Peripheral nerve injury can lead to neuropathic pain, a condition characterized by abnormal pain symptoms like hyperalgesia (more pain to noxious stimuli), allodynia (pain in response to innocuous stimuli) and spontaneous pain (pain in absence of external stimuli). The majority of treatments available are ineffective and display many side effects and most attempts to develop new analgesics have failed. There is, therefore a critical need to identify novel targets to develop new therapeutic approaches.
Our laboratory is studying the neural plasticity responsible for neuropathic pain using mouse genetics and behavioral/physiological approaches. Our goal is to find relevant ways to measure abnormal pain symptoms in rodent models of chronic pain and understand the underlying mechanisms to develop new treatments with improved translational efficacy.
One such pathway is the tetrahydrobiopterin (BH4) production pathway, whose role in neuropathic pain was identified through Human genetic studies. Using different tissue-specific inducible transgenic mouse lines to visualize and modulate the cells engaging the BH4 production pathway, we showed that modulating this pathway could be a viable therapeutic strategy. We are now testing the efficacy of new compounds that safely modulate BH4 production on pain hypersensitivity and other nerve injured-induced changes.
Another major complaint reported by many neuropathic pain patients is poor sleep quality, which leads to constant fatigue and lack of restorative sleep. The exact nature of the sleep disturbances caused by chronic pain is unknown, and yet this represents a critical aspect of neuropathic pain. In collaboration with Dr. Chloe Alexandre we work to characterize these sleep disturbances in mouse models of chronic pain and determine the neural networks responsible using various transgenic tools to visualize, activate or inhibit specific neurons.
Technology Expertise Keywords
Pain behavior; Electroencephalogram/electromyogram (EEG/EMG); Optogenetics; Chemogenetics; Cell-specific transgenic mice; Peripheral nerve injury; Sensory/motor functional recovery
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Liu Y*, Latremoliere A*, Li X*, Zhang Z*, Chen M, Wang X, Fang C, Zhu J, Alexandre C, Gao Z, Chen B, Ding X, Zhou JY, Zhang Y, Chen C, Wang KH, Woolf CJ, He Z. (2018). Touch and tactile neuropathic pain sensitivity are set by corticospinal projections. Nature. 2018 Sep;561(7724):547-550
Alexandre, C*, Latremoliere, A*, Ferreira, A, Miracca, G, Yamamoto, M, Scammell, TE, and Woolf, CJ (2017). Decreased alertness due to sleep loss increases pain sensitivity in mice. Nat Med 23, 768-774
Browne, L.E., Latremoliere, A., Lehnert, B.P., Grantham, A., Ward, C., Alexandre, C., Costigan, M., Michoud, F., Roberson, D.P., Ginty, D.D., and Woolf, C.J. (2017). Time-Resolved Fast Mammalian Behavior Reveals the Complexity of Protective Pain Responses. Cell Rep 20, 89-98
Latremoliere A*, Cheng L*, DeLisle M, Wu C, Chew S, Hutchinson EB, Sheridan A, Alexandre C, Latremoliere F, Sheu SH, Golidy S, Omura T, Huebner EA, Fan Y, Whitman MC, Nguyen E, Hermawan C, Pierpaoli C, Tischfield MA, Woolf CJ, Engle EC. (2018). Neuronal-Specific TUBB3 Is Not Required for Normal Neuronal Function but Is Essential for Timely Axon Regeneration. Cell Rep. 2018 Aug 14;24(7):1865-1879
Latremoliere, A., Latini, A., Andrews, N., Cronin, S.J., Fujita, M., Gorska, K., Hovius, R., Romero, C., Chuaiphichai, S., Painter, M., Miracca, G., Babaniyi, O., Remor, A.P., Duong, K., Riva, P., Barrett, L.B., Ferreiros, N., Naylor, A., Penninger, J.M., Tegeder, I., Zhong, J., Blagg, J., Channon, K.M., Johnsson, K., Costigan, M., and Woolf, C.J. (2015). Reduction of Neuropathic and Inflammatory Pain through Inhibition of the Tetrahydrobiopterin Pathway. Neuron 86, 1393-1406