Allosteric Small Molecule Inhibitor Of Nerve Growth Factor Signaling in Low Back Pain

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 DESCRIPTION (provided by applicant): There has been a dramatic increase in the world-wide incidence of chronic low back pain, which compromises the quality of life for millions of people and has a formidable socio-economic impact. A recent study published by the US Burden of Disease Collaborators showed that, in 2010, low back pain was the disease with the highest number of years lived with disability, and was responsible for the third largest disability-adjuste life- years in the US. Despite its prevalence and societal impact, the etiology of chronic back pain is poorly understood; as a result, many patients are not achieving optimal pain control through existing treatments. Nerve growth factor (NGF) and its cognate receptor tropomyosin-receptor-kinase (TrkA) system play a crucial role in the development and function of the nociceptive reception in humans. The dramatic clinical effects of targeting NGF among the myriad pain mediators in chronic conditions suggest that NGF has a special role in pain, including knee joint osteoarthritic pain. Our current knowledge, however, does not permit a conclusion on the potential efficacy of anti-NGFs for chronic back pain treatment, and also there is no documented record regarding the safety of this class of drug. Given the existing potential for anti-NGF treatment and a need for novel therapies for chronic back pain, the evaluation of pharmacological efficacy and safety of anti-NGF in low back pain is urgently needed to fill the gaps in current knowledge. Successful completion of the proposed studies will highlight the pharmacological efficacy and safety of a selective inhibitor of TrkA on alleviation of chronic back pain that is evoked by facet joint degeneration. Our results will also emphasize that a TrkA- selective inhibitor will reduce neural distribution in the facet joint tissues and alterations of neurotransmitter production through inhibition of sensory neuronal plasticity in the innervating dorsal root ganglion (DRG). Abbreviations used in the application: LBP, low back pain; NGF, nerve growth factor; TrkA, tropomyosin-receptor-kinase; FJD, facet joint degeneration; OA, osteoarthritis; IVD, intervertebral disc; BDNF, brain-derived neurotrophic factor; DRG, dorsal root ganglion; ERK/MAPK, extracellular signal-regulated kinase/mitogen-activated protein kinase; MIA, monosodium iodoacetate; BID, bis in die, twice a day.