the stimulus is prolonged or especially intense, more prolonged
hypersensitivity, which can lead to chronic pain. CaV channels in the spinal cord are important for the
induction and maintenance of hypersensitivity, but the Lipscombe lab has recently shown that peripheral
CaV2.2 channels in heat sensing neurons in skin are also critical for this process. This proposal will
expand this discovery to investigate the functional contribution of peripheral CaV channels to
hypersensitivity in Trpv1-nociceptor and Aδ low threshold mechanoreceptor (Aδ LTMR) nerve endings in
skin. In Aim 1, optogenetics and automated, real-time behavior tracking with high-speed videography will
be combined to assess behavioral responses induced by direct activation of either Trpv1-nociceptor
(heat-sensing) or Aδ LTMRs (mechano-sensing). Changes in evoked behavior will be assessed following
sensitization of either neuron population as well as the potential for selective inhibition of peripheral CaV
channels to attenuate these outputs. Aim 2 will investigate intracellular calcium dynamics in nerve
endings in skin associated with the development of hypersensitivity. Integration of optogenetics, 2-photon
in vivo calcium imaging, and pharmacology, will uncover the individual contribution of CaV2.2 and CaV3.2
channels to calcium events in Trpv1-nociceptor and Aδ LTMRs that trigger hypersensitivity. This work
will provide unique data on the role of peripheral CaV channels in the induction of hypersensitivity and
may identify novel sites of action for developing more effective pain therapeutics, thereby reducing
unwanted side effects from actions in the central nervous system. The proposed research builds on the
applicant’s experience and provides an opportunity to develop unique expertise in genetic, behavioral, 2-
photon imaging and computation techniques. Collaborating with the Fleischmann and Moore labs for 2-
photon calcium imaging gives the applicant essential experience in team science and integrating across
different levels of investigation. This fellowship will also support the applicant’s professional development
in rigorous scientific methods and effective scientific communication. The Brain Science environment at
Brown University is exceptional for training, it provides numerous avenues for support, training, and
resources to prepare the applicant for a career as an independent academic scientist.