PROJECT SUMMARY/ABSTRACT There is a pressing need to identify and validate new targets for chronic pain and new sources for novel compounds. This proposal will use novel extracts and pure compounds from multiple Cameroonian plants namely Paullinia pinnata, Petersianthus macrocarpus and Acacia sieberiana to probe the biology and therapeutic potential of an exciting non-opioid target for pain, focusing on calcium homeostasis especially through sigma 2 (σ-2) (aka transmembrane protein 97 (TMEM97)). “Agonists” for σ-2/TMEM97 reduce neuropathic and inflammatory pain in mice. Our primary research goal is to use a focused interdisciplinary approach to isolate bioactive compounds from traditional medicine and utilize these new tools in Cameroon to address research and education disparities that contribute to poor pain outcomes in Central Africa. This goal will be pursued with a unique collaboration that we have developed between researchers at the University of Dschang (Cameroon; Dr. Nguelefack), the University of Texas at Dallas (USA; Dr. Kolber) and the University of Kentucky (USA; Dr. Tidgewell). Preliminarily, the Nguelefack lab has shown that crude extracts of P. Pinnata, P. macrocarpus and A. sieberiana significantly decrease inflammatory and neuropathic pain in rats. The Tidgewell/Kolber groups have shown that the methanol extracts of P. pinnata show in vitro binding affinity to σ-2/TMEM97 and modulate primary sensory neurons. This proposal will utilize our interdisciplinary and international approach with in vitro evaluation of plant extracts, followed by fractionation, in vitro testing of σ-2/TMEM97 binding, and additional in vitro validation at UT Dallas and Dschang with pure compounds. In addition to the research focus on Ca2+ homeostasis, this proposal aims to build research and clinical capacity for the study of pain in Cameroon and surrounding countries. This will be accomplished using a mixture of capacity building initiatives including the training of Cameroon trainees in the US and Cameroon, the building of Dschang University as a center for pain research in central Africa, and the hosting of local workshops at Dschang to support the spread of research knowledge in Cameroon and surrounding countries.