Background & Aims
AMPA receptors (AMPARs) are essential for pain sensitization processes involved in various pain states. Non-selective AMPAR antagonists show analgesic properties in preclinical and clinical settings, but the adverse effects of targeting AMPAR broadly throughout the brain limit their therapeutic index and clinical utility. Transmembrane AMPAR regulatory proteins (TARPs) are AMPAR auxiliary subunits with region-specific expression that modulate AMPAR synaptic physiology and pharmacology. TARP ?8 is selectively expressed in pain-processing regions: spinal cord dorsal horn, anterior cingulate cortex, hippocampus, and amygdala (1,2). The selective expression pattern of TARP ?8 offers opportunities to develop novel first-in-class analgesics with an improved therapeutic index. We evaluated RTX-1738, a highly potent and selective, brain-penetrant, orally bioavailable AMPAR/TARP ?8 inhibitor in a variety of pain models.
Methods
All studies followed AAALAC guidance. Formalin: injected into the dorsal surface of the left hind paw 1 h after RTX-1738 administration. Carrageenan: injected sub-plantar to left hind paw 1 h after RTX-1738 administration, 2 h prior to the Von Frey test. CFA: injected sub-plantar to left hind paw 2 h after RTX-1738 administration; Von Frey measured prior to and 72 h after CFA injection. Paw incision: plantar muscles were clamped and cut longitudinally, and mean paw withdrawal was measured. Spinal nerve ligation (SNL): left L5 and L6 spinal nerves were isolated and tightly ligated, and mechanical allodynia was tested on the 10th to 12th days after surgery and on specified days, 1.5 h after dosing RTX-1738. Hot plate and tail flick were conducted prior to and 2 h after RTX-1738 dosing.
Results
Oral administration of RTX-1738 (3 mg/kg) showed robust efficacy across broad modalities of nociception involved in acute, persistent, inflammatory, and neuropathic pain models. In the formalin test, RTX-1738 attenuated nocifensive behavior to a similar extent as gabapentin. RTX-1738 attenuated tactile allodynia in the CFA and carrageenan models to a similar extent as naproxen and indomethacin, respectively. RTX-1738 also attenuated pain behavior in both the hot plate and tail flick tests to a similar extent as gabapentin, thermal hyperalgesia in the paw incision model of postoperative pain, and tactile and thermal hyperalgesia in the SNL model to a similar extent as gabapentin. RTX-1738 (3 mg/kg) was well tolerated. There were no observations of neurological or muscular dysfunction and no impairment of motor function in the rotarod test.
Conclusions
RTX-1738, a highly potent and selective, brain-penetrant, orally bioavailable AMPAR/TARP ?8 inhibitor showed significant efficacy across broad modalities of pain processing involved in acute, persistent, inflammatory, and neuropathic pain. These results support the role of AMPARs in pain processing and the potential to selectively target TARP ?8 AMPARs for development of novel broad-spectrum analgesics. In addition, a previous study reported preclinical analgesic effects with a different AMPAR/TARP ?8 inhibitor (1). These effects are enabled by the regiospecificity of TARP ?8 expression, which is restricted to areas of pain processing, and demonstrate that RTX-1738 was well tolerated in rodents at efficacious doses. These properties validate the use of AMPAR/TARP ?8 inhibitors for clinical testing across a broad range of pain indications.
References
1.Knopp KL, Simmons RMA, Guo W, Adams BL, Gardinier KM, Gernert DL, et al. Modulation of TARP ?8-containing AMPA receptors as a novel therapeutic approach for chronic pain. J Pharmacol Exp Ther. 2019;369:345-363.
2.Larsson M, Agalave N, Watanabe M, Svensson CI. Distribution of transmembrane AMPA receptor regulatory protein (TARP) isoforms in the rat spinal cord. Neuroscience. 2013;248:180-193.
Presenting Author
Jose A. Matta
Poster Authors
Topics
- Models: Chronic Pain - Inflammatory