Molecular mechanisms regulating sensory neuron function and phenotype during development and disease.
Research in Dr. Molliver’s laboratory focuses on two overlapping areas: 1) the development and functional regulation of sensory neurons, and 2) the molecular basis of sensory neuron signal transduction in pathological pain states. Work in the lab combines anatomical, molecular, behavioral and physiological techniques to address these issues. The principal focus is currently on the function of the P2Y family of G protein-coupled nucleotide receptors in sensory neurons. Ongoing studies indicate that peripherally-released nucleotides activate a combination of ionotropic and metabotropic receptors to modulate sensory neuron excitability. These receptors contribute to acute stimulus transduction, and also may underlie some of the plastic changes in neuronal function that occur in response to injury. This work has led to the hypothesis that nucleotide signaling is an important component of three-way communication between cutaneous sensory afferents, cells of the skin and the immune system. We are also developing models to examine the contribution of nucleotide signaling to visceral pain.
In a second project, investigation of trophic factor actions in the peripheral nervous system indicates that the nerve growth factor and glial cell line-derived trophic factor families regulate differentiation and target innervation during development, and regulate sensory neuron phenotype in adulthood. Both families of trophic factors can acutely enhance the function of the trp family of ligand-gated ion channels in sensory neurons and tonically modulate the expression of pain-related genes in response to inflammatory injury. Signaling by G protein-coupled receptors and trophic factor receptors are integrated in sensory neurons to regulate sensitivity to sensory stimuli, both through transcriptional regulation and through the modification of existing signaling machinery. The development of persistent hypersensitivity is likely to be a key factor in the generation of chronic pain.
Stone, L.S. and Molliver, D.C. In search of analgesia: emerging poles of GPCRs in pain. Mol Interv., 9: 234-51, 2009.
Dussor, G., Koerber, H.R., Oaklander, A.L., Rice, F.L. and Molliver, D.C. Neucleotide signaling and cutaneous mechanisms of pain transduction., Brain Res Rev, 60: 24-35, 2009
Malin, S.A., Davis, B.M., Koerber, H.R., Reynolds, I.J., Alber, K.M., Molliver, D.C. Thermal nociception and TRPV1 function are attenuated in mice lacking the nucleotide receptor P2Y2. Pain, doi:10.1016/j.pain.2008.01.026, 2008.
Malin, S.A. ,Davis, B.M., and Molliver, D.C. Production of dissociated sensory neuron cultures and considerations for their use in studying neuronal function and plasticity. Nature Protocols 2, 152-60, 2007.
Malin, S.A., Molliver, D.C., Koerber, H.R., Cornett, P., Frye, R., Albers, K.M., Davis, B.M. GDNF family members sensitize nociceptors in vitro and produce thermal hyperalgesia in vivo. J Neurosci 26, 8588-8599, 2006.
Molliver, D.C., Lindsay, J., Albers, K.M., and Davis, B.M. Overexpression of NGF or GDNF alters transcriptional plasticity evoked by inflammation. Pain 113, 277-84, 2004.