Abstract
Neuropathic pain caused by nerve damage is a common and severe class of chronic pain. Disease-modifying clinical therapies are needed as current treatments typically provide only symptomatic relief; show varying clinical efficacy; and most have significant adverse effects. One approach is targeting either neurotrophic factors or their receptors that normalize sensory neuron function and stimulate regeneration after nerve damage. Two candidate targets are glial cell line-derived neurotrophic factor (GDNF) and artemin (ARTN), as these GDNF family ligands (GFLs) show efficacy in animal models of neuropathic pain (Boucher et al., 2000; Gardell et al., 2003; Wang et al., 2008, 2014). As these protein ligands have poor drug-like properties and are expensive to produce for clinical use, we screened 18,400 drug-like compounds to develop small molecules that act similarly to GFLs (GDNF mimetics). This screening identified BT13 as a compound that selectively targeted GFL receptor RET to activate downstream signaling cascades. BT13 was similar to NGF and ARTN in selectively promoting neurite outgrowth from the peptidergic class of adult sensory neurons in culture, but was opposite to ARTN in causing neurite elongation without affecting initiation. When administered after spinal nerve ligation in a rat model of neuropathic pain, 20 and 25 mg/kg of BT13 decreased mechanical hypersensitivity and normalized expression of sensory neuron markers in dorsal root ganglia. In control rats, BT13 had no effect on baseline mechanical or thermal sensitivity, motor coordination, or weight gain. Thus, small molecule BT13 selectively activates RET and offers opportunities for developing novel disease-modifying medications to treat neuropathic pain.
Highlights
Neuropathic pain—defined by the International Association for the Study of Pain as “pain caused by a lesion or disease of the somatosensory nervous system”— severely impairs quality of life and is a significant socio-economic burden
The selected set of 54,000 compounds was further reduced by applying diversity criteria (Papp et al, 2006), and the resulting library of 18,400 compounds was screened at 5 μM concentration in a cell-based high-throughput assay with a luciferase readout in cells expressing GFRα1 and RET (Sidorova et al, 2010)
To address the putative trophic effects of the RET agonist BT13, we examined neurite outgrowth using adult rat sensory neurons that were isolated from lumbar (L4–L5) dorsal root ganglia (DRG) and cultured overnight in defined culture media on a laminin substrate
Summary
Neuropathic pain—defined by the International Association for the Study of Pain as “pain caused by a lesion or disease of the somatosensory nervous system”— severely impairs quality of life and is a significant socio-economic burden. The estimated prevalence of neuropathic pain ranges from 1–2 to 9.8% (Yawn et al, 2009; Smith and Torrance, 2012; van Hecke et al, 2014; IASP, 2015) and is expected to grow due to the aging population and increases in diseases that damage peripheral sensory neurons. Causes of neuropathic pain include traumatic nerve injury, disease (e.g., diabetes, cancer), infection (HIV), or exposure to certain drugs— chemotherapeutic agents (Ossipov, 2011; Finnerup et al, 2015). Existing treatments for neuropathic pain are not effective in a proportion of patients, and are often accompanied by intolerable adverse effects (Finnerup et al, 2015). The currently available drugs are not disease-modifying, i.e., they do not “cure” the disease
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
